Alan Dwi Setiawan

01071200089

LO dan WO Cardio Week 5

1. Illustrate the determinants of cardiac function in a ventricular pressure-volume loop.

In case a diagram was ever called for, it would be difficult to

represent everything mentioned here without making a big mess.
However, that's what the college seem to want. So here's a PV
loop diagram with all the things:

That's a lot of information, and the temptation is to unpack it

carefully, but at the same time wishing not to be overgenerous
with the reader's time.  For a succinct introduction to this subject
which sacrifices no detail, one could do no better than the Part
One summary of ventricular pressure-volume relationships. In
many ways, what follows is a series of longform footnotes and
appendices to this Part One entry. Trainees are reminded that
their goal is to pass the exam, and that extensive reading on this
subject (beyond the Part One level of detail) is in excess of their
specific needs. 

In terms of published literature, one cannot look past the first

half of Bastos et al (2020).  This would be the recommendation
for a trainee who has little time or patience for rambling non-
peer-reviewed resources. The second half of that
paper degenerates unattractively into a discussion of cardiac
resynchronisation therapy and mechanical assist devices, which
- though fascinating - scores no marks in the CICM First Part.

Basic features of the ventricular pressure-volume loop

At a fundamental level, Otto Frank is to blame for this. In 1899,

he published a loop of sorts in "Die grundform des arteriellen
pulses", which looked a bit like this:
The original Manuskript is of course unerreichbar, but these
diagrams are sufficiently famous to get reproduced in all sorts of
fanzines (this one is from Middeke, 2016, in J Am Soc
Hypertens). Frank recorded them from a frog ventricle which
was contracting without any afterload. Later investigators
moved onto dogs and humans, added afterload to their
experiments, and flipped the axes, resulting in the modern
pressure-volume loop appearance everybody will recognise.
Here's an example from Pak et al (1996) with a large reassuring
label across the top:

It is of course unfair to say that everybody would immediately

recognise this, because it is a real recording from a real human
LV and therefore subject to the sort of curvy messiness which
makes organic things so difficult to shove into the comforting
square mould of physics and maths. Because the real shape of
the ventricular PV loop is too squishy to teach PV relationships,
most textbooks tend to style it into an idealised form, choosing
to focus on the relationships it conveys rather than on the real
representation of pressure-volume numbers. Such an idealised
loop usually looks something like this:

Nobody would ever pass any sort of exam with a naked loop
like this, and at a minimum it would have to some sort of labels.
For example, one could at least label the major events of the
cardiac cycle which occur along the loop:

 The opening and closing points of the mitral and aortic

valves
 The diastolic filling period and systolic ejection
 The isovolumetric contraction and relaxation periods

And it would end up looking a little like this:

Additionally, one could also label it with the various boundaries

and functions of the ventricular pressure and volume
relationship:

 The stroke volume, which distends the LV and produces an

increase in end-diastolic pressure
 The end-diastolic pressure-volume relationship
(ESPVR), which describes ventricular elastance
 The end-systolic pressure-volume relationship
(ESPVR), which describes contractility
 The effective arterial elastance line which connects the
point of end-diastolic pressure and volume to the point of
end-systolic volume, and which vaguely relates to afterload
 Systolic and diastolic blood pressures, where the diastolic
pressure is measured at the point where the aortic valve
opens, and the systolic pressure being the highest pressure
achieved during the ventricular ejection
 End-systolic pressure, which is usually about 0.9 × SBP
according to Kelly et al (1992)

With these relationships plotted on it, the PV loop would look

like this:
 Some understanding of these boundary conditions is probably
necessary to fully grasp the interpretation of PV loops, but not
for passing CICM written questions, which thus far have been
satisfied with accurately labelled diagrams and regurgitated lists
of features. A time-poor trainee may wish to stop reading here
and move on to more important topics.

End-diastolic pressure-volume relationship

This relationship is described by the ventricular diastolic

pressure-volume curve, i.e. the increase in pressure observed in
the left ventricle which occurs when it fills in diastole. Here is a
representative normal curve measured by Zile et al (2004),
below and on the left. Working with humans in the enlightened
noughties, the investigators could not legally produce unsafe
ventricular overdistension to record its effects, and so to
demonstrate those effects we have to look into animal studies
from the seventies. To the right, for comparison, one can see
some dangerously overfilled ventricles from normal and
infarcted dogs (Glantz & Parmley, 1978).

To be completely precise (and to confuse things), this

relationship describes ventricular elastance, or change in
pressure per change in unit volume. Compliance, on the other
hand, is a change in volume per unit pressure. Elastance is a
better fit for what is being described here, as it relates best to the
stiffness of a mechanical system, i.e. its resistance to
deformation, or its tendency to recoil back into its original
 dimensions in response to a distending force. That is exactly
what you are interested in when you describe the change in
ventricular pressure which occurs when it becomes more stiff,
for example following an infarct. To discuss the change in
volume which occurs as the result of changing pressure would
have less meaning in that scenario, because the volume would
be much the same. The ventricular pressure, however, would
increase, and give rise to an increased left atrial pressure, which
would in turn produce all sorts of clinically relevant phenomena
like pulmonary oedema. Ergo, elastance is the preferred term. 

Normally the elastance of the LV is low, which allows a wide

range of LV volumes with minimal changes to the end-diastolic
pressure.  This can be illustrated by again borrowing the normal
curves from the abovereferenced NEJM article:

In this fashion, a healthy ventricle can increase its stroke volume

(and therefore cardiac output) dramatically, without increasing
the left atrial pressure and producing pulmonary oedema.  And,
where the left ventricle has increased elastance, the same stroke
volume would produce a higher end-diastolic pressure, with all
sorts of untoward effects. This sort increase in the elastance of
the ventricle (comparable to the decrease in its compliance) is
often seen in diastolic heart failure. Because an entire chapter is
dedicated to the discussion of this underappreciated disease
state, there will be no further mention of it here. Suffice it to
say, if one had to wring some sort of clinical relevance from this
whole thing, that would be it.

End-systolic pressure-volume relationship

The end-systolic pressure-volume relationship (ESPVR)

describes the maximal pressure that can be developed by the
ventricle at any given LV volume, and is one of the ways of
measuring and describing cardiac contractility. Without
restating the content of another chapter, the end-systolic
pressure is the pressure left behind after the end of systole, just
before the period of isovolumetric relaxation:
Thus, the ESPVR can be represented by the succession of
several PV loops at different volumes, which produces a linear
relationship of several end-systolic pressure/volume points:

As discussed in the chapter on the determinants of contractility,

the ESPVR (vaguely) represents the contractility of the
myocardium. The slope of this relationship changes as the
contractility increases or decreases. The upshot of this is that
with a higher contractility, the same stroke volume will produce
a higher pressure during ventricular systole:
Effective arterial elastance (Ea)

In order to fathom this concept, one needs to understand the

ventricular ejection as an exchange of volume between two
elastic containers, like one balloon emptying into
another. Consider:

 The ventricle empties blood into the arterial circulation.

 Ergo, during a single systole, as ventricular blood volume
decreases, arterial blood volume increases by the same
volume.
 As the result of receiving the stroke volume, arterial blood
pressure increases.
 The relationship of this pressure increase to the stroke
volume that caused it is the arterial elastance.

 When the stroke volume is wholly in the LV, the aortic pressure
produced by that volume will be zero, and when the stroke
volume has been ejected from the LV, the arterial pressure is the
end-systolic pressure. So, we now have a situation where a
change in arterial volume (equal to the stroke volume) results in
a change in pressure, i.e. this relationship is an elastance.
Specifically, this is effective arterial elastance (E a). This
parameter, being pressure divided by volume, represents the
elastance of the arterial system into which the ventricle is
ejecting:

Ea = P / V

where

 P = end-systolic pressure, and

 V = stroke volume

Sunegawa et al (1983) found that the relationship between the

stroke volume and the end-systolic pressure is a handy surrogate
for the arterial input impedance, a determinant of afterload
which requires complex analysis and which cannot be plotted on
the same graph as a PV loop. "Effective" arterial elastance was
the term which ultimately stuck, because actual arterial
elastance is not what this thing calculates. Rather, 

"...it is an integrative index that incorporates

the principal elements of arterial load,
including peripheral vascular resistance (PVR),
total arterial compliance, characteristic
impedance, and systolic and diastolic time
intervals "

- Chantler et al, 2008

So, effective arterial elastance is a parameter which is often

equated with afterload, but which is not actually afterload, and
which does not actually represent any specific property of the
arteries. It is merely a useful index of arterial vascular "load"
which functionally incorporates a lot of afterload-affecting
factors (when it is measured directly from a real PV loop).   In
simplistic thought experiments where only one variable (Ea) is
altered, it can be clearly seen to change the stroke volume and
blood pressure. For example, if everything else remains the
same and the arterial elastance (i.e. "afterload") increases, the
blood pressure will increase and the stroke volume will
decrease, as below:
Area of the pressure-volume relationship

Work, conventionally defined as force × distance, can be

expressed as pressure × volume (in joules). The derivation of
this is described elsewhere and also applies to work of
breathing. Thus, we can represent the work done by the
myocardium by measuring the area inside the pressure-volume
loop. However, that approximation would probably not be
completely accurate. Consider: while the myocardium is
contracting isovolumetrically, it is not changing its volume and
therefore not making any new PV loop area, but nobody would
doubt that it is doing work and using up oxygen. 

These assumptions appear to be correct. Khalafbeigui et al

(1979) were able to find a linear correlation between the PV
loop area and the myocardial oxygen consumption. Suga et al
(1981) added the "potential work" under the ESPVR curve and
determined that the relationship is still linear, but now with a
slope of about 30%, which describes the efficiency of
myocardial energy utilisation. The area under the ESPVR is the
end-systolic potential energy stored in the wall of the ventricle;
if the aortic valve didn't close, at least two thirds of this energy
would be used to eject even more blood from the ventricle (as
demonstrated by Suga et al in 1979). 

A comparison of right and left ventricular PV loops

 Question 16 from the second paper of 2019 expected the
trainees to compare the right and left ventricles along a series of
parameters ("structure, function and coronary circulation").
According to the examiner comments, "many marks may be
gained by a ....labelled PV loop for each ventricle". So, here
is such a loop, cobbled together out of some information
in Vonk-Noordegraaf et al (2013), which should hopefully
yield "many marks". 

Sumber : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267632/

2. Explain the mechanism of heart attack causing chronic heart failure

Figure 1 provides a general conceptual framework for discussing the development and
progression of heart failure. As shown, heart failure may be viewed as a progressive disorder
that is initiated after an “index event” either damages the heart muscle, with a resultant loss
of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to
generate force, thereby preventing the heart from contracting normally. This index event may
have an abrupt onset, as in the case of a myocardial infarction, it may have a gradual or
insidious onset, as in the case hemodynamic pressure or volume overloading, or it may be
hereditary, as in the case of genetic cardiomyopathies. Regardless of the nature of the inciting
event, the common feature in each of these index events is that they all, in some manner,
produce a decline in pump function of the heart. In most instances patients will remain
asymptomatic or minimally symptomatic after the initial decline in pumping capacity of the
heart or will develop symptoms only after the dysfunction has been present for some time.
Thus, when viewed within this conceptual framework, left ventricular (LV) dysfunction is
necessary but not sufficient for the development of the syndrome of heart failure.
Figure 1. Pathogenesis of heart failure. Heart failure begins after an index event produces an
initial decline in pumping capacity of the heart. After this initial decline in pumping capacity
of the heart, a variety of compensatory mechanisms are activated, including the adrenergic
nervous system, the renin-angiotensin system, and the cytokine system. In the short term
these systems are able to restore cardiovascular function to a normal homeostatic range, with
the result that the patient remains asymptomatic. However, with time the sustained activation
of these systems can lead to secondary end-organ damage within the ventricle, with
worsening LV remodeling and subsequent cardiac decompensation. As a result of resultant
worsening LV remodeling and cardiac decompensation, patients undergo the transition from
asymptomatic to symptomatic heart failure.

As shown in Figure 1, the compensatory mechanisms that are activated after the initial
decline in the pumping capacity of the heart are able to modulate LV function within a
physiological/homeostatic range, such that the functional capacity of the patient is preserved
or is depressed only minimally. The portfolio of compensatory mechanisms that have been
described include early activation of the adrenergic nervous system and salt- and water-
retaining systems in order to preserve cardiac output,6–8 as well as activation of a family of
vasodilatory molecules, including natriuretic peptides, prostaglandins (PGE2 and PGEI2), and
nitric oxide, to counteract the excessive vasoconstriction resulting from excessive activation
of the adrenergic and renin-angiotensin systems.9,10 However, our understanding of the family
of molecules that may be involved in this process is far from complete. Although patients
with depressed systolic function may remain asymptomatic or minimally symptomatic for
years, at some point patients will become overtly symptomatic, with a resultant striking
increase in morbidity and mortality. The transition to symptomatic heart failure is
accompanied by further activation of neurohormonal and cytokine systems, as well as a series
of adaptive changes within the myocardium, collectively referred to as “LV remodeling.”
Although there are further modest declines in the overall pumping capacity of the heart
during the transition to symptomatic heart failure, the weight of experimental and clinical
evidence suggests that heart failure progression occurs independently of the hemodynamic
status of the patient.

Neurohormonal Mechanisms for the Progression of Heart Failure

In the latter part of the 1980s and early 1990s, evidence began to appear that certain other
types of medical therapy might have a beneficial effect on the natural history of LV
dysfunction or myocardial failure, despite initial hemodynamic effects that were either
unimpressive11–13 or even adverse.11,12,14,15 These 2 types of therapies, namely, ACE inhibitors
and β-adrenergic blocking agents, have dramatically changed the way in which we
conceptualize heart failure. As will be discussed below, data generated from both
experimental model systems and clinical trials suggest that both types of therapy may prevent
the progression of pump dysfunction that characterizes the natural history of heart failure and
may halt or even reverse the progressive cardiac dilatation that occurs as heart failure
progresses. It is important to emphasize that the beneficial effects of these treatments are not
pharmacological but rather are due to favorable effects on the biology of the failing heart.
The aforementioned observations led to a point of view that heart failure should be viewed as
a “neurohormonal model,” in which heart failure progresses as a result of the overexpression
of biologically active molecules that are capable of exerting deleterious effects on the heart
and circulation.16 “Neurohormone” is largely a historical term, reflecting the original
observation that many of the molecules that were elaborated in heart failure were produced
by the neuroendocrine system and thus acted on the heart in an endocrine manner. However,
it has since become apparent that a great many of the so-called classic neurohormones such
as norepinephrine and angiotensin II are synthesized directly within the myocardium and thus
act in an autocrine and paracrine manner. Furthermore, molecules such as angiotensin II,
endothelin, natriuretic peptides, and tumor necrosis factor (TNF) are peptide growth factors
and/or cytokines that are produced by a variety of cell types within the heart, including
cardiac myocytes, and thus do not necessarily have a neuroendocrine origin. Nonetheless, the
important unifying concept that arises from the neurohormonal model is that the
overexpression of portfolios of biologically active molecules can contribute to disease
progression independently of the hemodynamic status of the patient, by virtue of the
deleterious effects that these molecules exert on the heart and circulation.

The evidence in support of the foregoing point of view is derived from 2 lines of
investigation. First, a number of experimental models have shown that pathophysiologically
relevant concentrations of neurohormones17–19 or overexpression of single components of
their signal transduction cascade20–22 is sufficient to mimic some aspects of the heart failure
phenotype. Second, clinical studies have shown that antagonizing neurohormones leads to
clinical improvement in patients with heart failure.23–30 Thus, a logical explanation for the
progression of heart failure is that long-term activation of a variety of neurohormonal
mechanisms produces direct end-organ damage within the heart and circulation. Accordingly,
progressive activation of neurohormonal mechanisms may explain why heart failure may
develop insidiously many years after an acute myocardial infarction, despite the absence of
ongoing ischemia. The neurohormonal model also explains why the so-called heart failure
phenotype appears remarkably consistent in patients with different etiologies for their heart
failure, insofar as disease progression is ultimately driven by very similar portfolios of
biologically active molecules, regardless of the inciting cause.

Thus far, a variety of proteins, including norepinephrine, angiotensin II, endothelin,

aldosterone, and TNF, have been implicated as some of the potentially biologically active
molecules whose biochemical properties are sufficient to contribute to disease progression in
the failing heart. Disease progression may also be engendered by the loss of the beneficial
effects of endogenous vasodilators such as nitric oxide, natriuretic peptides, prostaglandins,
and kinins, which are insufficient to counteract the peripheral vasoconstriction that results for
endothelial cell dysfunction and the vasoconstrictor properties of angiotensin II and
norepinephrine. The most powerful compensatory mechanism activated to support the failing
heart is perhaps an increase in cardiac adrenergic drive.31 Unlike other compensatory
mechanisms, adrenergic activation accesses all the known means by which myocardial
performance can be stabilized or increased.7 These include an increase in contractile function,
increase in heart rate, cardiac myocyte hypertrophy, and volume expansion/increased end-
diastolic volume (via β-adrenergic signaling of nonosmotic vasopressin release).7 However,
in addition to the positive effects on stabilizing myocardial performance, increased
myocardial adrenergic signaling, particularly through β1-adrenergic receptor pathways,32 is
also highly cardiomyopathic.18,22,33 A summary of some of these helpful and harmful
adrenergic receptor pathways is given in Table 1, although this table is somewhat
oversimplified.
 TABLE 1. Biological/Physiological Responses Mediated by Postjunctional
Adrenergic Receptors in the Human Heart

Biological Response Adrenergic Receptor

Beneficial effects

Positive inotropic response     β1, β2 >>α1C

Positive chronotropic β1, β2

response    

Vasodilation     β1 (epicardial), β2 (small vessel)

Harmful effects

Cardiac myocyte growth     β1> β2 >>α1C

Fibroblast hyperplasia     β2

Myocyte damage/myopathy     β1> β2, α1C

Fetal gene induction     β1

Myocyte apoptosis     β1

Proarrhythmia     β1, β2, α1C

Vasoconstriction     α1C
 TABLE 1. Biological/Physiological Responses Mediated by Postjunctional
Adrenergic Receptors in the Human Heart

Biological Response Adrenergic Receptor

As implied by a greater number of harmful than helpful effects of activation of the adrenergic
receptor pathways listed in Table 1, the net effect of a sustained increase in cardiac
adrenergic activity in the failing heart is to promote myocardial disease progression and to
accelerate the natural history of heart failure. Indeed, repeated observations of the salutary
effects of β-blocking agents in clinical trials have shown that chronically elevated β-
adrenergic signaling has adverse effects on contractile function, remodeling, and heart failure
morbidity and mortality. As shown in Table 2,134–136 these effects appear to be primarily
delivered through β1-receptor signaling, inasmuch as both β1-receptor selective (metoprolol
CR/XL and bisoprolol) or nonselective agents (carvedilol, bucindolol) have similar salutary
effects in terms of molecular responses and clinical outcomes. The reasons for this are 2-fold:
the increased myopathic potential of β1- versus β2- or α1-receptor signaling that is summarized
in Table 132,34 and the binding affinity selectivity of norepinephrine for β1 versus β2 or
α1 receptors.32 Thus, the beneficial effects of β-blocking agents appear to be due to the class
effects of β1-receptor blockade, at least in terms of molecular responses35 and clinical
outcomes.28,36

TABLE 2. Class Effects of β-Adrenergic Blockade in Chronic Heart Failure

Effect Studies β-Blockers

CV indicates cardiovascular; HF, heart failure; MERIT-HF, Metoprolol

CR/XL Randomized Intervention Trial in Congestive Heart Failure;
CIBIS-II, Cardiac Insufficiency Bisoprolol Study II; COPERNICUS,
Carvedilol Prospective Randomized Cumulative Survival Study; and MDC,
Metoprolol in Dilated Cardiomyopathy Trial.

Reduction in total MERIT-HF,28 CIBIS-II,36 CO Metoprolol CR/XL,

mortality PERNICUS134 bisoprolol,
carvedilol

Reduction in CV MERIT-HF, CIBIS-II, Metoprolol CR/XL,

 TABLE 2. Class Effects of β-Adrenergic Blockade in Chronic Heart Failure

Effect Studies β-Blockers

mortality COPERNICUS, BEST42 bisoprolol,

carvedilol,
bucindolol

Reduction in CV or MDC,135 CIBIS-II, MERIT- Metoprolol tartrate,

HF hospitalizations HF, COPERNICUS, US metoprolol CR/XL,
Carvedilol,27 BEST136 bisoprolol,
carvedilol,
bucindolol

Improved HF MDC, CIBIS-II, MERIT-HF, Metoprolol tartrate,

symptoms US Carvedilol metoprolol CR/XL,
bisoprolol,
carvedilol

Reduced need for MDC, BEST Metoprolol tartrate,

cardiac bucindolol
transplantation

Reduction in BEST136 Bucindolol

myocardial
infarction

The adverse effects of β-adrenergic signaling on heart failure natural history would seem to
dictate that any type of antiadrenergic therapy would be equally effective, as long as it
inhibited the β1-adrenergic signaling. However, recent clinical trial data indicate that the type
of antiadrenergic therapy, particularly receptor blockade versus reducing norepinephrine
release, is critically important.37–39 The likely explanation for the polar difference in the
response of these 2 general classes of antiadrenergic agents is that, during the crucial early
period of adrenergic inhibition, sympatholytic agents produce an irreversible removal of
adrenergic support, with inability to recruit adrenergic drive when needed to support cardiac
function. In contrast, β-blockers are mass-action agents whose inhibition can be easily
reversed by norepinephrine competition, which allows for retention and recruitment of the
powerful adrenergic support mechanism on an as-needed basis. Extensions of these
observations include the potentially favorable effects of therapeutic approaches that allow the
beneficial aspects of adrenergic inotropic support to be maintained in the presence of β-
blockade40 or the addition to β-blockade to positive inotropic device therapy.41 On the basis of
experience with the β-sympatholytic agent bucindolol in the Beta-Blocker Evaluation of
Survival Trial (BEST),42 it is apparent that β-blocking agents can interact with certain
characteristics of heart failure subpopulations to produce differences in clinical response.
This is in contrast to the rather unvarying pharmacological properties and clinical responses
to ACE inhibitors. These observations highlight the complexities encountered in therapeutic
development in heart failure, wherein surprises predominate, and the only way to directly test
hypotheses is in phase III clinical trials.

Of major relevance to antiadrenergic strategies in heart failure is the impact of adrenergic

receptor polymorphisms on myocardial disease progression and on therapeutic response. For
example, a double adrenergic receptor polymorphism, an α2C deletion/loss of function
genotype (α2C Del322-325), combined with a high-functioning β1-receptor genotype
(β1 Arg389), confers a 10-fold risk for the development of heart failure.43 The
α2C polymorphism likely leads to a reduction in the natural brake on norepinephrine release
provided by α2 receptors, and the increased adrenergic drive in these individuals then
presumably damages the heart to a greater extent in individuals with the high-functioning
β1 receptor polymorphism. Transgenic mice with genetic ablation of the α2C receptor have
elevated norepinephrine levels and develop evidence of cardiomyopathy.44 Importantly, the
α2C polymorphism is enriched in black persons,43 and it provides a potential explanation for
certain characteristics of heart failure in this population, including worse cardiac function and
prognosis per a given degree of functional incapacity. When transgenically overexpressed in
mouse hearts,45 the high-functioning β1Arg389 receptor variant, which by prevalence is the
wild-type form of the β1-adrenergic receptor, is much more cardiomyopathic than the lower-
functioning β1Gly389 polymorphic counterpart. There is evidence from the BEST study (S.
Liggett, MD, P. Lavori, MD, M.R. Bristow, MD, unpublished data, 2005) that the clinical
response to bucindolol was affected in a predictable manner by these genetic variants. On the
basis of these and other observations, we may be close to the time when genotyping will be a
necessary prerequisite to selecting the proper treatment for chronic heart failure patients, at
least in terms of antiadrenergic therapy.

Is the Neurohormonal Model Adequate to Explain the Progression of Heart Failure?

Despite the many strengths of the neurohormonal model in terms of explaining disease
progression and the many insights that neurohormonal models have provided in terms of drug
development for heart failure, there is increasing clinical evidence to suggest that our current
neurohormonal models fail to completely explain disease progression in heart failure. Our
current medical therapies for heart failure will stabilize heart failure and in some cases
reverse certain aspects of the disease process. However, in the overwhelming majority of
patients, heart failure will progress, albeit at a slower rate. Moreover, as heart failure
progresses, many patients will be refractory and/or intolerant to conventional medical therapy
and often require withdrawal of conventional medical therapies.46 In addition, many types of
neurohormonal inhibition have been shown to be ineffective or even harmful in heart failure
patients (reviewed in Mann et al47). Although the precise mechanism(s) for this attenuation,
loss, or lack of effectiveness of neurohormonal antagonism is not known, there are at least 5
potential explanations that warrant a brief discussion. One obvious explanation is that it may
not be possible to achieve complete inhibition of the renin-angiotensin system or the
adrenergic system in heart failure because of dose-limiting side effects of ACE inhibitors and
β-blockers. A second explanation is that there may be alternative metabolic signaling for
neurohormones that are not antagonized by conventional treatment strategies (eg, the
conversion of angiotensin I to angiotensin II within the myocardium by tissue
chymase).48,49 Indeed, the results of recent clinical trials in which angiotensin receptor
antagonists and aldosterone antagonists have been shown to have benefit when added to
conventional therapy with ACE inhibitors and β-blockers clearly support this point of
view.30,50,51 Third, the currently available portfolio of neurohormonal antagonists, namely,
ACE inhibitors and β-blockers, may not antagonize all of the alterations in biologically active
systems that become activated in the setting of heart failure (Table 3). Indeed, given the
inherent biological redundancy of all mammalian systems, it is perhaps predictable that there
will be a number of biologically active molecules that are sufficient to contribute to disease
progression by virtue of their toxic effects on the heart and the circulation. Thus, it is likely
that with the current technologies for gene expression monitoring, as well as the innovative
cloning strategies that are being used, it is only a matter of time before investigators identify
new families/classes of biologically active molecules that are capable of contributing to
disease progression. A fourth factor is that some heart failure–activated
neurohormonal/cytokine signaling pathways capable of producing harmful effects in cardiac
myocytes is isolated systems (eg, endothelin, TNF) may have also have favorable effects
when functioning in the complex heart failure milieu. A fifth explanation for the loss of
effectiveness of neurohormonal antagonism is that, at some point, heart failure may progress
independently of the neurohormonal status of the patient. Thus, analogous to the limitations
described for hemodynamic models for heart failure, neurohormonal models may be
necessary but not sufficient to explain all aspects of disease progression in the failing heart.

TABLE 3. Overview of LV Remodeling

Alterations in myocyte biology

Excitation contraction coupling    

Myosin heavy chain (fetal) gene expression    

β-Adrenergic desensitization    

Hypertrophy    

Myocytolysis    
 Cytoskeletal proteins    

Myocardial changes

Myocyte loss    

Necrosis        

Apoptosis        

Alterations in extracellular matrix    

Matrix degradation    

Replacement fibrosis    

Alterations in LV chamber geometry

LV dilation    

Increased LV sphericity    

LV wall thinning    

Mitral valve incompetence    

LV Remodeling as a Cause of Disease Progression in Heart Failure

Natural history studies have shown that progressive LV remodeling is directly related to
future deterioration in LV performance and a less favorable clinical course in patients with
heart failure.52–54 Although some investigators currently view LV remodeling simply as the
end-organ response that occurs after years of exposure to the deleterious effects of long-term
neurohormonal stimulation, others have suggested that LV remodeling may contribute
independently to the progression of heart failure.52,55 Although a complete discussion of the
complex changes that occur in the heart during LV remodeling is well beyond the intended
scope of this brief review, it is worth emphasizing that the process of LV remodeling extends
to and affects importantly the biology of the cardiac myocyte, the volume of myocyte and
nonmyocyte components of the myocardium, and the geometry and architecture of the LV
chamber (Table 3). Although each of these various components of the remodeling process
may contribute importantly to the overall development and progression of heart failure, the
reversibility of heart failure is determined by whether the changes that occur at the level of
the myocyte, the myocardium, or the LV chamber are reversible. In this regard, the changes
that occur at the level of the myocyte and the LV chamber appear to be at least partially
reversible in some experimental and/or clinical models.14,56–58

A number of changes that occur during the process of LV remodeling may contribute to
worsening heart failure. Principal among these changes is the increase in LV wall stress that
occurs during LV remodeling. Indeed, one of the first observations with respect to the
abnormal geometry of remodeled ventricle was the consistent finding that the remodeled
heart was not only larger but was also more spherical in shape.59 As depicted in Table 4, the
increase in LV size and resultant change in LV geometry from the normal prolate ellipse to a
more spherical shape creates a number of de novo mechanical burdens for the failing heart,
most notably an increase in LV end-diastolic wall stress. Insofar as the load on the ventricle
at end-diastole contributes importantly to the afterload that the ventricle faces at the onset of
systole, it follows that LV dilation itself will increase the work of the ventricle and hence the
oxygen utilization as well. In addition to the increase in LV end-diastolic volume, LV wall
thinning also occurs as the ventricle begins to remodel. The increase in wall thinning along
with the increase in afterload created by LV dilation leads to a functional “afterload
mismatch” that may further contribute to a decrease in forward cardiac output.60–63 Moreover,
the high end-diastolic wall stress might be expected to lead to episodic hypoperfusion of the
subendocardium, with resultant worsening of LV function,64–66 as well as increased oxidative
stress, with the resultant activation of families of genes that are sensitive to free radical
generation (eg, TNF and interleukin-1β).

TABLE 4. Mechanical Disadvantages Created by LV Remodeling

Increased wall stress (afterload)

Afterload mismatch

Episodic subendocardial hypoperfusion

Increased oxygen utilization

 Sustained hemodynamic overloading

Worsening activation of compensatory mechanisms

Myocardial desynchronization

Given the potential central importance of LV remodeling in the progression of heart failure,
the following section will focus on the basic cellular and molecular mechanisms that are
responsible for this process. Although the complex changes that occur in the heart during LV
remodeling have canonically been described in anatomic terms, the process of LV
remodeling also has an important impact on the biology of the cardiac myocyte, changes in
the volume of myocyte and nonmyocyte components of the myocardium, and the geometry
and architecture of the LV chamber (Table 3). Although each of these various components of
the remodeling process may contribute importantly to the overall development and
progression of heart failure, it is extremely unlikely that any single aspect of the remodeling
process itself will satisfactorily explain the progressive cardiac decompensation that occurs as
heart failure advances. Accordingly, the remaining discussion will focus on the collective
changes that occur in the cardiac myocyte, the myocardium, and the LV chamber, with an
emphasis on those aspects of the remodeling process that might potentially contribute to
disease progression.

Sumber : https://www.ahajournals.org/doi/10.1161/circulationaha.104.500546

3. What are other etiologies factor for chronic heart failure

Aetiologies
A wide range of cardiac conditions, hereditary defects, and systemic diseases can result in HF
(BOX 1). Patients with HF can have mixed aetiologies, which are not mutually exclusive, and
HF aetiologies vary considerably between high-income and developing countries41,83. HF has
an estimated 17 primary aetiologies, as determined by the Global Burden of Disease Study84.
More than two-thirds of all cases of HF can be attributed to four underlying conditions:
ischaemic heart disease, chronic obstructive pulmonary disease, hypertensive heart disease,
and rheumatic heart disease. Although the Global Burden of Disease Study aims to
approximate the burden of right-sided HF from chronic obstructive pulmonary disease,
studies estimating the prevalence of right-sided HF are limited and require further study84.
High-income regions are disproportionally affected by ischaemic heart disease and chronic
obstructive pulmonary disease compared with low-income regions, which in turn are
primarily affected by hypertensive heart disease, rheumatic heart disease, cardiomyopathy,
and myocarditis2. The assessment and management of cardiovascular risk around the world
requires the tailoring of policies to population-specific risks and underlying aetiologies33.
Ischaemic heart disease
Medical descriptions of angina pectoris date back to 1772, but understanding of the
pathophysiology underlying the syndrome did not progress until the late 19th century, when
calcification and thrombosis of the coronary arteries were first described85,86. Early studies,
such as the Framingham Heart Study, identified the risk factors for coronary artery disease,
including hypertension, hyperlipidaemia, diabetes, and smoking. The rate of death from
cardiovascular causes has steadily declined since the 1960s with increased recognition of
cardiovascular risk factors and greater attention to primary prevention87. The incidence of
ischaemic heart disease, hypertension, diabetes, and other chronic diseases tends to parallel
the increased consumption of food high in fat and sugar, and sedentary behaviour. The
incidence and prevalence of these chronic diseases tend to increase unless preventive health
strategies are implemented4. This pattern of shifting disease prevalence is described as an
epidemiological transition that is strongly associated with the economic development of a
country or region.
Ischaemic heart disease was the leading underlying cause of death globally in 2013,
accounting for 15.7% of all age-standardized deaths, equating to a total of 8,139,900 deaths5.
The Global Burden of Disease Study estimates that the prevalence of ischaemic HF between
1990 and 2010 increased from 240 to 270 per 100,000 person-years in men, and was stable at
190 per 100,000 in women88. Using the estimated rate of myocardial infarctions as a
surrogate for the incidence of ischaemic heart disease, there is evidence for epidemiological
transitions among both industrialized and developing nations. Age-standardized rates of
myocardial infarction decreased between 1990 and 2010 in high-income countries in
Australasia, Europe, and North America88. Within these regions, the greatest increase in the
number of myocardial infarctions was in Eastern Europe88. In Sweden, the prevalence of
ischaemic heart disease among patients with HF declined between 2006 and 2010 by
approximately 7–8%39. In the Olmsted County cohort, the proportion of ischaemic HFrEF
declined from 39.8% to 29.4% between 2000 and 2010, whereas the proportion of ischaemic
HFpEF increased from 29.0% to 32.6% in this same time period32. The decrease in the
proportion of patients with HFrEF is likely to be attributable to a reduction in myocardial
infarction through both primary and secondary prevention strategies. Furthermore, patients
with active myocardial infarction are more swiftly treated with percutaneous coronary
intervention and other medical therapies89. With respect to the global burden of ischaemic
heart disease, the incidence of acute myocardial infarction worldwide is highest in Eastern
Europe and Central Asia, with >340 cases per 100,000 person-years for men and 180 cases
per 100,000 person-years for women88. The lowest rates of acute myocardial infarction were
observed in high-income nations in Asia88.

Hypertensive heart disease

An increase in blood pressure exposes cardiac myocytes to elevated mechanical stress and
neurohormones, which increase myocardial mass and result in left ventricular hypertrophy.
These cardiac changes can further progress to HFpEF or HFrEF, even in the absence of
obstructive epicardial coronary arteries and myocardial infarction90. NHANES data from the
USA show that, between 1999 and 2012, the proportion of patients treated for hypertension
improved from 59.8% to 74.7%, and the proportion of patients with hypertension and
adequately controlled blood pressure improved from 53.3% to 68.9%73. This improvement in
blood pressure control is likely to have contributed to the decline in the incidence of HF. In
the Olmsted County cohort, 73.6% of patients with HFrEF had hypertension compared with
89.3% of patients with HFpEF32. The lifetime risk of HF for individuals with blood pressure
>160/90 mmHg is double that of those with blood pressure <140/90 mmHg47. Early
randomized trials on hypertension control reported that effective treatment of moderate
(≥140/90 mmHg) and severe hypertension (≥180/110 mmHg) reduces the risk of HF by
87%91. In the USA, antihypertensive treatment has reduced the incidence of HF by
approximately 50%35.
Although hypertension has been recognized as a potent cardiovascular risk factor for many
decades, gaps in the treatment of high blood pressure still remain. Hypertension affects all
socioeconomic classes. Clinical evaluation of 1,515 consecutive cardiac referrals in Nigeria
resulted in a diagnosis of hypertensive HF in 61% of patients92. However, this study was
limited in that patients did not receive advanced diagnostic imaging or invasive angiography
to confirm the low prevalence of ischaemic heart disease. Investigators in the PURE
study93 found that, within a sample of patients with hypertension from high-income countries,
only 49% of patients with blood pressure >140/90 mmHg were aware of their diagnosis,
while 46.7% received treatment, and 19.0% had adequate control of their hypertension. In
low-income countries, the rate of awareness was 40.8%, 31.7% received treatment, and
12.7% had adequate control93. These rates reflect the opportunity for improved management
of hypertension globally in reducing preventable cardiovascular diseases.

Valvular and rheumatic HF

In developed countries, most cases of valvular heart disease are degenerative in nature, and
the incidence of rheumatic heart disease is exceedingly low. The prevalence of any valve
disease diagnosed using echocardiography is estimated to be 2.5% in the USA; prevalence
increases substantially with age to 11.7% in individuals aged >75 years94. The prevalence of
clinically diagnosed valvular disease is 1.8%94. In 2010, approximately 106,000 valve
surgeries were performed in the USA3.
Data on the prevalence of HF among patients with clinical or echocardiographic diagnosis of
valvular disease is scarce. Globally, the greatest burden of valvular disease is valvular HF
that is secondary to rheumatic heart disease. In high-income nations, the substantial decline in
prevalence of valvular disease is attributable to improvements in living conditions and
availability of antibiotic therapy. The incidence of rheumatic fever has fallen below 1 case
per 100,000 person-years in developed nations95. In developing countries, however, valvular
HF resulting from rheumatic disease contributes substantially to morbidity and mortality. In
Sudan, the incidence of rheumatic fever is >100 cases per 100,000 person-years95. A
conservatively estimated 15.6 million people have rheumatic heart disease globally, with
470,000 new cases and 233,000 deaths per year96. When echocardiography is used to screen
affected populations in developing countries, the prevalence of rheumatic heart disease
increases tenfold97. Despite the high prevalence of rheumatic heart disease in low-income
countries, the global age-standardized mortality has decreased 22% from 375.5 to 293.2
deaths per 100,000 between 1990 and 2013 (REF. 5).
Go to:

Cardiomyopathies
Quantifying the global burden of cardiomyopathy is difficult given variations in diagnostic
capabilities and coding practices5. A study of an Italian outpatient cohort estimated that the
distribution of HF aetiologies was 36.0% dilated cardiomyopathy, 45.6% ischaemic
cardiomyopathy, 12.9% hypertensive cardiomyopathy, and 5.5% from other causes83. The
prevalence of cardiomyopathy in low-income countries is also poorly understood, and larger
epidemiological studies are required98. The available data suggest that infectious,
inflammatory, and nutritional deficiencies cause HF more commonly in sub-Saharan Africa
than in middle-income and high-income countries99. An estimated 26.0% of the HF cases in
sub-Saharan Africa have been attributed to the cardiomyopathies, specifically idiopathic
dilated cardiomyopathy, HIV-related cardiomyopathy, hypertrophic cardiomyopathy, and
endomyocardial fibrosis. Endomyocardial fibrosis is an endemic cardiomyopathy primarily
described in Uganda and other regions with profound malnutrition from low protein and high
cassava diets. An estimated 24% of dilated cardiomyopathies observed in sub-Saharan Africa
might be secondary to myocarditis and autoimmune disorders60,100. Myocarditis has an
estimated prevalence of 0.5% to 4.0% globally, and aetiologies vary depending on the
region101.

Chagas cardiomyopathy
Chagas disease is an endemic parasitic disease caused by the protozoan Trypanosoma cruzi,
and was estimated to affect 5.7 million people worldwide in 2010, mostly in Latin America.
The use of insecticides to reduce the numbers of the insect that spreads the parasite
(Triatoma, commonly referred to as the kissing bug) since 1990 has reduced the prevalence
of Chagas disease from a peak of 15–30 million102,103. The Global Burden of Disease Study
estimates that the age-standardized mortality for Chagas disease decreased by 51.7% between
1990 and 2013 (REF. 5). In 2005, an estimated 300,000 immigrants were living with Chagas
disease in the USA104.
Chagas disease remains the most common cause of nonischaemic cardiomyopathy in Latin
America104. A cohort study observed that 38.3% of patients with Chagas disease progressed
to being diagnosed with HF after a 10-year follow-up period105. In the early stages of the
disease, patients are likely to develop abnormalities of the cardiac conduction system that can
be asymptomatic or detected after reported palpitations or syncopal events. HF symptoms are
typically caused by biventricular dysfunction with a greater prominence of right-sided HF
symptoms. Chagas cardiomyopathy has a higher mortality than other nonischaemic
cardiomyopathies, and patients are at greater risk of sudden cardiac death and malignant
arrhythmias than other patients with HF. Deaths from cardiovascular causes account for
nearly two-thirds of all Chagas-related deaths106. Antiparasitic treatment with benznidazole in
patients with Chagas cardiomyopathy did not improve clinical outcomes or 5-year
mortality107. The recommended management for Chagas cardiomyopathy is based on
strategies for HFrEF107.

Congenital heart disease

Global estimates of the prevalence of congenital heart disease range from 0.4% to 5.0% of all
births108. In the USA, the prevalence of congenital heart disease is estimated to be
approximately 1%108. Patients with congenital heart disease tend to under-report their HF
symptoms compared with patients with noncongenital HF109. Exercise testing is usually
required to understand functional limitations in patients with congenital heart disease,
because echocardiographic criteria for HFrEF and HFpEF might not be relevant in this
patient cohort. Among adult patients with congenital heart disease, 51% reported NYHA
class II to III HF symptoms, and exercise testing revealed further functional limitations109. HF
is seen more commonly in patients with congenital heart disease and single or systemic right
ventricles108. Adults with six major categories of congenital heart defects (atrial septal
defects, congenitally corrected transposition of the great vessels, tetraology of Fallot,
transposition of the great arteritis, Ebstein anomaly, and Fontan circulation) all had markedly
reduced exercise capacity on cardiopulmonary exercise testing110.
The global burden of congenital heart disease has been underappreciated in low-income
countries. Most congenital lesions are not diagnosed at birth and might present only after
progression to severe symptoms, and the limited availability of imaging technologies in the
developing world further restricts diagnostic capabilities111. Echocardiographic studies in
school-aged children in Africa reported high rates of rheumatic and congenital heart
disease111. Another small study, in which echocardiography was used to diagnose congenital
heart disease in Mozambique, reported a prevalence of 230 cases per 100,000 in school-aged
children, with 80% of cases being newly diagnosed.
Sumber : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868779/
4. Describe contractile proteins in the myocyte

Several distinct proteins are responsible for cardiac muscle cell contraction (Fig. 1.18). Two
of the proteins, actin and myosin, are the chief contractile elements. Two other proteins,
tropomyosin and troponin, serve regulatory functions. Myosin is arranged in thick filaments,
each composed of lengthwise stacks of approximately 300 molecules. The myosin filament
exhibits globular heads that are evenly spaced along its length and contain myosin ATPase,
an enzyme that is necessary for contraction to occur. Actin, a smaller molecule, is arranged in
thin filaments as an alpha-helix consisting of two strands that interdigitate between the thick
myosin filaments (see Fig. 1.8). Titin (also termed connectin) is a protein that helps tether
myosin to the Z line of the sarcomere and provides elasticity to the contractile process.
Tropomyosin is a double helix that lies in the grooves between the actin fi laments and, in
the resting state, inhibits the interaction between myosin heads and actin, thus preventing
contraction. Troponin sits at regular intervals along the actin strands and is composed of
three subunits. The troponin T (TnT) subunit links the troponin complex to the actin and
tropomyosin molecules. The troponin I (TnI) subunit inhibits the ATPase activity of the
actin–myosin interaction. The troponin C (TnC) subunit is responsible for binding calcium
ions that regulate the contractile process.

Sumber : E-Book = Pathophysiology of Heart Disease Lilly

5. Describe the excitation-contraction coupling

Excitation-contraction coupling (ECC) is the process whereby an action potential triggers a

myocyte to contract, followed by subsequent relaxation. The following figure and text
summarizes some of the key events that occur during cardiac muscle excitation-contraction
coupling:
Key steps in cardiac excitation-contraction coupling:

1. Action potentials traveling along the sarcolemma and down into the transverse
tubule (T-tubule) system depolarize the cell membrane.
2. Voltage-sensitive dihydropyridine (DHP) receptors (L-type calcium channels)
open to permit calcium entry into the cell during phase 2 of the action
potential.
3. Calcium influx triggers a subsequent release of calcium that is stored in
the sarcoplasmic reticulum (SR) through calcium-release channels
("ryanodine receptors"), and increases intracellular calcium concentration
from about 10-7 to 10-5 M.
4. Free calcium binds to troponin-C (TN-C) that is part of the regulatory complex
attached to the thin filaments. When calcium binds to the TN-C, this induces a
conformational change in the regulatory complex such that troponin-I (TN-I)
exposes a site on the actin molecule that is able to bind to the myosin ATPase
located on the myosin head. This binding results in ATP hydrolysis that
supplies energy for a conformational change to occur in the actin-myosin
complex. The result of these changes is a movement ("ratcheting") between
the myosin heads and the actin, such that the actin and myosin filaments slide
past each other thereby shortening the sarcomere length. Ratcheting cycles
occur as long as the cytosolic calcium remains elevated.
5. At the end of phase 2, calcium entry into the cell slows and calcium is
sequestered by the SR by an ATP-dependent calcium pump (SERCA, sarco-
endoplasmic reticulum calcium-ATPase), thus lowering the cytosolic calcium
concentration and removing calcium from the TN-C. To a quantitatively
smaller extent, cytosolic calcium is transported out of the cell by the sodium-
calcium-exchange pump. Unbinding of calcium from TN-C induces a
 conformational change in the troponin complex leading, once again, to TN-I
inhibition of the actin binding site. At the end of the cycle, a new ATP binds to
the myosin head, displacing the ADP, and the initial sarcomere length is
restored.  
 

Mechanisms that enhance the concentration of cytosolic calcium increase the amount of ATP
hydrolyzed and the force generated by the actin and myosin interactions, as well as the
velocity of shortening. Physiologically, cytosolic calcium concentrations are influenced
primarily by beta-adrenoceptor-coupled mechanisms. Beta-adrenergic stimulation, as occurs
when sympathetic nerves are activated, increases cAMP which in turn activates protein
kinase to increase in calcium entry into the cell through L-type calcium channels. Activation
of the IP3 signal transduction pathway also can stimulate the release of calcium by the SR
through IP3 receptors located on the SR. Furthermore, activation of the cAMP-dependent
protein kinase phosphorylates a protein (phospholamban) on the SR that normally inhibits
calcium uptake. This disinhibition of phospholamban leads to an increased rate of calcium
uptake by the SR. Therefore, beta-adrenergic stimulation increases the force and shortening
velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e.,
positive lusitropy).

Another potential regulatory mechanism for ECC involves altering the affinity of TN-C for
calcium. There are investigational drugs that enhance TN-C calcium affinity and thereby
exert a positive inotropic influence on the heart. One potential downside with these drugs,
however, is that enhanced TN-C binding to calcium can reduce the rate of relaxation, thereby
causing diastolic dysfunction.

In systolic heart failure, ECC can be impaired at several different sites. First, there can be
decreased influx of calcium into the cell through L-type calcium channels (resulting from
impaired signal transduction), which decreases subsequent calcium release by the SR. There
can also be a decrease in TN-C affinity for calcium, so that a given increase in calcium in the
vicinity of the troponin complex has less of an activating effect on cardiac contraction. In
some forms of diastolic heart failure, there is evidence that the function of the SR ATP-
dependent calcium pump is impaired. This defect would retard the rate of calcium uptake by
the SR and reduce the rate of relaxation, leading to diastolic dysfunction.

Sumber : https://www.cvphysiology.com/Cardiac%20Function/CF022

6. Describe physiology of contractile function of the heart

Contractile function of the heart is conducted through composite processes such as

sympathetic and parasympathetic heart rate control, core conduction system activities (thin
[actin, tropomyosin, and troponin] and thick [myosin] filaments), calcium regulatory
pathways that orchestrate shortening and relaxation, and humoral substances
like catecholamines.17 The failing heart has high energy demands that place considerable
stress on the cardiac contractile machinery, which in turn diminishes myocardial contractility.
The myocyte contractile defects observed in failing hearts were shown to be reversed after
pulsatile-flow LVAD unloading, with improved shortening and relaxation in isolated
myocytes and isolated strips of ventricular tissue.18,19 Improvements in LVAD-induced
contractile dysfunction can be partially explained by changes in Ca++ handling, such as faster
sarcolemmal Ca++ entry and shorter action potential durations, higher sarcoplasmic
reticulum Ca++ content, improved abundance of sarcoplasmic reticulum (SR)/endoplasmic
reticulum calcium ATPase, decreased abundance of Na+/Ca++ exchanger, and beneficial
changes in L-type calcium channel and ryanodine receptor (RyR) function.18,20–22 There is an
increase in RyR clusters that are not near sarcolemmal L-type calcium channels due to
reduced density of the tubular system (t-system); hence, they are not contained by couplons.
This shift of RyR clusters away from sarcolemmal L-type calcium channels can affect the
excitation-contraction coupling for two reasons: first, these nonjunctional RyR clusters can
result in decreased calcium release from SR; and second, they create asynchronous calcium
release due to a reduced open probability, which does not correlate with the quick opening of
junctional RyR clusters. A recent study demonstrated a direct relationship linking the
distance between nonjunctional RyR clusters and the change in left ventricular (LV) ejection
fraction (EF) in post-LVAD patients.23 The authors reported that the EF improved when the
distance was less than 1 μm, whereas a distance that exceeded 1 μm was not associated with
improvement in EF. An intact t-system at the time of LVAD implantation may serve as a
predictor for cardiac recovery induced through unloading (Fig. 9.4).23
The action potential initiates the excitation-contraction cycle in
ventricular cardiomyocytes. Depolarization starts with sodium (Na+) channels activating the
L-type Ca++ current that causes local Ca++-induced Ca++ release (CICR) in the SR. The
increased cytosolic Ca++ binds to myofilaments, causing contraction followed by diastolic Ca+
+
 elimination, i.e., dissociation of Ca++ from the contractile filaments and the excess cytosolic
Ca++ extruded via SR-Ca++ ATPase, Na+-Ca++ exchanger, and sarcolemmal Ca++ pump.
Abnormalities in Ca++ regulation may lead to increased diastolic Ca++, which is the hallmark
of contractile dysfunction in end-stage chronic HF patients.24 Therapeutic measures targeting
Ca++ homeostasis may facilitate the reverse remodeling in HF patients. Fischer et al. recently
showed that increased SR-Ca++ leak correlated with deteriorating LV function after LVAD
implantation, and this SR-Ca++ leak was significantly reduced by Ca++ calmodulin-dependent
protein kinase II (CaMKII) inhibition. CaMKII hyperphosphorylates RYR2, leading to
disturbed diastolic closure of RYR2, and has a cascading effect on the Ca++ homeostasis in
HF patients.24 The observation that CaMKII inhibition reduces the SR-Ca++ leak in HF
suggests that CaMKII inhibition may be a promising therapeutic target for cardiac
remodeling after LVAD implantation.25 Furthermore, CICR in rodent HF models suggests
that the mechanical unloading by heterotopic abdominal heart transplantation increases
calcium transient amplitude and normalizes the calcium spark frequencies and L-type
calcium channel activity in cardiomyocytes.26 The role of short-term continuous-flow LVAD
unloading was studied in an ovine model of acute myocardial infarction (MI), where it was
observed that mechanical unloading prevented cardiac remodeling and dysfunction.
Compared to a non-LVAD control group, calcium handling proteins were not altered, thereby
preserving calcium cycling and improving cardiac function.27 These recent investigations
demonstrate that extensive structural remodeling of the t-system, along with its depletion and
change in orientation, plays an important role in the development and progression
of ventricular dysfunction.
The effect of mechanical unloading on cytoskeletal proteins has been studied in LVAD
clinical studies. Birks et al. showed significant differences (between the time of implantation
and explantation/transplantation) in the regulation of nonsarcomeric proteins (lamin A/C,
spectrin), integrins (β1, β5, β6, α5, and α7), and sarcomeric proteins that changed only in the
recovered group (β-actin, α-tropomyosin, α1-actinin, and α-filament A).28 They also reported
that vinculin, Wiskott-Aldrich syndrome protein, p21-activated kinase, Rho, and Graf levels
decreased in the recovery group and increased in the nonrecovery group.28 These observations
warrant further investigations on the role of the previously reported proteins in cardiac
reverse remodeling.29 Cardiac ankyrin repeat protein (CARP) has been associated
with cardiac hypertrophy, acts as transcription cofactor under mechanical stress and pressure
overload, and has a critical role in the Nkx2.5 transcriptional pathway that regulates the
ventricular muscle gene expression in the developing heart.30 A recent report on the CARP
revealed increased levels in HF that eventually returned to normal levels after LVAD support.
They also reported that CARP levels were increased after transaortic constriction in mice
lacking βII spectrin, which the authors previously reported as an essential nodal
protein following its significant alteration in their human and animal HF
studies.30,31 Together, these observations indicate the potentially important role of cytoskeletal
proteins in the myocardial reverse remodeling processes and further investigations are
warranted.
Sumber : https://www.sciencedirect.com/topics/medicine-and-dentistry/contractile-function

7. Describe pathophysiology of heart failure

 Frank-Starling mechanism

Introduction
The Frank-Starling relationship is based on the link between the initial length of myocardial
fibers and the force generated by contraction.  There is a predictable relationship between the
length between sarcomeres and the tension of the muscle fibers. There is an optimal length
between sarcomeres at which the tension in the muscle fiber is greatest, resulting in the
greatest force of contraction. If sarcomeres are closer together or further apart compared to
this optimal length, there will be a decrease in contraction tension and strength.
The greater the ventricular diastolic volume, the more the myocardial fibers are stretched
during diastole. Within a normal physiologic range, the more the myocardial fibers are
stretched, the greater the tension in the muscle fibers and the greater force of contraction of
the ventricle when stimulated. The Frank-Starling relationship is the observation that
ventricular output increases as preload (end-diastolic pressure) increases.

Mechanism
The left ventricular performance (Frank-Starling) curves relate preload, measured as left
ventricular end-diastolic volume (EDV) or pressure, to cardiac performance, measured as
ventricular stroke volume or cardiac output. On the curve of a normally functioning heart,
cardiac performance increases continuously as preload increases. During states of increased
left ventricular contractility, for example, due to norepinephrine infusion, there is a greater
cardiac performance for a given preload. This is represented graphically as an upward shift of
the normal curve. Conversely, during states of decreased left ventricular contractility
associated with systolic heart failure, there is decreased cardiac performance for a given
preload as compared to the normal curve. This is represented by a downward shift of the
normal curve. Decreased contractility also can result from a loss of myocardium as with
myocardial infarction, beta-blockers (acutely), non-dihydropyridine Ca++ channel blockers,
and dilated cardiomyopathy.[4][5][6]
Changes in afterload, which is the force of resistance that the ventricle must overcome to
empty contents at the beginning of systole, will also shift the Frank-Starling curve. A
decrease in afterload will cause an upward shift of the ventricular performance curve in a
similar fashion to an increase in inotropy. Conversely, an increase in afterload will cause a
downward shift of the curve in a similar fashion to a decrease in inotropy.  
An increase in catecholamines, such as norepinephrine, during exercise, will result in an
upward shift of the Frank-Starling curve. Catecholamines achieve this increase by binding to
a myocyte beta1-adrenergic receptor, a G protein-coupled receptor, ultimately resulting in
increased Ca++ channel release from the sarcoplasmic reticulum, which enhances the force of
contraction.

Clinical Significance
The Frank-Starling mechanism plays a role in the compensation of systolic heart failure,
buffering the fall in cardiac output to help preserve sufficient blood pressure to perfuse the
vital organs. Heart failure caused by the impaired contractile function of the left ventricle
causes a downward shift of the left ventricular performance curve. At any given preload, the
stroke volume will be decreased as compared to normal. This reduced stroke volume leads to
incomplete left ventricular emptying. Consequently, the volume of blood that accumulates in
the left ventricle during diastole is greater than normal. The amplified residual volume
increases the stretch of the myocardial fibers and induces a greater stroke volume with the
next contraction via the Frank-Starling mechanism. This allows for better emptying of the
enlarged left ventricle and preserves cardiac output.[9]
The benefit of the Frank-Starling mechanism in the compensation of systolic heart failure is
limited. In severe heart failure with a greater cardiac contractility malfunction, the ventricular
performance curve may be nearly flat at higher diastolic volumes, reducing the increased
cardiac output with increases in chamber filling. In this circumstance, a severe elevation at
the EDV and left ventricular EDP may result in pulmonary congestion.
The Frank-Starling mechanism also plays a compensatory role in patients with dilated
cardiomyopathy. There is commonly dilation of both the right and left ventricles with
decreased contractile function in dilated cardiomyopathy. As impaired myocyte contractility
results in depression of ventricular stroke volume and cardiac output, the Frank-Starling
mechanism has compensatory effects. As the elevated ventricular diastolic volume increases
the stretch on the myocardial fibers, there will be a subsequent increase in stroke volume. 
Along with the Frank-Starling mechanism, neurohormonal activation mediated by the
sympathetic nervous system also compensates for dilated cardiomyopathy by increasing heart
rate and contractility, helping to buffer the decreased cardiac output. These compensatory
mechanisms may lead to a lack of symptoms during the early stages of ventricular
dysfunction. With progressive myocyte degeneration and volume overload, clinical
symptoms of systolic heart failure will develop. 
In patients with impaired myocardial systolic failure, clinicians use inotropic drugs to
increase the force of ventricular contraction. Pharmacologic inotropic agents include cardiac
glycosides, such as digitalis; sympathomimetic amines such as dopamine and epinephrine;
and phosphodiesterase-3 inhibitors, such as milrinone.  They all work through different
mechanisms to enhance cardiac contraction by increasing the intracellular calcium
concentration, enhancing actin and myosin interaction. This will have the hemodynamic
effect of shifting a depressed ventricular performance (Frank-Starling) curve in an upward
direction toward normal. At a given preload (left ventricular EDP), the stroke volume and
cardiac output are increased.
With the progressive loss of ventricular contractility, increased preload (pressure) in the
left ventricle will surpass the hydrostatic forces of the pulmonary venous system, resulting in
pulmonary congestion. In a patient suffering from systolic heart failure with reduced ejection
fraction and resultant pulmonary congestion, treatment with a diuretic, such as furosemide or
hydrochlorothiazide, or a pure venous vasodilator, such as nitrates, reduces the preload
without much change in stroke volume. This is because the Frank-Starling curve is almost
horizontal at higher preload levels in a patient whose curve is shifted downward due to
systolic contractile dysfunction. However, excessive diuresis or venous vasodilation can
result in an unwanted fall in stroke volume, resulting in hypotension. 
Arteriolar vasodilation therapy, like hydralazine, also has value when treating systolic heart
failure with pulmonary congestion. Arteriolar vasodilators result in a decrease in afterload,
allowing for an increase in stroke volume—the improved left ventricular emptying results in
a decreased preload and improvement of pulmonary symptoms. There is the potential added
benefit of combining treatment with a vasodilator and a positive inotropic agent, allowing for
a larger increase in stroke volume than would be seen with monotherapy. Even
with combination therapy with a vasodilator and inotropic agent, the Frank-Starling curve
will not improve to the performance level of a normal ventricle.
Sumber : https://www.ncbi.nlm.nih.gov/books/NBK470295/

 Neurohormonal alterations

Several important neurohormonal compensatory mechanisms are activated in heart failure in

response to the decreased cardiac output (Fig. 9.9). Three of the most important involve (1)
the adrenergic nervous system, (2) the renin–angiotensin–aldosterone system, and (3)
increased production of antidiuretic hormone (ADH). In part, these mechanisms serve to
increase systemic vascular resistance, which helps to maintain arterial perfusion to vital
organs, even in the setting of a reduced cardiac output. That is, because blood pressure (BP)
is equal to the product of cardiac output (CO) and total peripheral resistance (TPR),

BP = CO x TPR
a rise in TPR induced by these compensatory mechanisms can nearly balance the fall in CO
and, in the early stages of heart failure, maintain fairly normal BP. In addition,
neurohormonal activation results in salt and water retention, which in turn increases
intravascular volume and left ventricular preload, maximizing stroke volume via the Frank–
Starling mechanism.
Although the acute effects of neurohormonal stimulation are compensatory and beneficial,
chronic activation of these mechanisms often ultimately proves deleterious to the failing heart
and contributes to a progressive downhill course, as described later.

Adrenergic Nervous System

The fall in cardiac output in heart failure is sensed by baroreceptors in the carotid sinus and
aortic arch. These receptors decrease their rate of firing in proportion to the fall in BP, and
the signal is transmitted by the 9th and 10th cranial nerves to the cardiovascular control
center in the medulla. As a result, sympathetic outflow to the heart and peripheral circulation
is increased, and parasympathetic tone is diminished. There are three immediate
consequences (see Fig. 9.9): (1) an increase in heart rate, (2) augmentation of ventricular
contractility, and (3) vasoconstriction caused by stimulation of -receptors on the systemic
veins and arteries. The increased heart rate and ventricular contractility directly augment
cardiac output (see Fig. 9.2). Vasoconstriction of the venous and arterial circulations is also
initially beneficial. Venous constriction augments blood return to the heart, which increases
preload and raises stroke volume through the Frank–Starling mechanism, as long as the
ventricle is operating on the ascending portion of its ventricular performance curve.
Arteriolar constriction increases the peripheral vascular resistance and therefore helps to
maintain blood pressure (BP  CO  TPR). The regional distribution of alpha-receptors is such
that during sympathetic stimulation, blood flow is redistributed to vital organs (e.g., heart and
brain) at the expense of the skin, splanchnic viscera, and kidneys.

Renin–Angiotensin–Aldosterone System
This system is also activated early in patients with heart failure (see Fig. 9.9), mediated by
increased renin release. The main stimuli for renin secretion from the juxtaglomerular cells of
the kidney in heart failure patients include (1) decreased renal artery perfusion pressure
secondary to low cardiac output, (2) decreased salt delivery to the macula densa of the kidney
owing to alterations in intrarenal hemodynamics, and (3) direct stimulation of
juxtaglomerular 2-receptors by the activated adrenergic nervous system. Renin is an enzyme
that cleaves circulating angiotensinogen to form angiotensin I, which is then rapidly cleaved
by endothelial cell-bound angiotensin-converting enzyme (ACE) to form angiotensin II (AII),
a potent vasoconstrictor (see Chapter 13). Increased AII constricts arterioles and raises total
peripheral resistance, thereby serving to maintain systemic blood pressure. In addition, AII
acts to increase intravascular volume by two mechanisms: (1) at the hypothalamus, it
stimulates thirst and therefore water intake; and (2) at the adrenal cortex, it acts to increase
aldosterone secretion. The latter hormone promotes sodium reabsorption from the distal
convoluted tubule of the kidney into the circulation (see Chapter 17), serving to augment
intravascular volume. The rise in intravascular volume increases left ventricular preload and
thereby augments cardiac output via the Frank–Starling mechanism in patients on the
ascending portion of the ventricular performance curve (see Fig. 9.3).

Antidiuretic Hormone

Secretion of this hormone (also termed vasopressin) by the posterior pituitary is increased
in many patients with heart failure, presumably mediated through arterial baroreceptors, and
by increased levels of AII. ADH contributes to increased intravascular volume because it
promotes water retention in the distal nephron. The increased intravascular volume serves to
augment left ventricular preload and cardiac output. ADH also appears to contribute to
systemic vasoconstriction. Although each of these neurohormonal alterations in heart failure
is initially beneficial, continued activation ultimately proves harmful. For example, the
increased circulating volume and augmented venous return to the heart may worsen
engorgement of the lung vasculature, exacerbating congestive pulmonary symptoms.
Furthermore, the elevated arteriolar resistance increases the afterload against which the
failing left ventricle contracts and may therefore impair stroke volume and reduce cardiac
output (see Fig. 9.9). In addition, the increased heart rate augments metabolic demand and
can therefore further reduce the performance of the failing heart. Continuous sympathetic
activation results in downregulation of cardiac -adrenergic receptors and upregulation of
inhibitory G proteins, contributing to a decrease in the myocardium’s sensitivity to
circulating catecholamines and a reduced inotropic response. Chronically elevated levels of
AII and aldosterone have additional detrimental effects. They provoke the production of
cytokines (small proteins that mediate cell–cell communication and immune responses),
activate macrophages, and stimulate fibroblasts, resulting in fibrosis and adverse remodeling
of the failing heart. Because the undesired consequences of chronic neurohormonal activation
eventually outweigh their benefits, much of today’s pharmacologic therapy of heart failure is
designed to moderate these “compensatory” mechanisms, as examined later in the chapter.

Natriuretic Peptides

In contrast to the ultimately adverse consequences of the neurohormonal alterations described

in the previous section, the natriuretic peptides are natural “beneficial” hormones secreted in
heart failure in response to increased intracardiac pressures. The best studied of these are
atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is stored in atrial
cells and is released in response to atrial distension. BNP is not detected in normal hearts but
is produced when ventricular myocardium is subjected to hemodynamic stress (e.g., in heart
failure or during myocardial infarction). Recent studies have shown a close relationship
between serum BNP levels and the clinical severity of heart failure. Actions of the natriuretic
peptides are mediated by specific natriuretic receptors and are largely opposite to those of the
other hormone systems activated in heart failure. They result in excretion of sodium and
water, vasodilatation, inhibition of renin secretion, and antagonism of the effects of AII on
aldosterone and vasopressin levels. Although these effects are beneficial to patients with
heart failure, they are usually not sufficient to fully counteract the vasoconstriction and
volume-retaining effects of the other activated hormonal systems.

Other Peptides

Among other peptides that are generated in heart failure is endothelin-1, a potent
vasoconstrictor, derived from endothelial cells lining the vasculature (see Chapter 6). In
patients with heart failure, the plasma concentration of endothelin-1 correlates with disease
severity and adverse outcomes. Drugs designed to inhibit endothelin receptors (and therefore
blunt adverse vasoconstriction) improve LV function in heart failure patients, but long-term
clinical benefits have not been demonstrated.

Sumber : E-Book = Pathophysiology of Heart Disease Lilly

 Ventricular remodelling

Ventricular Hypertrophy and Remodeling

Ventricular hypertrophy and remodeling are important compensatory processes that develop
over time in response to hemodynamic burdens. Wall stress (as defined earlier) is often
increased in developing heart failure because of either LV dilatation (increased chamber
radius) or the need to generate high systolic pressures to overcome excessive afterload (e.g.,
in aortic stenosis or hypertension). A sustained increase in wall stress (along with
neurohormonal and cytokine alterations) stimulates the development of myocardial
hypertrophy and deposition of extracellular matrix. This increased mass of muscle fibers
serves as a compensatory mechanism that helps to maintain contractile force and counteracts
the elevated ventricular wall stress (recall that wall thickness is in the denominator of the
Laplace wall stress formula). However, because of the increased stiffness of the
hypertrophied wall, these benefits come at the expense of higher than- normal diastolic
ventricular pressures, which are transmitted to the left atrium and pulmonary vasculature (see
Fig. 9.8). The pattern of compensatory hypertrophy and remodeling that develops depends on
whether the ventricle is subjected to chronic volume or pressure overload. Chronic chamber
dilatation owing to volume overload (e.g. Chronic mitral or aortic regurgitation) results in 
the synthesis of new sarcomeres in series with the old, causing the myocytes to elongate. The
radius of the ventricular chamber therefore enlarges, doing so in proportion to the increase in
wall thickness, and is termed eccentric hypertrophy. Chronic pressure overload (e.g., caused
by hypertension or aortic stenosis) results in the synthesis of new sarcomeres in parallel with
the old (i.e., the myocytes thicken), termed concentric hypertrophy. In this situation, the wall
thickness increases without proportional chamber dilatation, and wall stress may therefore be
reduced substantially. Such hypertrophy and remodeling help to reduce wall stress and
maintain contractile force, but ultimately, ventricular function may decline, allowing the
chamber to dilate out of proportion to wall thickness. When this occurs, the excessive
hemodynamic burden on the contractile units produces a downward spiral of deterioration
with progressive heart failure symptomatology.
 Sumber : E-Book = Pathophysiology of Heart Disease Lilly
 Fluid retention (congestion)

Abstract
Heart failure (HF) is one of the most common reasons for admission to hospital. It is
associated with long in-patient stays, and has a high in-hospital and post-discharge morbidity
and mortality, whether left ventricular ejection fraction (LVEF) is reduced (HFREF) or
normal (HeFNEF).[1,2] Congestion, or fluid overload, is a classic clinical feature of patients
presenting with HF. In some patients, pulmonary congestion develops very rapidly because of
a sudden increase in LV filling pressures, and a precipitating factor is often recognised, such
as acute myocardial ischaemia, or uncontrolled hypertension. In this circumstance, the
oedema is localised predominantly to the pulmonary airspaces (pulmonary oedema), while
the total amount of fluid in the cardiovascular system remains unchanged.[3] For most
patients, however, congestion is a more generalised process that usually develops more
gradually (peripheral oedema), and its management will be the focus of discussion in this
review.
Chronic fluid accumulation is responsible for a substantial number of hospital admissions,
and identifies patients with a worse prognosis than those admitted due to a sudden increase in
LV filling pressures.[4] Peripheral congestion in patients with heart failure usually develops
over weeks or even months, and patients may present ‘acutely’ having gained over 20 litres
of excess fluid, and hence over 20 kg of excess weight. The aim of management is to remove
the excess fluid, so that the patient is no longer congested when they leave hospital, now
transitioning to a diagnosis of ‘chronic HF (CHF)’. However, for many patients, some degree
of congestion remains even with treatment,[5,6] and it is not clear how many patients with
CHF have subclinical congestion – that is, have an excess of body fluid falling short of the
volume required to cause overt peripheral oedema.

Why Do Patients with Heart Failure Retain Fluid?

The development of peripheral oedema in patients with HF is related to fluid excess. As the
heart starts to fail, renal perfusion falls. The kidneys respond by increasing the production of
renin, leading to more aldosterone production, which is consequently followed by sodium and
water retention.[7] Arginine vasopressin (AVP) is also released,[8,9] further enhancing fluid
retention and stimulating thirst. The activation of the renin–angiotensin–aldosterone and AVP
systems maintain cardiac preload (more fluids) and afterload (vasoconstriction, mainly due to
angiotensin II), thereby maintaining the homeostasis of the cardiovascular system but at a
cost of increased systemic venous pressure (VP). The heart itself tends to worsen with time as
the failing LV tends to dilate, as does the left atrium, particularly if mitral regurgitation
develops. The elevated VP can further reduce renal blood flow as the gradient between mean
renal arterial pressure (often itself decreased by the HF process) and VP declines. Glomerular
filtration rate falls, enhancing and perpetuating the vicious cycle.

How Do We Identify Congestion?

The accumulation of fluids is a gradual process. In normal circulation, there is continuous
filtration of fluid from the intravascular space into the tissues at a rate dependent on the
gradient between the intravascular and extravascular hydrostatic pressure. Any filtered fluid
is then drained by the lymphatics. Overt cardiogenic peripheral oedema develops because the
fluid retention results in an increase in intravascular hydrostatic pressure and a commensurate
increase in the filtration rate, which eventually exceeds the capacity of the lymphatics to
drain fluid away (see Figure 1).

Figure 1:
A Simplified Pathophysiology of Pulmonary Oedema or Peripheral Oedema
Development in Patients with HFREF or HeFNEF
HeFNEF = heart failure with normal ejection fraction; HFREF = heart failure with reduced
ejection fraction; LV= left ventricular.
Some patients do not present until they have developed widespread peripheral oedema. In
such cases the need for medical intervention is obvious. However, a substantial number of
cases of subclinical congestion will not be clinically recognised, despite the presence of
symptoms (i.e. breathlessness). In patients with no known cardiac disease, particularly in
older people,[11,12] the identification of subclinical congestion (and underlying cardiac
dysfunction) at an earlier stage might change the trajectory of the disease. In patients who are
already known to have HF, whether subclinical congestion is important is not clear.
It used to be said that assessment by an experienced clinician is probably adequate to
determine fluid status.[13] However, the art of clinical examination is declining, partly
because of the widespread availability of echocardiography and other functional or
biochemical tests, partly because accurate assessment can take a long time, particularly in
patients with poor mobility, and partly because clinical signs are not often specific for the
disease; all of this leads to doctors being less skilled in clinical assessment.[14] Moreover,
clinicians often disagree when faced with typical signs of HF, which may have an unreliable
relationship to diagnostic findings, including chest X-rays.[15] Nevertheless, a well-
conducted clinical examination in patients with suspected HF is still a powerful tool to
identify sicker patients who have a worse prognosis, irrespective of their LVEF.[16]
The most reliable clinical sign indicating volume overload is a raised jugular venous pressure
(JVP), which also provides powerful prognostic information.[17] However, the clinical
assessment of the JVP is often challenging and subjective[18] and its assessment by
ultrasound might thus be useful. In the vast majority of cases, assessing the jugular vein by
ultrasound is possible and allows the identification of patients with more advanced
congestion and higher natriuretic peptides (NPs),[19] who are at higher risk of adverse
outcomes.[20] Assessing the inferior vena cava diameter by echocardiography provides
complementary information to clinical examination, is validated against invasively measured
haemodynamics and is readily available in echocardiographic departments.[21,22]
The use of NPs as a measure of cardiac dysfunction is advised by current guidelines. NPs are
one of the body’s defences against congestion.[23] Any stretch of the myocardium leads to an
increase in NP level, and raised levels in a treated patient suggests that there is residual
congestion, regardless of LVEF. It is important to remember that circulating plasma levels
should be adjusted for age and that co-morbidities, including atrial fibrillation, renal
dysfunction and obesity, may influence NP levels.[24] In clinical settings without easy access
to echocardiography, measuring the NP level is a simple and reliable tool, efficient in terms
of patient and staff time. Serial NP assessment at home is feasible with a finger-stick test and
this approach in high-risk patients might detect possible decompensation early.[25]
Invasive devices have potential as tools to predict congestion.[26] Possible variables that can
be measured include trans-thoracic impedance, pulmonary artery pressure and left atrial (LA)
pressure. Implantable devices, such as cardiac resynchronisation therapy (CRT) pacemakers
and/or defibrillators (ICDs) can measure intrathoracic impedance, thus estimating pulmonary
congestion, but their predictive value is still uncertain.[27]
In the HOMEOSTASIS trial, measurements of LA pressure were taken twice daily in 40
patients with advanced HF. After the first 3 months, treatment was personalised based on the
readings, which led to a fall in LA pressure (17.6 mmHg in the first 3 months to 14.8 mmHg;
P =0.003), the prescription of higher doses of angiotensin-converting-enzyme inhibitors
(ACE-I) and beta-blockers, a lesser need for high doses of loop diuretics and improvement in
both New York Heart Association (NYHA) class and LVEF.[28]
In the CHAMPION trial, pulmonary arterial pressure was measured daily using wireless
devices permanently implanted into the pulmonary artery. There was a 37 % decrease in the
number of hospitalisations for HF over the 15 months of follow-up.[29]
An objective measure of ‘congestion’ might be helpful not only to allow physicians to tailor
treatments to specific targets, but also to allow more reproducible randomised controlled
trials designed to assess decongestive strategies, particularly when markers of cardiac
dysfunction (such as LVEF) are not significantly impaired. For example, the ALDO-DHF
and TOPCAT trials in patients with HeFNEF suggested that while spironolactone might
worsen renal function and anaemia in patients with low circulating NPs (and thus,
presumably, little congestion), it significantly reduced HF hospitalisations in patients with
higher N-terminal of the prohormone brain natriuretic peptide (NT-proBNP).[30,31] The
majority of HF trials nowadays include raised NPs as a major criterion for enrolment
Sumber : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490880/

8. Define clinical manifestations of heart failure

Heart failure — sometimes known as congestive heart failure — occurs when the heart
muscle doesn't pump blood as well as it should. When this happens, blood often backs up and
fluid can build up in the lungs, causing shortness of breath. Certain heart conditions, such as
narrowed arteries in the heart (coronary artery disease) or high blood pressure, gradually
leave the heart too weak or stiff to fill and pump blood properly. Proper treatment can
improve the signs and symptoms of heart failure and may help some people live longer.
Lifestyle changes — such as losing weight, exercising, reducing salt (sodium) in your diet
and managing stress — can improve your quality of life. However, heart failure can be life-
threatening. People with heart failure may have severe symptoms, and some may need a heart
transplant or a ventricular assist device (VAD). One way to prevent heart failure is to prevent
and control conditions that can cause it, such as coronary artery disease, high blood pressure,
diabetes and obesity.

Symptoms

Heart failure

Heart failure can be ongoing (chronic), or it may start suddenly (acute). Heart failure signs
and symptoms may include:

 Shortness of breath with activity or when lying down

 Fatigue and weakness
 Swelling in the legs, ankles and feet
 Rapid or irregular heartbeat
 Reduced ability to exercise
 Persistent cough or wheezing with white or pink blood-tinged mucus
 Swelling of the belly area (abdomen)
 Very rapid weight gain from fluid buildup
 Nausea and lack of appetite
 Difficulty concentrating or decreased alertness
 Chest pain if heart failure is caused by a heart attack

Causes

Heart failure often develops after other conditions have damaged or weakened the heart.
However, heart failure can also occur if the heart becomes too stiff. In heart failure, the main
pumping chambers of the heart (the ventricles) may become stiff and not fill properly
between beats. In some people, the heart muscle may become damaged and weakened. The
ventricles may stretch to the point that the heart can't pump enough blood through the body.
Over time, the heart can no longer keep up with the typical demands placed on it to pump
blood to the rest of the body.

Heart failure can involve the left side (left ventricle), right side (right ventricle) or both sides
of your heart. Generally, heart failure begins with the left side, specifically the left ventricle
— your heart's main pumping chamber.

Type of heart failure Description

Left-sided heart failure Fluid may back up in the lungs, causing

shortness of breath.

Right-sided heart failure Fluid may back up into the abdomen, legs and
feet, causing swelling.

Systolic heart failure (also called heart failure The left ventricle can't contract vigorously,
with reduced ejection fraction) indicating a pumping problem.

Heart failure with preserved ejection fraction The left ventricle can't relax or fill fully,
indicating a filling problem.

Any of the following conditions can damage or weaken your heart and can cause heart
failure. Some of these can be present without your knowing it:

 Coronary artery disease and heart attack. Coronary artery disease is the most
common form of heart disease and the most common cause of heart failure. The
disease results from the buildup of fatty deposits in the arteries, which reduces blood
flow and can lead to heart attack.

A heart attack occurs suddenly when a coronary artery becomes completely blocked.
Damage to your heart muscle from a heart attack may mean that your heart can no
longer pump as well as it should.
  High blood pressure. If your blood pressure is high, your heart has to work harder
than it should to circulate blood throughout your body. Over time, this extra exertion
can make your heart muscle too stiff or too weak to properly pump blood.

 Faulty heart valves. The valves of the heart keep blood flowing in the proper
direction. A damaged valve — due to a heart defect, coronary artery disease or heart
infection — forces the heart to work harder, which can weaken it over time.

 Damage to the heart muscle. Heart muscle damage can have many causes, including
certain diseases, infection, heavy alcohol use, and the toxic effect of drugs, such as
cocaine or some drugs used for chemotherapy. Genetic factors also can play a role.

 Inflammation of the heart muscle (myocarditis). Myocarditis is most commonly

caused by a virus, including the COVID-19 virus, and can lead to left-sided heart
failure.

 A heart problem that you're born with (congenital heart defect). If your heart and
its chambers or valves haven't formed correctly, the healthy parts of your heart have to
work harder to pump blood, which may lead to heart failure.

 Abnormal heart rhythms (arrhythmias). Abnormal heart rhythms may cause your

heart to beat too fast, creating extra work for your heart. A slow heartbeat also may
lead to heart failure.

 Other diseases. Long-term diseases — such as diabetes, HIV, an overactive or

underactive thyroid, or a buildup of iron or protein — also may contribute to chronic
heart failure.

Causes of sudden (acute) heart failure also include:

 Allergic reactions

 Any illness that affects the whole body

 Blood clots in the lungs

 Severe infections

 Use of certain medications

 Viruses that attack the heart muscle

Risk factors
A single risk factor may be enough to cause heart failure, but a combination of factors also
increases your risk.

Risk factors for heart failure include:

 Coronary artery disease. Narrowed arteries may limit your heart's supply of oxygen-
rich blood, resulting in weakened heart muscle.

 Heart attack. A heart attack is a form of coronary artery disease that occurs
suddenly. Damage to your heart muscle from a heart attack may mean your heart can
no longer pump as well as it should.

 Heart valve disease. Having a heart valve that doesn't work properly raises the risk of
heart failure.

 High blood pressure. Your heart works harder than it has to if your blood pressure is
high.

 Irregular heartbeats. These abnormal rhythms, especially if they are very frequent

and fast, can weaken the heart muscle and cause heart failure.

 Congenital heart disease. Some people who develop heart failure were born with
problems that affect the structure or function of their heart.

 Diabetes. Having diabetes increases your risk of high blood pressure and coronary
artery disease. Don't stop taking any medications on your own. Ask your doctor
whether you should make changes.

 Some diabetes medications. The diabetes drugs rosiglitazone (Avandia) and

pioglitazone (Actos) have been found to increase the risk of heart failure in some
people. Don't stop taking these medications on your own, though. If you're taking
them, ask your doctor if you need to make any changes.

 Certain other medications. Some medications may lead to heart failure or heart

problems. They include nonsteroidal anti-inflammatory drugs (NSAIDs); certain
anesthesia medications; and certain medications used to treat high blood pressure,
cancer, blood conditions, irregular or abnormal heartbeats, nervous system diseases,
mental health conditions, lung and urinary problems, inflammatory diseases, and
infections.

 Alcohol use. Drinking too much alcohol can weaken the heart muscle and lead to
heart failure.
  Sleep apnea. The inability to breathe properly while you sleep results in low blood-
oxygen levels and an increased risk of irregular heartbeats. Both of these problems can
weaken the heart.

 Smoking or using tobacco. If you smoke, quit. Using tobacco increases your risk of
heart disease and heart failure.

 Obesity. People who have obesity have a higher risk of developing heart failure.

 Viruses. Certain viral infections can cause damage to the heart muscle.

Complications

Complications of heart failure depend on the severity of heart disease, your overall health and
other factors such as your age. Possible complications can include:

 Kidney damage or failure. Heart failure can reduce the blood flow to your kidneys,
which can eventually cause kidney failure if left untreated. Kidney damage from heart
failure can require dialysis for treatment.

 Heart valve problems. The valves of the heart, which keep blood flowing in the right
direction, may not work properly if your heart is enlarged or if the pressure in your
heart is very high due to heart failure.

 Heart rhythm problems. Heart rhythm problems may lead to or increase your risk of
heart failure.

 Liver damage. Heart failure can cause fluid buildup that puts too much pressure on
the liver. This fluid backup can lead to scarring, which makes it more difficult for your
liver to work properly.

Sumber : https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-
causes/syc-20373142

9. Describe management of heart failure

Medications

 Angiotensin-converting enzyme (ACE) inhibitors. These drugs relax blood vessels

to lower blood pressure, improve blood flow and decrease the strain on the heart.
Examples include enalapril (Vasotec, Epaned), lisinopril (Zestril, Qbrelis, Prinivil) and
captopril.

 Angiotensin II receptor blockers. These drugs, which include losartan (Cozaar),

valsartan (Diovan) and candesartan (Atacand), have many of the same benefits
 as ACE inhibitors. They may be an option for people who can't
tolerate ACE inhibitors.

 Beta blockers. These drugs slow your heart rate and reduce blood pressure. Beta
blockers may reduce signs and symptoms of heart failure, improve heart function, and
help you live longer. Examples include carvedilol (Coreg), metoprolol (Lopressor,
Toprol-XL, Kapspargo Sprinkle) and bisoprolol.

 Diuretics. Often called water pills, diuretics make you urinate more frequently and
keep fluid from collecting in your body. Diuretics, such as furosemide (Lasix), also
decrease fluid in your lungs so you can breathe more easily.

Because diuretics make your body lose potassium and magnesium, your doctor may
also prescribe supplements of these minerals. If you're taking a diuretic, your doctor
will likely monitor levels of potassium and magnesium in your blood through regular
blood tests.

 Aldosterone antagonists. These drugs include spironolactone (Aldactone, Carospir)

and eplerenone (Inspra). These are potassium-sparing diuretics that have additional
properties that may help people with severe systolic heart failure live longer.

Unlike some other diuretics, spironolactone and eplerenone can raise the level of
potassium in your blood to dangerous levels, so talk to your doctor if increased
potassium is a concern, and learn if you need to modify your intake of food that's high
in potassium.

 Inotropes. These medications are given by IV to people with severe heart failure who
are in the hospital. Inotropes help the heart pump blood more effectively and maintain
blood pressure.

 Digoxin (Lanoxin). This drug, also called digitalis, increases the strength of your
heart muscle contractions. It also tends to slow the heartbeat. Digoxin reduces heart
failure symptoms in systolic heart failure. It may be more likely to be given to
someone with a heart rhythm problem, such as atrial fibrillation.

 Hydralazine and isosorbide dinitrate (BiDil). This drug combination helps relax

blood vessels. It may be added to your treatment plan if you have severe heart failure
symptoms and ACE inhibitors or beta blockers haven't helped.

 Vericiguat (Verquvo). This newer medicine for chronic heart failure is taken once a
day by mouth. It's a type of drug called an oral soluble guanylate cyclase (sGC)
stimulator. In studies, people with high-risk heart failure who took vericiguat had
 fewer hospital stays for heart failure and heart disease-related deaths compared with
those who received an inactive pill (placebo).

 Other medications. Your doctor may prescribe other medications to treat specific

symptoms. For example, some people may receive nitrates for chest pain, statins to
lower cholesterol or blood-thinning medications to help prevent blood clots.

Surgery or other procedures

Surgery or other procedures to implant cardiac devices may be recommended to treat the
underlying problem that led to heart failure. Surgery or other procedures for heart failure may
include:

 Coronary bypass surgery. If severely blocked arteries are causing your heart failure,
your doctor may recommend coronary artery bypass surgery. The procedure involves
taking a healthy blood vessel from your leg, arm or chest and connecting it below and
above the blocked arteries in your heart. The new pathway improves blood flow to
your heart muscle.

 Heart valve repair or replacement. If a faulty heart valve causes your heart failure,
your doctor may recommend repairing or replacing the valve. Surgeons can repair the
valve by reconnecting valve flaps or by removing excess valve tissue so that the
leaflets can close tightly. Sometimes repairing the valve includes tightening or
replacing the ring around the valve.

Heart valve repair or replacement may be done as open-heart surgery, a minimally

invasive surgery or a heart procedure using flexible tubes called catheters (cardiac
catheterization).

 Implantable cardioverter-defibrillators (ICDs). An ICD is used to prevent

complications of heart failure. It isn't a treatment for heart failure itself. An ICD is a
device similar to a pacemaker. It's implanted under the skin in your chest with wires
leading through your veins and into your heart.

The ICD monitors the heart rhythm. If the heart starts beating at a dangerous rhythm,
or if your heart stops, the ICD tries to pace your heart or shock it back into normal
rhythm. An ICD can also work as a pacemaker and speed your heart up if it is going
too slow.

 Cardiac resynchronization therapy (CRT). Also called biventricular

pacing, CRT is a treatment for heart failure in people whose lower heart chambers
(ventricles) aren't pumping in sync with each other. A device called a biventricular
 pacemaker sends electrical signals to the ventricles. The signals trigger your ventricles
to contract in a more coordinated way, which improves the pumping of blood out of
your heart. CRT may be used with an ICD.

 Ventricular assist devices (VADs). A VAD — also known as a mechanical

circulatory support device — is a device that helps pump blood from the lower
chambers of your heart (ventricles) to the rest of your body. Although a VAD can be
placed in one or both ventricles of your heart, it is most frequently implanted in the left
ventricle.

Your doctor may recommend a VAD if you're waiting for a heart transplant.
Sometimes, a VAD is used as a permanent treatment for people who have heart failure
but who aren't good candidates for a heart transplant.

 Heart transplant. Some people have such severe heart failure that surgery or
medications don't help. These people may need to have their hearts replaced with a
healthy donor heart.

Sumber : https://www.mayoclinic.org/diseases-conditions/heart-failure/diagnosis-
treatment/drc-20373148

10. Pharmacology of the drugs used in management of heart failure

Treatment Goals
Traditionally, treatments for heart failure have concentrated on relieving the effects of fluid
retention (pulmonary and peripheral oedema) with diuretics and on increasing contractility of
the myocardium with digoxin. Now a wider range of approaches is available to modulate
most of the various compensatory systems that are activated in heart failure. The aims of
treatment are:
 to improve symptoms
 to improve functional capacity
 to improve quality of life
 to increase survival.
Much can be done to improve the condition and prognosis of a patient with heart failure
without using drugs. Dietary salt restriction, avoidance of alcohol, a planned exercise
programme and weight loss have all been shown to be beneficial. Both surgical
reconstruction of the myocardium and sophisticated biventricular pacing devices can also
play a part. However, drug treatment forms the cornerstone of the management of a patient
with chronic heart failure and very significant advances have been made in the last 20 years
in our understanding of which drugs to use in particular circumstances. This increased
understanding has led to dramatic improvements in the outlook for patients with heart failure:
the annual mortality rate for patients with moderate (Class II–III) heart failure has fallen by
more than 50% in 20 years.
The evidence-base is reviewed in this paper regarding the different pharmacological
approaches to the management of heart failure. An attempt to draw all the data together to
provide some recommendations on how the various drugs may be used alone or in
combination to the best effect in different types of patient has also been done. Some
important questions remain unanswered, particularly about the relevance of the (largely
American and European) evidence-base to Malawian patients.

Diuretics
Diuretics have been a fundamental part of the treatment of heart failure for decades. In fact,
because the use of diuretics was well established before the advent of controlled clinical trials
and evidence-based practice, there is little formal evidence of their effectiveness. But
virtually all patients with heart failure receive diuretics and all those who took part in the
trials that have demonstrated the effectiveness of Angiotensin Concerting Enzyme (ACE)
inhibitors, β-blockers and the other drugs discussed below were taking diuretics in addition to
the test drug. So it is standard practice to give a patient with heart failure a thiazide or loop
diuretic, with the addition of the potassium sparing agents amiloride, or triamterene
depending on the degree of oedema and the intensity of the effect that is required - as well as
another drug.1,2

Vasodilators
Venous and arterial vasodilators reduce pre-load and after-load on the heart, respectively.
They should thereby relieve heart failure. Two groups of vasodilators have been studied
systematically: a combination of hydralazine and isosorbide dinitrate and the ACE inhibitors.
The latter have many other effects in addition to vasodilatation.
Two large, controlled studies performed in the USA determined the effects of hydralazine 75
mg four times a day (37.5 mg qid for first two weeks) and isosorbide dinitrate 40 mg four
times a day (20 mg qid for first two weeks). The Vasodilator-Heart Failure Trial I (VHeFT I)
compared the vasodilators (and prazosin) with placebo in patients with NYHA Class I–III
heart failure (LVEF ≤45%) who were allowed to continue using digoxin and diuretics but
who were not allowed long-acting nitrates, calcium antagonists, β-blockers or
antihypertensive drugs. 3 After one year, mortality in the placebo treated patients was 20%
while it was only 12% in the patients treated with the hydralazine and isosorbide. It is
interesting to note that black (American) patients benefited more from the vasodilators than
the white patients did. There was no benefit from prazosin.
VHeFT II compared the same hydralazine-isosorbide regimen with the ACE inhibitors
enalapril 5–10mg twice daily in a similar population. Enalapril produced a lower mortality at
two years (18%) than the hydralazine-isosorbide combination (25%). The lower mortality
with Enalapril was due to a reduction in sudden death and was more prominent in patients
with less severe heart failure (Class I or II). White patients responded very much better to the
ACE inhibitors than black patients.4 Unfortunately, the benefits of treatment with hydralazine
and isosorbide have not been studied in depth since these VHeFT trials were reported some
15 years ago. We are therefore left to speculate about the possibility that these two drugs
could be particularly helpful to black (Malawian) patients with heart failure.

ACE inhibitors
ACE inhibitors have many properties that make them very effective drugs for the treatment of
heart failure. By virtue of their ability to reduce circulating angiotensin II levels, they are
vasodilators that reduce both preload and afterload; they reduce sympathetic stimulation; they
have an anti-proliferative effect and thereby affect ventricular remodeling and reduce left
ventricular mass.
In addition to VHeFT II, there have been four, important, large studies of the effects of ACE
inhibitors in heart failure. The Cooperative North Scandinavian Enalapril Survival Study
(CONSENSUS) showed a 40% (p = 0.002) reduction in mortality at 6 months in Class IV
patients treated with enalapril 5–20mg twice daily. At 1 year, mortality was reduced by 31%
(p = 0.001). The effect on mortality was due to a reduction in death from progression of heart
failure rather than sudden death.5 All the patients received diuretics in addition to the trial
treatment, 94% also received digitalis and 50% received vasodilators, mainly isosorbide.
The SOLVD (Studies of Left Ventricular Dysfunction) Treatment trial6 showed that enalapril
(2.5 – 10mg twice daily), added to conventional therapy (though an effort was made to
discontinue use of non-ACE inhibitor vasodilators) significantly reduced mortality risk by
16% (35.2% enalapril v. 39.7% place bo) in the treatment of mild to moderate heart failure,
with most of the benefit being attributed to the reduction in risk of death due to progressive
heart failure. The risk of death or hospitalization for progressive heart failure was also lower
in the enalapril treated group.
The SOLVD Prevention trial looked at the use of enalapril in patients with asymptomatic left
ventricular dysfunction (LVEF< 36%) who were not receiving any drug treatment for their
heart failure.7 Combined mortality and cases of heart failure were significantly lower in the
enalapril group compared with placebo (relative risk reduction 29%). However, the
reductions in all-cause mortality and death from cardiovascular causes with enalapril were
not significantly different from placebo. The absolute survival benefit of enalapril over
placebo in the three year course of the SOLVD trials was about 8%, equivalent to one life
saved for every 300 patients treated per year.
An overview of the effects of ACE inhibitors on mortality and morbidity in patients with
heart failure from 32 randomised trials and a total of 7,105 patients has been published.8 A
number of ACE inhibitors were used in these trials and the analysis was conducted with the
assumption that an ACE inhibitor class-effect was responsible for the effects observed in the
trials. This is not necessarily the case.9 However, overall there was a statistically significant
reduction in total mortality (odds ratio 0.77, p<0.001) and in the combined end-point of
mortality plus hospitalization for CHF (odds ration 0.65, p=0.001). Patients with the lowest
left ventricular ejection fraction appeared to gain the greatest benefit. The greatest effect was
seen during the first three months of treatment but additional benefit was seen during further
treatment. The reduction in death was mainly due to the reduction in deaths due to
progressive heart failure.
There is good evidence, therefore, to support the use of ACE inhibitors in patients with
moderate or severe congestive heart failure. There are some concerns, however. A reanalysis
of the data from the SOLVD studies has just been published10, suggesting that there may be
racial differences in the response of patients to ACE inhibitors. Enalapril treatment in this
trial was associated with a 44% reduction in the risk of hospitalization for heart failure in the
white patients (p<0.001) but was without significant effect in black patients. Similarly,
enalapril treatment produced significant reductions in systolic and diastolic blood pressure in
the white patients but not in the black patients.
Compliance with ACE inhibitors treatment is also disappointing. Many doctors are failing to
give these drugs to their patients with heart failure, even though their useful effects have been
known for over five years. And patients who are prescribed them often fail to take them -
maybe because of the common occurrence of a troublesome cough, a side-effect of ACE
inhibitors that has been attributed to their effect on kinin degradation.
When ACE inhibitors are prescribed for heart failure they are often given in doses which may
be appropriate for the treatment of hypertension but which are lower than those studied in the
definitive heart failure trials.11 Thus, CONSENSUS, VHeFT II and SOLVD used doses of
enalapril of about 15mg daily, whereas doses of 2.5–5mg are routinely used in clinical
practice. One study of lisinopril has explored this issue. The ATLAS (Assessment of
Treatment with Lisinopril and Survival) trial in patients with moderate or severe heart failure
(LVEF £30% despite treatment with diuretics for ≥2 months) added a low or a high dose of
lisinopril to the treatment of patients who were already receiving diuretics and digoxin. The
higher dose of the drug (about 35mg daily) reduced all cause mortality and all cause
hospitalization by 12% compared with the low dose (about 5mg).12

Spironolactone
Aldosterone has many properties in addition to promoting sodium reabsorption in the distal
nephron. Many of its effects may precipitate or exacerbate heart failure. Aldosterone
increases the excitability and contractility of cardiac myocytes; it increases the reactivity of
vascular smooth muscle; it promotes the growth of fibroblasts; it increases the turnover of
collagen.13,14 There are good grounds, therefore, to expect an aldosterone antagonist to have
useful effects in patients with heart failure. The RALES (Randomised Aldactone Evaluation
Study) trial took 1663 patients with symptomatic congestive heart failure (LVEF ≤35%),
receiving standard care with a diuretic plus an ACE inhibitor and compared the effects of
addition of spironolactone (mean dose 25mg daily) or placebo. Spironolactone reduced the
overall risks of death, death due to progressive heart failure and sudden cardiac death all by
about 30%. It also reduced rates of hospitalization.15 This is a very impressive result, which
led to early termination of the study, and it would argue for inclusion of spironolactone in the
treatment regimen for most patients with heart failure, were it not for the relatively high
incidence of side effects (gynaecomastia etc) experienced by the patients in this trial.
Eplerenone is a “selective” aldosterone receptor antagonist that should be free of those side
effects of spironolactone which are due to the latter's antagonism of oestrogen and androgen
receptors. A mortality study is currently being performed with eplerenone in patients with
symptomatic heart failure.

β- blockers
Activation of the sympathetic nervous system plays an important part in the pathogenesis of
heart failure and therapeutic modulation of sympathetic activity has a correspondingly
important role in the management of the syndrome. Some effects of sympathetic activity are
beneficial to the patient with heart failure and it is for this reason that β-adrenoreceptor
blocking drugs were contra-indicated in patients with heart failure, particularly on account of
their negative inotropic activity. Thus, nor-adrenaline has a positive inotropic effect and it
causes vasoconstriction of non-essential blood vessels. However, it is now appreciated that
prolonged increases in sympathetic drive are harmful. Chronic elevations in the levels of
circulating noradrenaline damage the myocardium by causing it to hypertrophy (leading to
decreased compliance), they cause myocardial ischaemia, and they are directly toxic to
cardiac myocytes. Even effects that used to be thought to be beneficial are now seen to be
generally harmful, for example peripheral vasoconstriction increases afterload.
For these reasons β-blockers have now been used extensively in the management of heart
failure due to left ventricular dysfunction and there is very good evidence of their
effectiveness, at least in the milder forms of this disease.17,18 There has been a lingering
concern that sympathetic drive may be essential to keep the heart working at all in very
severe heart failure and the use of β- blockers at this end of the heart failure spectrum has
therefore been very limited. Now, new mixed _- and β-adrenoreceptor blocking drugs have
been shown to be useful even in severe heart failure. For mild or moderately severe heart
failure, metaanalyses of trials of β- blockers involving more than 15,000 patients and more
than 2000 deaths have provided convincing evidence of a marked effect of β- blockers on
both morbidity and mortality from heart failure. 17,18 These meta-analyses suggest that for
every 100 patients treated for one year about 4 lives will be saved and four admissions to
hospital will be avoided.18,19 β-blockers have an effect as great as or greater than that of ACE
inhibitors. Most patients however, in trials of β- blockers were already taking ACE inhibitors,
so the benefits of β- blockade appear to be additional to those of the ACE inhibitors. A recent
study in patients with heart failure has shown that concentrations of angiotensin II are lower
in patients who are taking β- blockers as well as ACE inhibitors than they are in patients
taking the latter alone - providing support for the use of combinations of these two classes of
drug.20 Cardio-selectivity does not influence the effects of the β- blockers in this situation;
thus propranolol a non-selective β- blocker and atenolol and metoprolol, β1 (cardio) selective
β- blockers, all of which are available in Malawi may be helpful to patients with Class I–III
heart failure, although they are not approved for this use in the UK or the USA. β- blockers
are of limited use, and may be dangerous, in acute exacerbations of heart failure, so initiation
of β- blocker therapy is not recommended in patients with no haemodynamic reserve, as
indicated by obvious fluid retention, symptoms at rest or recent admission to hospital for
decompensated heart failure.18 They are best reserved as part of a strategy for preventing
heart failure; they are best used in patients with milder symptoms to delay deterioration and
to increase the length and quality of life. Like ACE inhibitors, β- blockers need to be started
in low doses18; they also require slow titration over weeks or months before patients can
attain maintenance doses: start low and go slow.17 Once again there are suggestions of racial
differences in the patients' responses to these drugs. In this case, black patients appear to
benefit less from β- blockers than white patients do.
Carvedilol is a non-selective β- blocker, an _1- blocker and an endothelin ET-1 antagonist. It
is the only β- blocker that has received regulatory approval for use in heart failure. It has been
compared with placebo in a double-blind trial in 2289 patients with severe heart failure
(LVEF < 25%) over a mean duration of 10.4 months.21,22 The patients continued to receive
diuretics and ACE inhibitors or an All antagonist but were excluded if they had required an _-
blocker, a β- blocker, a Class I antiarrythmic drug or a calcium channel blocker in the
previous few weeks. The trial was stopped early because of the very good effects of
carvedilol, which produced a 35% mean reduction in risk of death (cumulative risk of death
at one year 18.5% placebo v. 11.4% carvedilol) and a halving in the risk of worsening of
heart failure. White and black patients derived roughly equal benefit from this drug.23 There
have been no direct comparisons of carvedilol and metoprolol, which is the β- blocker most
commonly prescribed for heart failure in the USA but one authority believes that such data as
are available do not suggest any major clinical difference between the two drugs.18
One recent study has examined the effects of carvedilol, metoprolol and placebo on
myocardial gene expression in patients with heart failure due to idiopathic dilated
cardiomyopathy.24 The effects of the treatments on three different groups of genes involved in
the regulation of contractility were examined. Gene expression in all three groups was
initially abnormal in these patients. Both β- blockers improved left ventricular function
(Ejection Fraction) and produced favourable changes in the genes implicated in loss of
contractile function and in pathological hypertrophy of the myocardium. There were no
qualitative differences between metoprolol and carvedilol in their effects on any
measurement, and both were better than placebo. The uthors suggest that β- adrenergic
stimulation contributed to induction of pathological gene expression which was reversed by
β- blockade more comprehensively and more frequently than by placebo treatment.

Digoxin
After years of controversy digoxin is regaining credibility as a treatment for heart failure. Its
place in the management of atrial fibrillation has never been seriously challenged. The
rehabilitation of digoxin follows from the results of the DIG (Digitalis Investigation Group)
study performed in the USA.25 In this study, digoxin increased cardiac contractility, increased
cardiac output, decreased filling pressures and volumes and decreased peripheral resistance.
It did not reduce all-cause mortality in heart failure but it reduced mortality due to worsening
heart failure, and hospitalization for worsening heart failure was also significantly reduced. It
appears that digoxin increased the risk of sudden death (arrythmias and myocardial
infarction) but reduced mortality due to worsening heart failure - leaving patients with a
choice to make between quality and duration of life expectancy. The best responses were
found in patients with more severe heart failure.

Inotropic agents
Digoxin is still the only positive inotrope available for long-term oral use and its role is only
just being redefined. Other drugs have been tried too, in the expectation that positive
inotropic stimulation of the failing heart would improve cardiac performance. In fact there
has been a long series of disappointments (vesnarinone, milrinone, flosequinan, etc.) and
some evidence that inotropic drugs can increase mortality rather than reduce it. With the
exception of digoxin, positive inotropic drugs have no place in the management of chronic
heart failure.

Conclusions
How should we be managing our patients with heart failure? Before reaching any conclusions
we should remember two weaknesses in the data available to help us. First, the evidence to
support the use of diuretics is weak by modern standards. Second, from the perspective of the
Malawian patient there is virtually no directly relevant evidence to support the use of ACE
inhibitors, β- blockers, vasodilators, digoxin or aldosterone antagonists. This is because all
the definitive trials with these drugs have been performed in the USA, Europe or Australasia.
There is some evidence that black and white patients respond differently to each of these
types of drug, but the “black” patients who took part in the trials may have been at least as
different from Malawians as they are from the white participants in the trials. The differences
in response are, presumably, due to genetic polymorphisms and until the studies are repeated
in the appropriate population it is as well to remember that we are extrapolating results from
one population to another, and possibly a very different one.
With these caveats, there is a wealth of evidence that demonstrates the effectiveness - and
safety - of β- blockers, ACE inhibitors and vasodilators in patients with chronic congestive
heart failure. Only a couple of trials support the use of spironolactone or digoxin but they are
convincing.
Diuretics remain the first-line treatment in these patients, an ACE inhibitor, titrated to high
dose, should be added for the patient with moderate degrees of heart failure or for the patient
who does not respond well to the diuretic. Addition of a β-blocker, such as atenolol or
metoprolol, may help the patient whose heart failure is still poorly controlled or in whom
ACE inhibitors are contraindicated.
ACE inhibitors substantially reduce the risk of death for heart failure patients. One death is
prevented for every 74 patients who are treated with an ACE inhibitor for one year. The
combination of an ACE inhibitor plus a β- blocker prevents one death for every 21 patients
treated for one year.17
The two-year mortality rate in patients with mild or moderately severe heart failure and who
are treated with a diuretic plus digoxin is about 34%. Addition of an ACE inhibitor to this
regimen reduces the rate to about 22% and adding a β- blocker as well brings the rate down to
14%. Alternatively, adding a combination of hydralazine and isosorbide dinitrate to the
diuretic and digoxin is associated with a two-year mortality rate of 26%. Hydralazine and
isosorbide should be considered for the black patient who does not respond well to either
ACE inhibitor or β-blockers - or who cannot afford ACE inhibitors.
For the patient with severe heart failure the outlook is less encouraging. Treatment with a
diuretic and digoxin alone carries a six month mortality of 44%. This may be reduced to
about 20% by the addition of an ACE inhibitor and to 5–15% by further addition of
spironolactone and/or a β- blocker. However, the outcome in these patients is very variable
and it probably depends at least as much on individual patient characteristics as it does on the
treatment regimen that is chosen. Diuretics and ACE inhibitors are the mainstay of treatment
in these patients, with the addition of a β- blocker (preferably carvedilol), spironolactone and
digoxin depending on response.

Figure 1
Flow diagram illustrating the treatment options available for the management of chronic heart
failure
Sumber : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345495/

11. Describe the pathological changes of heart and vessel’s abnormalities

Cardiovascular diseases are conditions that affect the structures or function of your heart, such as:

 Abnormal heart rhythms, or arrhythmias
 Aorta disease and Marfan syndrome
 Congenital heart disease
 Coronary artery disease (narrowing of the arteries)
 Deep vein thrombosis and pulmonary embolism
 Heart attack
 Heart failure
 Heart muscle disease (cardiomyopathy)
 Heart valve disease
 Pericardial disease
 Peripheral vascular disease
 Rheumatic heart disease
 Stroke
 Vascular disease (blood vessel disease)

Cardiovascular disease is the leading cause of death in the U.S. It’s important to learn about your
heart to help prevent it. If you have it, you can live a healthier, more active life by learning about
your disease and taking care of yourself.
Types of cardiovascular disease can have various causes, so it’s important to know the difference.

Abnormal Heart Rhythms

The heart is an amazing organ. It beats in a steady, even rhythm, about 60 to 100 times each
minute. That's about 100,000 times each day. Sometimes your heart gets out of rhythm. Your
doctor calls an irregular or abnormal heartbeat an arrhythmia. An arrhythmia (also called a
dysrhythmia) can bring on an uneven heartbeat or a heartbeat that is either too slow or too fast.

Aorta Disease and Marfan Syndrome

The aorta is the large artery that leaves your heart and brings oxygen-rich blood to the rest of your
body. These two conditions can cause the aorta to widen or tear. This raises the chance of things
like:

 Atherosclerosis (hardened arteries)

 High blood pressure
 Connective tissue disorders that can weaken your blood vessel walls, such as scleroderma,
osteogenesis imperfecta, Ehlers-Danlos syndrome, and polycystic kidney disease 
 Injury
If you have aorta disease, you’ll need a team of specialists and surgeons to take part in your
treatment.

Cardiomyopathies
This is the term for diseases of the heart muscle. They’re sometimes simply called enlarged heart.
People with these conditions have hearts that are unusually big, thick, or stiff. Their hearts can’t
pump blood as well as they should. Without treatment, cardiomyopathies get worse. They can lead
to heart failure and abnormal heart rhythms.
Cardiomyopathy may sometimes run in families, but it can also be caused by high blood pressure,
diabetes, obesity, metabolic diseases, or infections.

Congenital Heart Disease

This is a problem in one or more parts of the heart or blood vessels. It happens before birth.
About 8 out of every 1,000 children get it. They may have symptoms at birth, but some people
with it don’t have symptoms until childhood or even adulthood.
In most cases, we don't know why it happens. Genes may play a role, or it can happen if a baby is
exposed to viral infections, alcohol, or drugs before it’s born.

Coronary Artery Disease

You may hear this called CAD. It’s when plaque builds up and hardens the arteries that give your
heart vital oxygen and nutrients. That hardening is also called atherosclerosis.

Deep Vein Thrombosis and Pulmonary Embolism

Blood clots can form in your deep veins, usually in your legs. This is deep vein thrombosis (DVT).
They can break loose and travel through your bloodstream to your lungs, where they can block
blood flow. This condition is called pulmonary embolism. It’s life threatening and needs
immediate medical attention.
You might be at higher risk of DVT because of your genes or family history. Other things that can
increase risk include sitting for a long time, like in a car or on a plane; long-term bed rest;
pregnancy; and using birth control pills or hormone replacement.

Heart Failure
This term can be scary. It doesn’t mean your heart has "failed," or stopped working. It means your
heart doesn’t pump as strongly as it should. This will cause your body to hold in salt and water,
which will give you swelling and shortness of breath.
Heart failure is a major health problem in the United States, affecting more than 6.5 million
people. It is the leading cause of hospitalization in people older than 65.
The number of people diagnosed with heart failure is projected to rise 46% by 2030, according to
the American Heart Association.

Heart Valve Disease

Your valves sit at the exit of each of your four heart chambers. They keep blood flowing through
your heart.
Sometimes, there are problems with these valves. Examples of heart valve problems include:
Aortic stenosis. Your aortic valve narrows. It slows blood flow from your heart to the rest of your
body.
Mitral valve insufficiency. Your mitral valve doesn’t close tightly enough. This causes blood to
leak backward, leading to fluid backup in the lungs.
Mitral valve prolapse. The valve between your left upper and left lower chambers doesn’t close
right.

Pericarditis
This condition is rare and means the lining surrounding your heart is inflamed. An infection often
causes this.
Rheumatic Heart Disease
This happens when rheumatic fever, an inflammatory disease that’s most common in children,
damages your heart valves.
Rheumatic fever starts with untreated strep throat and can affect many parts of your child’s body.
If your doctor thinks your child may have had rheumatic fever, they’ll do a physical exam and
give tests including X-rays and EKGs to look for heart damage.

Stroke
Strokes happen when something slows or blocks blood flow to your brain. Your brain can’t get the
oxygen and nutrients it needs, and brain cells start to die. When blood can’t get to the part of your
brain that controls a certain function, your body doesn’t work like it should.
A stroke can happen because of a blocked artery or a leaking or burst blood vessel. It needs
immediate treatment to limit brain damage and other complications.
Stroke is the leading cause of disability and one of the top causes of death in the United States.

Other Vascular Diseases

Your circulatory system is made up of the vessels that carry blood to every part of your body.
Vascular disease includes any condition that affects your circulatory system. These include
diseases of the arteries that go to your legs (peripheral vascular disease) and slow blood flow to
your brain, causing strokes.
Sumber : https://www.webmd.com/heart-disease/guide/diseases-cardiovascular

12. Overview of other vascular and heart disease

Vascular disease is any condition that affects the network of your blood vessels.
This network is known as your vascular or circulatory system. "Vascular" comes from a Latin
word for hollow container. If your entire network of blood vessels were stretched end-to-end, they
could circle the Earth multiple times.
Some of these vessels move blood. As your heart beats, it pumps blood with oxygen and nutrients
to feed your tissues and carry off waste. Arteries move blood away from the heart. Veins return it.
Lymph vessels and lymph nodes are part of a separate cleaning system that rids your body of
damaged cells. They also help protect you from infections and cancer. The vessels pick up fluid
from tissues throughout your body. That fluid drains back into veins under your collarbones.
Vascular diseases range from problems with your arteries, veins, and vessels that carry lymph to
disorders that affect how your blood flows. A disease can mean your tissues aren’t getting enough
blood, a condition called ischemia, as well as other serious, even life-threatening, problems.

Vascular Disease Types

Aneurysm
An aneurysm is a bulge in the wall of any blood vessel. It's most often seen in the aorta, the main
blood vessel leaving your heart. You can get an aortic aneurysm in your chest, where it's called
thoracic, or your belly, where it's called abdominal.
Small aneurysms generally pose no threat. But they put you at risk for other problems:

 Plaque deposits may build up where the aneurysm is.

 A clot may form there and then break off and get stuck somewhere else, which could be
very dangerous.
 The aneurysm might get bigger and press on other organs, which causes pain.

Because the artery wall is stretched and thinner at the spot of an aneurysm, it's fragile and could
burst under stress, like a balloon. The sudden rupture of an aortic aneurysm can be deadly.
Atherosclerosis and peripheral artery disease
Coronary arteries supply blood to your heart muscle. Peripheral arteries carry blood to other
tissues and organs. Both can have deposits of fat, cholesterol, and other substances on their inside
walls called plaque. Over time, plaque can build up, so the vessel becomes narrow and it’s harder
for blood to flow. Or a plaque could rupture, blocking blood flow.
Eventually, the artery will be so narrow that your tissues don't get enough blood. You can have
different symptoms and problems, based on where it happens. For example:

 Blockage in coronary arteries can cause chest pain (angina) or a heart attack.

 If it's in the carotid arteries that supply your brain, it can lead to a stroke or mini stroke,
which is called a transient ischemic attack (TIA).
 Blockage in the kidneys can lead to trouble with how they work, uncontrolled high blood
pressure, and heart failure.
 A blockage in your leg can lead to leg pain or cramps when you're active -- a condition
called claudication -- a skin color change, sores or ulcers, and your legs feeling tired.

When you don't have any blood flow to a part of your body, the tissues could die. If that happens,
you may lose a limb or an organ.
Blood clots in veins (VTE)
A blood clot in a vein inside a muscle -- usually in your lower leg, thigh, or pelvis -- is a deep vein
thrombosis (DVT). If the clot breaks loose and travels to your lungs, it becomes a pulmonary
embolism (PE). Your doctor may call these clots in your veins venous thromboembolisms, or
VTE.
Causes include:

 Conditions that slow blood flow or make blood thicker, such as congestive heart
failure and certain tumors
 Damaged valves in a vein
 Damaged veins from an injury or infection
 Genetic disorders that make your blood more likely to clot
 Hormones, such as estrogen from pregnancy and birth control pills
 Long bed rest or not being able to move much
 Surgery, especially some operations on your hips and legs

Damaged vein valves or a DVT can cause long-term blood pooling and swelling in your legs, too.
That problem is called chronic venous insufficiency. If you don't do anything about it, fluid will
leak into the tissues in your ankles and feet. Over time, it may make your skin break down and
wear away.
Blood clotting disorders
Some illnesses make your blood more likely to form clots. You could be born with one, or
something may happen to you. These types of disorders can cause:

 Higher-than-normal levels of clot-forming substances, including fibrinogen, factor 8, and

prothrombin
 Not enough blood-thinning (anticoagulant) proteins, including antithrombin, protein C,
and protein S
 Trouble breaking down fibrin, the protein mesh that holds clots together
 Damage to the endothelium, the lining of your blood vessels

Buerger's disease
This rare disease most often happens in the small and medium arteries and veins in your arms and
legs. They swell up and may form clots, cutting off blood supply to your fingers, hands, toes, or
feet. These body parts will hurt, even when you're resting. If it's severe, you might lose fingers or
toes.
Although we don’t know what causes it, there's a strong tie to tobacco use -- including cigars and
chewing tobacco -- and secondhand smoke.
Lymphedema
Your lymphatic system doesn't have a pump, the way your blood circulation system does. It relies
on valves in the vessels and muscle contractions to keep the lymph moving.
When vessels or nodes are missing or don't work right, fluid can build up and cause swelling, most
often in your arms or legs. This is called lymphedema.
Primary lymphedema is rare. It happens when you're born without certain lymph vessels or when
you have a problem with the tubes themselves.
When there’s a blockage or pause in your lymphatic system, it’s called secondary lymphedema. It
can happen because of:

 Cancer and cancer treatments, including radiation

 Deep vein thrombosis (DVT)
 Infection
 Scar tissue formation
 Serious injury
 Surgery

Peripheral venous disease and varicose veins

Unlike arteries, veins have flaps inside called valves. When your muscles contract, the valves
open, and blood moves through the tubes. When your muscles relax, the valves close so the blood
flows in only one direction.
Damaged valves may not close the way they should when your muscles relax. This allows blood
to flow in both directions, and it can pool.
This is what happens with varicose veins. They may bulge like purple ropes under your skin. They
can also look like small red or purple bursts on your knees, calves, or thighs. These spider veins
happen because of swollen small blood vessels called capillaries. After a day of activity, your legs
might ache, sting, or swell.
More women than men get varicose veins, and they often run in families. Pregnancy, being
very overweight, or standing for long times can cause them.
Because your blood is moving more slowly, it may stick to the sides of your veins, and clots can
form.
Raynaud's phenomenon (Raynaud's disease or Raynaud's syndrome)
When you're cold or excited, the small arteries of your fingers and your toes may twitch or cramp.
This can temporarily shut down blood supply to the area, making your skin look white or bluish
and feel cold or numb.
The working conditions of some jobs bring on Raynaud's. The symptoms could also be related to
other diseases, including lupus, rheumatoid arthritis, and scleroderma. People with Buerger’s
disease can also have Raynaud’s phenomenon.
Sumber : https://www.webmd.com/heart-disease/vascular-disease

Common types of heart disease include: 

 Coronary artery disease (CAD), also called coronary heart disease

o The most common type of heart disease in the U.S. 

o Affects the blood flow to the heart and can lead to a heart attack

 Arrhythmia 

o A change in the heart’s sequence of electrical impulses 

o Can result in heartbeats that are too fast (tachycardia), too slow (bradycardia),

or irregular (palpitations)

 Heart valve disease 

o Occurs when a valve in the heart is damaged or diseased

 Heart failure 

o A condition in which the heart does not work as well as it should, resulting in

fluid buildup
 o Heart failure does not mean the heart has stopped beating

What Are Symptoms of Heart Disease?

Coronary artery disease may not cause any symptoms. When symptoms do occur, they often
happen with exercise and may include:

 Pain, pressure, or discomfort in chest

 Pain, tingling, or discomfort in the arms, back, neck, jaw, or stomach

 Shortness of breath

 Heart attack (may be the first symptom of coronary artery disease)

o Heart attack is a medical emergency. If you experience any symptoms listed

below call 911 and get to a hospital’s emergency department immediately. 

o Pain, pressure, or discomfort in the center of the chest

o Pain, tingling, or discomfort the arms, back, neck, jaw, or stomach

o Shortness of breath

o Nausea

o Vomiting

o Belching 

o Indigestion/heartburn

o Sweating or cold, clammy skin

o Fast or uneven heartbeat

o Dizziness or lightheadedness

Arrhythmia may not cause any symptoms or only minor symptoms such as the feeling of a
skipped heartbeat or fluttering in the chest or neck. When symptoms do occur, they may
include:
  Fatigue 

 Weakness 

 Dizziness 

 Lightheadedness, fainting, or near-fainting spells 

 Rapid heartbeat or pounding in the chest 

 Shortness of breath 

 Anxiety 

 Chest pain or pressure 

 In severe cases, collapse and sudden cardiac arrest 

o Cardiac arrest is a medical emergency and can be fatal. If someone you know

is experience any symptoms listed below call 911 and get to a hospital’s

emergency department immediately. 

 Sudden loss of responsiveness 

 No normal breathing (not breathing at all or gasping for air)

Symptoms of heart valve disease include:

 Shortness of breath

 Fatigue

 Swelling in the feet, ankles, or legs

 Elevated neck veins

 Heart murmur 

 Chest pain
  Dizziness or fainting

 Fever

 Rapid weight gain

 Irregular heartbeat

Symptoms of heart failure include:

 Tiredness

 Weakness

 Lightheadedness

 Dizziness

 Shortness of breath

 Trouble breathing

 Fatigue

 Racing heartbeat, even at rest

 Elevated neck veins

 Swelling in the feet, ankles, legs, and abdomen

1. Coronary artery disease (CAD): Sometimes referred to as Coronary Heart

Disease (CHD), results from decreased myocardial perfusion that causes angina,
myocardial infarction (MI), and/or heart failure. It accounts for one-third to one-half
of the cases of CVD.
2. Cerebrovascular disease (CVD): Including stroke and transient ischemic attack (TIA)
3. Peripheral artery disease (PAD): Particularly arterial disease involving the limbs that
may result in claudication
4. Aortic atherosclerosis: Including thoracic and abdominal aneurysms
Sumber : https://www.ncbi.nlm.nih.gov/books/NBK535419/