Cardiac Endocrine

Function

Gaston R. Vergara, MD
Cardiology Division
University of Mississippi Medical Center
 Cardiac Endocrine Function

Background

• In 1964 Jamieson et al noted intracellular granules in atrial myocites

• In 1976 Marie et al noted fluid and electrolyte variations in the rat,

which were associated with changes in the granules

• In 1981 Adolfo J. de Bold et al from the University of Ottawa

published the first study describing the natriuretic properties of an
atrial extract or Atrial Natriuretic Factor (ANF):

A rapid and potent natriuretic response to intravenous injection of atrial

myocardial extracts in rats.
Life Sci. 28, 89-94
 Cardiac Endocrine Function
Atria contains abundant electron-dense granules: ANP storage sites

Jamieson, JD et al Cell Biol. 23: 151, 1964

 Cardiac Endocrine Function

Background

• In 1984 Kangawa et al published the human Atrial Natriuretic Peptide

(ANP) amino acid sequence

• In 1988 Maekawa et al published the sequence analysis of cDNA of B-

type Natriuretic Peptide (BNP), called BNP because initially was
isolated from pig brain
 Cardiac Endocrine Function

Background

• Since then other peptides with natriuretic properties have been

described by other groups. They are produced in the heart, CNS,
endothelium, kidneys and GI tract

• The heart has also been found to be the site of a few other hormones:
- Adrenomedullin (AM)
- Cardiotrophin-1 (CT-1)
- Aldosterone (?) and aldosterone-derivatives
 Natriuretic Peptides

Synthesis and structure

• Peptides with natriuretic properties include:

1. ANP
2. BNP
3. CNP (C-type natriuretic peptide)
4. DNP (Dendroaspis natriuretic peptide) – demonstrated in atrial
human myocites only by immunochemestry
5. Urodilatin, uroguanylin and guanylin

• ANP and BNP are produced within the heart, CNP by endothelial
cells and CNS, urodilatin by tubular cells (present in urine but not in
plasma), and uroguanylin and guanylin by the GI tract
 Natriuretic Peptides

Synthesis and structure

• All natriuretic peptides (NP) are similar in structure, characterized by a

17 AA peptide ring with a cysteine bridge. This ring has remained well
preserved phyllogenetically, underlying its functional importance

• Conversely there is a high degree of variability among the NH2 and

COOH terminal ends of the different NPs
 Natriuretic Peptides

Synthesis and structure

• Two genes (Nppa and Nppb) encode for ANP and BNP respectively.
They are located in the short arm of chromosome-1

• Both are synthetized in the form of pre-pro-hormones of 151 AA for

ANP and 134 AA for BNP. The C-terminal end is the bioactive form,
and contains the 17 AA ring.
 Natriuretic Peptides

Peptide chains of ANP, BNP, CNP and DNP. From Production/secretion pathways of BNP. From Clerico et
Clerico et al. Am J Physiol 290: H17- H29, Jan 2006 al. Am J Physiol 290: H17- H29, Jan 2006
 Natriuretic Peptides

Synthesis and structure

• ANP preferentially produced in the atria, while BNP is mostly

produced in the ventricles and particularly in patients with chronic
cardiac diseases

• It is likely that in the healthy state most of the ANP and BNP are
produced in the atria
 Natriuretic Peptides
Chronic cardiac conditions induced the secretion/production of
BNP, with changes in the molar ratio of BNP over ANP

From Clerico et al. Am J Physiol 290: H17- H29, Jan 2006

 Natriuretic Peptides

Regulation of secretion

• Mechanical (wall stretching) and humoral

• Wall stretch is the main stimulus for ANP secretion and it is believed
to be the most important one for BNP too.

• This phenomenon is termed stretch-secretion coupling and is not

entirely understood. Calcium is implicated in this mechanism and is
believed it requires a pool of previously synthetized and storaged NPs.
 Natriuretic Peptides: regulation
Chest X-
Rays
Upright
and
Immersed

Note the
increase in
heart
volume
on
immersion

Echt et al., (1974) Pflugers Arch, 352:211-217

 Natriuretic Peptides
Regulation of secretion

• Humoral factors implicated in NPs secretion/production

Stimulants Inhibitors
Endothelin-1 Beta-adrenergic agonists
Angiotensin-II
Glucocorticoids/T4-T3
Cytokines (TNF/Il-1/Il-6)
Insulin
Alpha-adrenergic agonists
Prostaglandins
Hydroxyvitamin-D3
 Natriuretic Peptides
Biological Effects

• Most of the best characterized NPs actions are mediated via

natriuretic peptide receptors (NPR)

• There are three type of NPRs

Receptor Ligand Signal system

NPR-A ANP and BNP cGMP

NPR-B CNP cGMP

NPR-C ANP, BNP and CNP Clearance receptor

 Natriuretic Peptides
NPRs and Neutral Endopeptidase (NEP)

From Levin et al. NEJM 339(5); 321-328: Jul 2003

 Natriuretic Peptides
NPRs ligands and prominent cell/tissue distribution

From Pandey K. Peptides 26; 901-932: 2005

 Natriuretic Peptides
Summary of physiologic effects of natriuretic peptides

From Levin et al. NEJM 339(5); 321-328: Jul 2003

 Natriuretic Peptides
Metabolic clearance of NPs

• ANP half life ~3 min

BNP half life ~23 min (this is due to its lower affinity for NPR-C)

• Natriuretic peptides are cleared via

- NPR-C
- Proteolytic cleavage by neutral endopeptidase (NEP) (widespread
distribution)
 Natriuretic Peptides
Resistance to biological action of NPs

• Patients with CHF have extremely high levels of very powerful

natriuretic hormones; however, they show signs of fluid retention and
vasoconstriction due to a relatively poor activity of the natriuretic
peptide system. This has been termed the “endocrine paradox” of the
heart

• This blunted response to NPs (demonstrated experimentally and

clinically) suggests resistance to the biological effects of NPs.

• It also has been shown that treatment of CHF with ACEI, aldo-blockers
and beta-blockers decreases NP levels and normalizes their kinetics
and biological effects
 Natriuretic Peptides
Mechanisms for resistance to natriuretic peptides

Prereceptor level Receptor level Postreceptor level

-Inactive peptides in plasma -Down-regulation of NPR-A and -Altered intracellular signaling

NPR-B decreased cGMP
altered pathways
downstream
-Increased degradation -Altered NPs receptor binding
(NEP/ACE) increased NPR-C or desensitization
and endopeptidases

-Decreased GFR
 Natriuretic Peptides
Clinical applications

• Natriuretic peptides have been clinically studied in CHF, ARF and cancer

• In CHF currently nesiritide (Natrecor), recombinant BNP, is only approved for

treatment of symptomatic (acute decompensated) heart failure in patients who
are not in cardiogenic shock. There is ongoing debate whether it worsens
mortality and renal function based on 2 meta-analysis published last year. Not
available in the US; carperitide (alpha-ANP) has shown to improve symptoms in
patients with acutely decompensated CHF. Also investigational use in CAD.

• In ARF natriuretic peptides have not been able to show improvement in

mortality or need for HD. Given the high incidence of hypotension seen in
clinical trials is considered harmful for ARF patients.

• Finally, given their anti-mytotic properties natriuretic peptides are being

evaluated in the therapy against malignancies. At least in vitro they have shown
to decrease the number of adenocarcinoma cells by causing DNA synthesis
inhibition.
 Natriuretic Peptides
STARS – BNP trial
Background

• BNP has well established diagnostic and prognostic value

• Several drugs used in the rx of CHF reduced BNP levels

including: spironolactone (RALES), valsartan (VAL-HeFT),
enalapril. The effect of beta-blockers on BNP levels remains
controversial
 Natriuretic Peptides
STARS – BNP trial
Methods
• Multicenter
• Inclusion: older than 18 yo, Class II-III NYHA, EF <45%, in stable
condition, on a stable medical regimen (diuretics, acei/arb, beta-
blockers)
• Exclusion: recent ACS, CKD, cirrhosis, asthma/copd
• Two groups; BNP guided therapy, w/ goal <100 pg/ml, and clinically
guided therapy
• F/U every 3 months

Endpoints
• Primary: composite of unplanned hospital stay due to CHF or death
due to CHF
• Secondary: all cause mortality, CHF related death, all cause hospital
stay and CHF related hospital stay
Natriuretic Peptides
STARS – BNP trial
Natriuretic Peptides
STARS – BNP trial
Diuretics were
the most
commonly
changed med.
There was a
more
aggressive
uptitration of
BB and ACEi in
the BNP group.
 Changes in per-patient use of evidence-based medical
therapy during first three months (mean % of
recommended dosage received)

Medical therapy by group Baseline 3 mo p

(%) (%)
•ACE inhibitors/ARBs
•BNP-guided therapy 94 106 <0.05
•Standard management 94 98 NS
•Beta blockers
•BNP-guided therapy 58 77 <0.05
•Standard management 57 67 <0.05
Jourdain P et al. J Am Coll Cardiol 2007; 49:1733-1739.
 Clinical outcomes after at least six months of
therapy (median, 15 months)

End point BNP-guided Clinically guided p

therapy, n=110 therapy, n=110
(%) (%)
HF-related death 24 52 <0.001
or unplanned
hospitalization*
Event-free 84 73 <0.01
survival
HF-related 20 44 <0.0001
hospitalization
*Primary end point
Jourdain P et al. J Am Coll Cardiol 2007; 49:1733-1739.
 Natriuretic Peptides
Clinical applications
 Endogenous Ouabain-like hormone
• Natriuretic and digitalis-like effect
• Molecularly it is cholesterol derivative (w/ a similar
structure to steroids)
• Ouabain-like hormone is likely produced either in the
adrenal gland and/or the hypothalamus
• Binds to Na/K ATP-ase reducing its activity and
therefore decreasing Na/Ca cotransport NA/K ATP-
ase dependent resulting in an increase in
cytoplasmatic Ca. This same effect is seen in
smooth muscle cells and might be responsible for
the enhanced vascular tone in some pts w/ essential
htn.
 Adrenomedullin
Synthesis and structure

• Adrenomedullin (AM) is a highly conserved 52 amino-acid peptide

with a six-residue ring structure formed by disulfide linkage

• Originally isolated from pheochromocytoma cells

• Synthetized as pre-pro-hormone

• Belongs to a family of peptides which includes calcitonin-gene

related peptide, calcitonin and amylin
 Adrenomedullin

Function

• Acts selectively via a calcitonin receptor-like receptor (CRLR)

associated with a receptor activity-modifying protein (RAMP). There
are 3 types of RAMPs and AM interacts with RAMP-2 and RAMP-3

• AM receptors are termed AM-1 and AM-2

• AM and its receptors are widely spread, including heart, kidneys, lung,
GI tract, endocrine system, etc

• Its biological actions concern electrolyte balance and the function of

the cardiovascular system
 Adrenomedullin
Function

Function Mechanism
Inhibits Na reabsorption Direct modulation at tubular level
Interference with aldosterone secretion

Vasodilatation (including coronoaries) Endothelium dependent and independent

NO-cGMP mediated
cAMP mediated (shared mechanism with BNP
in aortic smooth muscle cells)

Increases cardiac output

Modulation in organ growth and

differentiation

Its infusion:
-Attenuates transition from LVH to CHF Likely due to vasodilation in microvasculature
-Decreases the size of infarction in rat models
 Adrenomedullin
Perspective

• AM levels are elevated in patients with CHF, severe HTN, renal failure
and septic shock

• The source of AM in CHF has been shown to be the heart and its levels
correlate with severity of disease

• It may be responsible for the vasodilatation observed in cirrhosis and

hyperthyroidism

• AM augments collateral flow development in response to ischemia,

would this preclude a therapeutic role in CAD (?)

• Implicated in sepsis-associated hemodynamic and microcirculatory

disorders

• It has angiogenic effects/properties and it’s been implicated in the

pathophysiology of malignancies and diabetic retinopathy
 Cardiotrophin-1
Synthesis and structure

• Cardiotrophin-1 (CT-1) is a 201 amino-acid peptide of the interleukin-6

(Il-6) cytokine superfamily

• CT-1 mRNA has been found in several organs including the heart,
skeletal muscle and others

• The heart is believed to be the main source of circulating CT-1

• CT-1 binds the glycoprotein 130 (gp130)/leukemia inhibitory factor

(LIF) receptor complex. Via this receptor it activates mythogen-
activated protein kinase and JAK-STAT signaling pathways

• CT-1 receptor activation might delay the onset of CHF via prevention
of LV dilatation
 Aldosterone
• At this point is not clear whether the human heart produces aldo
(Mizuno Y et al, Circulation 2001; 103: 72-77) or it exctracts it from the
circulation (Tsunamoto et al, JACC 2000; 36 (3): 838-844)

• Aldosterone-synthase mRNA only found in human fetal heart and CHF,

but not in normal hearts

Mizuno et al Circulation. 2001;103:72-77 Tsunamoto et al, JACC 2000; 36 (3): 838-844

 Aldosterone
• Aldosterone in rat heart correlates with serum levels

• Most if not all aldo in rat heart derives from circulation

• In conclusion, is not clear whether the heart produces or extracts aldo

from the circulation, and if so under which circumstances

Gomez Sanchez, Endocrinology 145:4796-802 2004

 Cardiac Endocrine Function

In Summary

The heart is not only a passive actor that responds

automatically to extrinsic stimuli such as
hemodynamic load, and the nervous, endocrine and
immune systems input; but rather a dynamic player
which actively participates in the regulation of the
cardiovascular system by behaving as an endocrine
organ.