Expert Review of Cardiovascular Therapy

ISSN: 1477-9072 (Print) 1744-8344 (Online) Journal homepage: http://www.tandfonline.com/loi/ierk20

Epidemiology of left ventricular hypertrophy in

hypertension: Implications for the clinic

Dana Cramariuc & Eva Gerdts

To cite this article: Dana Cramariuc & Eva Gerdts (2016): Epidemiology of left ventricular
hypertrophy in hypertension: Implications for the clinic, Expert Review of Cardiovascular
Therapy, DOI: 10.1080/14779072.2016.1186542

To link to this article: http://dx.doi.org/10.1080/14779072.2016.1186542

Accepted author version posted online: 09

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Download by: [Universite Laval] Date: 14 May 2016, At: 04:31

 Publisher: Taylor & Francis

Journal: Expert Review of Cardiovascular Therapy

DOI: 10.1080/14779072.2016.1186542
Epidemiology of left ventricular hypertrophy in hypertension: Implications for the clinic

Dana Cramariuc

Department of Heart Disease

Haukeland University Hospital

5021Bergen

Norway
Expert Review of Cardiovascular Therapy

Phone: +4755970534/2220

E-mail: dana.cramariuc@helse-bergen.no

Eva Gerdts

Department of Clinical Science

University of Bergen

P.O. Box 7804

5020 Bergen

Norway

Phone: +4755973054/2170

Fax: +4755975150

E-mail: eva.gerdts@uib.no *corresponding author

1
 Abstract:

Left ventricular hypertrophy (LVH) is a common complication to hypertension, indicating the

presence of hypertensive heart disease, which puts the patient at a very high risk for

subsequent clinical cardiovascular events like sudden cardiac death, stroke, myocardial

infarction and heart failure. The epidemiology of LVH has changed in recent years as a

consequence of the development of new diagnostic tools and demographic changes in

hypertensive populations. In individual hypertensive patients, the presence and type of LVH
Expert Review of Cardiovascular Therapy

and associated systolic and diastolic myocardial dysfunction is modified by the co-presence of

other cardiovascular risk factors and comorbidities and as well as activation of the

reninangiotensin-aldosterone system and other molecular mechanisms involved in LVH

pathophysiology. The purpose of this review is to give a clinical update on LVH in

hypertension.

Keywords: left ventricular hypertrophy; left ventricular concentric geometry; arterial

hypertension; obesity; sex; left ventricular systolic function; left ventricular diastolic function;

echocardiography; myocardial function; hypertensive heart disease

2
 1. Introduction

Left ventricular hypertrophy (LVH) is a common complication even in mild hypertension,

found in up to 30% of patients [1, 2]. However, traditional electrocardiographic (ECG)

criteria are not very accurate in detection of LVH. Chronic systemic hypertension leads to

structural and functional changes in the heart. These changes include LVH, fibrosis of the

myocardial interstitium and coronary angiopathy. Modern non-invasive cardiac imaging

offers an integrated assessment of these factors for diagnosis of hypertensive heart disease, as

recently pointed out in a joint position paper from the European Association of

Cardiovascular Imaging and the American Society of Echocardiography on use of

echocardiography in adult hypertension [3].

Expert Review of Cardiovascular Therapy

The epidemiology of LVH has changed following development of new diagnostic

tools and demographic changes in hypertensive and other populations, in particular aging and

the obesity epidemic [4, 5]. A number of hemodynamic and non-hemodynamic factors have

been documented to influence development of LVH (Figure 1).Whenever LVH is present, this

represents a very high risk for subsequent clinical cardiovascular events including sudden

cardiac death, myocardial infarction, stroke and heart failure [2, 6, 7]. However, going beyond

simplified identification of LVH may be necessary to further stratify and manage individual

CV risk in patients with LVH [8, 9].The purpose of this review is to give a clinical update on

LVH in hypertension.

2. Pathophysiology of LVH

Chronic arterial hypertension leads to increased wall stress both in the systemic

arteries and in the left ventricle (LV) [10]. Increased wall stress impairs LV systolic

performance and induces compensatory cardiomyocyte hypertrophy and increased LV wall

thickness to reduce wall stress, following Laplace’s law. As a consequence, the ratio between

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 wall thickness and internal chamber diameter (relative wall thickness) increases, and LV

geometry becomes more concentric [11]. Women have smaller LVs than men, and

consequently LV geometry is more often concentric in women [12, 13]. Furthermore,

increased aortic stiffness, as often found in elderly women with longstanding hypertension, is

also particularly associated with increased relative wall thickness and asymmetric septum

hypertrophy, even in the absence of general LVH, reflecting the impact of hypertensive

damage to the aorta on LV geometry [5, 14].

Increased sympathetic nervous system activity leads to neuroendocrine activation in

hypertension, including stimulation of the renin-angiotensin system (RAS), the natriuretic

peptide family and the adrenoceptor signaling cascade [15].The RAS system is a major
Expert Review of Cardiovascular Therapy

regulator of blood pressure and hypertrophic response in hypertension. Angiotensin II is

produced systemically or locally in several organs, including in the heart and arteries.

Angiotensin II stimulates sympathetic activity and aldosterone production. The classical

cardiovascular effects of angiotensin II, including hypertension, cardiovascular remodeling,

oxidative stress, inflammation, and fibrosis, are mainly mediated by the angiotensin type 1

receptor. Aldosterone promotes endothelial dysfunction, vascular remodeling, oxidative stress

and inflammation through the mineralocorticoid receptor. Cross talk and synergistic

cardiovascular effects have been demonstrated between these systems [16].

Other main pathways and signaling molecules of importance for the hypertrophic

response to arterial hypertension include endothelin-1 and G proteins, micro ribonucleic acids

(miRNAs), oxidative stress, heat shock proteins, calcium and some kinases [17]. The

endothelin system is an important regulator of arterial tone and regional blood flow, and also

influences cell proliferation, extracellular matrix synthesis and renal water and sodium

handling [18]. Its biological effect is mostly mediated by endothelin-1. In human

hypertension, high plasma endothelin concentrations have been measured in malignant

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 hypertension and pregnancy-induced hypertension. However, intolerable side-effects, in

particular headache and fluid retention, have halted clinical trials with non-selective as well as

selective endothelin type A receptor antagonists in hypertension.

Vascular smooth-muscle contraction is regulated by the cytosolic calcium

concentration and by the calcium sensitivity of myofilaments. The Rho kinases (ROCK) are

involved in the transmission of contractile signaling within smooth muscle tissue, and

activation promotes muscle contraction and actin cytoskeleton re-organization [19]. Studies in

hypertensive rat models have demonstrated that selective inhibition of ROCK was associated

with relaxation of vascular smooth muscle cells and reduced cardiac fibrosis, suggesting a

future potential target for management of hypertension-associated LVH.

Expert Review of Cardiovascular Therapy

Several studies on genetics in LVH have focused on polymorphisms in RAS-genes

like the angiotensin converting enzyme (ACE I/D) and angiotensin genes (AGT -6G-A,

M235T, -20A-C), but results have been inconsistent. An association with higher LV mass was

found with D allele in the ACE gene in some studies. Epistatic (gene-gene interaction) effects

associated with hypertensive LVH was explored in the population-based observational

Hypertension Genetic Epidemiology Network (HyperGEN) study [20]. The results suggested

an epistatic effect on LVH between the ACE I/D and AGT -20A-C genetic variants among

white, but not among African American hypertensive participants.

Also epigenetic regulation of hypertensive LVH has been reported, in particular

targeting miRNA expression [21]. MiRNAs are small, non-coding RNA molecules that act as

post-transcriptional regulators of gene expression. Several miRNAs have demonstrated a role

in development of physiological as well as pathological LVH. Furthermore, sex-specific and

estrogen dependent regulation of miRNA networks by the estrogen receptor beta has been

reported, which may be relevant for the observed sex differences in myocardial function and

fibrosis in hypertensive LVH [22].

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 Reduced myocardial perfusion may be found in patients with LVH, independent of

presence of epicardial coronary artery disease. The mismatch between coronary arterial

capacity and increased LV mass as well as hypertension-induced perivascular fibrosis and

endothelial dysfunction may all contribute to reduced coronary flow reserve in such patients

[23]. In particular reduced myocardial perfusion has been demonstrated in the endocardial

parts of the LV wall in patients with concentric LVH using contrast echocardiography [24].

Taken together, these observations suggest that LVH-associated relative myocardial ischemia

may contribute to exertional dyspnea or angina pectoris which is commonly reported from

patients with hypertensive LVH. A recent publication assessing coronary flow reserve by

phase contrast cine-magnetic resonance imaging (MRI) found that coronary flow reserve was
Expert Review of Cardiovascular Therapy

significantly lower in patient with heart failure with preserved ejection fraction (HFPEF)

compared to hypertensive patients with LVH, suggesting that reduced myocardial perfusion

may play a role in progression from compensatory LVH to HFPEF [25]. In patients with

nonST elevation myocardial infarction, higher coronary plaque area was associated with

reduced myocardial perfusion independent of presence of a significant coronary artery

stenosis [26], but the association of non-obstructive coronary atherosclerosis with myocardial

ischemia has so far not been explored in hypertensive patients.

In obese subjects, a number of non-hemodynamic determinants of LVH have been

identified (Figure 1), including altered renal sodium handling, increased blood volume,

insulin resistance, stimulation of the sympathetic nervous system, visceral fat production of

angiotensinogen, adipokines, pro-inflammatory cytokines (mainly belonging to the tumor

necrosis ± and interleukin 6 families) and mineralocorticoid-releasing factors [27]. This

obesity associated inflammation leads to increased tissue water content and reactive fibrosis

in the myocardium. Furthermore, fat accumulation in the epicardium may infiltrate the

myocardium, further adding to increased LV mass, beyond the paracrine effects of cytokines

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 and adipokines produced from visceral fat [28]. Co-presence of hypertension increases in

parallel with degree of obesity, and 75% of subjects with body mass index >35 kg/m2 have

hypertension, exposing the LV for hemodynamic as well as non-hemodynamic stimulators of

hypertrophy (Figure 1).

2.1 Non-hypertensive causes of LVH

Although hypertension is the most common cause of LVH, LVH may also be found in

athletes, and in subjects with cardiomyopathies or storage disorders. In athletes, the heart

physiologically adapts to regular intense physical training [29]. The adaptation may differ in

endurance compared to strength sports, but is typically associated with increased vagal tone,

left atrial and LV chamber dilatation and increase in LV wall thickness. In most athletes, an
Expert Review of Cardiovascular Therapy

eccentric LVH is found by echocardiography, but pathologically increased wall thickness

(>12 mm) is rare, reported in 0.4-1.7%. Contrasting findings in pathological LVH,

physiological LVH in athletes is associated with normal systolic and diastolic function, and

without detectable myocardial fibrosis on MRI. In particular speckle tracking or tissue

Doppler echocardiography are useful in differentiation between pathological and

physiological LVH.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant trait caused by

mutations in cardiac sarcomere protein genes [30]. Hypertensive LVH may in some subjects

be difficult to distinguish from HCM. In such cases, LVH on 12 lead ECG without

repolarization abnormalities and LVH regression during antihypertensive treatment will favor

hypertensive LVH. In contrast, marked repolarization abnormalities, conduction disease or

Qwaves on ECG, LV wall thickness e 15 mm in any segment, right ventricular hypertrophy

and late gadolinium enhancement on MRI located in the thickest LV segments or at the right

ventricular insertion points on the LV will favor HCM.

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 Fabry disease is a X-linked lysosomal storage disorder caused by mutations in the

gene coding for ±-galactosidase A. Genetic screening in subjects with LVH has reported up to

12 % prevalence of Fabry disease [31]. Fabry disease leads to progressive accumulation of

complex sphingolipids in multiple organs, including the heart, which results in LVH,

myocardial fibrosis, progressive cardiomyopathy and death. Typically, Fabry disease may be

the underlying cause in young patients with cryptogenic stroke who are diagnosed with LVH.

Since enzyme replacement therapy is available for Fabry patients with organ involvement,

correct diagnosis is crucial.

3. Epidemiology
Expert Review of Cardiovascular Therapy

The prevalence of LVH varies depending on the imaging method used for the detection, the

criteria used and the clinical characteristics of the study population. In particular, ECG,

echocardiography and MRI are commonly used for the diagnosis of LVH, but also computer

tomography may be a validated optional modality in selected patients [32]. Recent research

has documented that partially different subjects within the same population are identified by

these imaging methods [33].

3.1 Electrocardiography

In a recent publication based upon 5800 Finns [34], age and sex adjusted prevalence of LVH

by Sokolow-Lyon criterion was 8.8% in normotensive subjects, and 10.5% and 13.1% in

grade 1 and 2 hypertensive subjects, respectively. In this population, LVH by Cornell voltage

criterion was present in 5.1% in normotensive subjects compared to 9% and 13.1% in grade 1

and grade 2 hypertensive subjects. Thus, the prevalence of LVH by these ECG criteria

increased with the severity of the hypertension [34]. Other population based cohorts have

found even lower prevalence of ECG LVH. In the MRFIT study including men aged 35-57

years of age, the prevalence of ECG LVH (by Minnesota code 3.1-3.3 voltage criterion + STT

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 changes) was 2.4% [35], and in the Framingham Heart Study ECG LVH (by Framingham

criterion) was found in 2.9% of men and 1.5% of women [36].

3.2 Echocardiography

In the Framingham Heart Study, the prevalence of LVH by echocardiography was

15.5% among women and 21% among men [2]. LVH by echocardiography is common in

hypertensive subjects, found in 20-50% with mild hypertension and in up to 90% of patients

with severe hypertension [1, 37]. The actual prevalence of LVH varies with the clinical

characteristics of the studied population. In particular sex, age, hypertension, diabetes,

metabolic syndrome and obesity have been identified as factors influencing LVH

epidemiology [13, 27, 38]. LVH has primarily been studied in middle-aged or old subjects,
Expert Review of Cardiovascular Therapy

but a recent publication from the Jerusalem Longitudinal Cohort Study found that in mostly

hypertensive subjects aged 85 years, LVH was present in 70% of women and 62% of men

[39].

LVH may be the result of ventricular dilatation, wall thickening or a combination, and

the actual LV geometry will reflect the interaction between volume and pressure overload

factors in the individual patient. Traditionally LVH has been divided into eccentric LVH

(normal relative wall thickness) and concentric LVH (increased relative wall thickness)

(Figure 2). During antihypertensive treatment, a particular reduction in the high risk

concentric LVH type has been observed [40]. From the Dallas Heart Study, a new 4-group

classification of LVH was proposed based on MRI studies, taking not only LV mass/height1.7

and the ratio between LV mass and volume, as a measure of concentricity, into account, but

also the LV end-diastolic volume indexed for body surface area, as a measure of dilatation

(Figure 2). In particular the subgroup of eccentric LVH without LV dilatation was found to

have better systolic function and comparable levels of plasma natriuretic peptides to the group

without LVH. However, additional validation is needed before this more refined LVH

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 classification can be recommended. It was therefore not included in the European Association

of Cardiovascular Imaging and the American Society of Echocardiography guidelines on

chamber quantification [41]. Although many clinical trials have documented regression of

LVH and LV strain during antihypertensive treatment, less success in inducing LVH

regression was recently reported from the observational Strong Heart Study [42]. In a subset

of 851 hypertensive subjects re-examined after 4 years, LVH regression was only found in

3% of men and 10% of women. In addition, new-onset LVH was documented in 14% of men

and 15% of women. In particular obesity, lack of blood pressure control and renal damage

were identified as confounders of lack of LVH regression, while no association of type of

antihypertensive treatment was found [42].

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4. CV risk in LVH

There is comprehensive documentation that LVH diagnosed by ECG, echocardiography and

MRI is a strong and independent predictor of higher CV morbidity and mortality [2, 6, 7, 33,

36, 43]. Even in subjects aged 85 years, LVH predicted increased 5-year mortality

independent of confounders including sex, diabetes, ischemic heart disease and physical

activity [39]. Data from the Framingham Heart Study show that presence of LVH diagnosed

by ECG, x-ray or echocardiography was associated with a 3-fold increased risk for CV events

and a 5 to 9-fold increased risk for sudden cardiac death [44]. In subjects diagnosed with ECG

LVH in the Framingham Study, 35% of men and 20% of women died within 5 years of

diagnosis. The prognostic value of the Romhilt-Estes LVH score was recently published from

the Atherosclerosis Risk In Communities (ARIC) study [45]. Those with score e 5 had 4-fold

higher incidence rate of all-cause mortality (60.5%) than those with score 0 (13.8%). Of the 6

ECG components of the score, 4 were individually predictive of all-cause mortality: Pterminal

force, QRS amplitude, LV strain and intrinsicoid deflection.

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 In mild-moderate uncomplicated hypertension, all-cause mortality is influenced not

only by presence of LVH on the echocardiogram, but also of LV geometry [1]. 10-years,

allcause mortality was 20% in those with concentric LVH, 10% in those with eccentric LVH,

5% in those with concentric remodeling and 1% in those without LVH [1]. Also other studies

have documented that CV risk is highest in concentric LVH [40]. In African Americans with

hypertension, it was demonstrated that presence of LVH on the echocardiogram was

associated with impaired prognosis independent of presence of coronary artery stenoses on

angiography [46], and independent of the LV ejection fraction (EF). In the LIFE study,

regression of LVH by Sokolow-Lyon criterion or by Cornell product criterion was associated

with a 14% and 17% lower rate of cardiovascular morbidity and mortality over 4.8 years
Expert Review of Cardiovascular Therapy

follow-up [47], respectively, independent of achieved blood pressure and other confounders.

The same trial also demonstrated that cardiovascular morbidity and mortality was 2-fold

higher in those with persistent or new-onset ECG strain pattern compared to those without

[48]. Also the benefit from combining ECG and echocardiography for identification of LVH

has been documented. Patients with LVH present both on ECG and echocardiogram are at

particularly high risk for hospitalization with heart failure, pointing to the added value of

combining different methods in assessment of LVH [49]. In the LIFE echocardiography

substudy, the prevalence of LVH on echocardiography was reduced from 70% at baseline to

20% after 5 years. Beyond the blood pressure reduction and type of antihypertensive drug

treatment, reduction of LVH contributed independently to improved prognosis [6, 47]. In

particular African race, female sex, arterial stiffness, renal dysfunction and obesity have been

identified as factors associated with persistent concentric LVH in hypertension [6, 40]. A

recent meta-analysis documented that despite LVH regression in hypertensive patients, the

CV risk remained higher in these subjects compared to those persistently without LVH [50].

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 The prognostic importance of the new 4-group classification of LVH by MRI from the Dallas

Heart Study has been validated using echocardiography in the LIFE study [8]. The prevalence

of eccentric non-dilated LVH was 12%, eccentric dilated LVH 20%, concentric non-dilated

LVH 29% and concentric dilated LVH 14%, while normal LV mass was found in 25% [8].

During 4 years follow-up, increased all-cause and CV mortality was observed in all groups

except the eccentric non-dilated LVH group that had comparable outcome to those with

normal LV mass.

5. Diagnosis of LVH

5.1 Electrocardiography

The ECG remains the first line of method for detection of LVH in hypertensive patients. Of
Expert Review of Cardiovascular Therapy

note, the commonly used QRS voltage criteria only apply to adults older than 35 years, since

standards for subjects aged 16 to 35 years are not as well-established [51]. The main

limitation of ECG diagnosis of LVH is the low sensitivity, although several criteria have high

specificity and validation against anatomical LVH and prognosis [52]. In particular the

Sokolow-Lyon and Cornell Product criteria are well validated and simple to use in clinical

practice (Table 1). Sokolow-Lyon criterion may overestimate LVH in tall slim subjects, and

Cornell product criterion is superior in identification of LVH in obese subjects [53, 54].

Romhilt-Estes score is calculated from 6 ECG features, and a score point e 5 is consistent

with ECG LVH (Table 1)[45].

5.2 Echocardiography

Anatomic LV mass may be diagnosed by echocardiography using Devereux’s autopsy

validated equation based upon measurements performed on 2-dimensional or M-mode images

[55]. The calculated LV mass must be indexed to body size to identify LVH. Current joint

European and American Society of Echocardiography guidelines for quantitative

echocardiography consider LVH to be present if LV Mass/body surface area exceeded 95

12
 g/m2 in women and 115 g/m2 in men [41]. Of note, these cut-off values are based upon

findings in 7 healthy populations excluding all subjects with hypertension, obesity or

diabetes. In particular in obese subjects, indexation for body surface area will significantly

underscore the prevalence of LVH, and indexation for body height in the allometric power of

2.7 is recommended [56]. The performance of LV mass/height2.7 to identify LVH has been

documented in several different populations, and the prevalence of LVH has been reported as

13% in normotensive obese subjects to 75% in obese hypertensive subjects. The optimal

normalization of LV mass to identify LVH is still discussed.

Use of 3-dimensional (3D) echocardiography for assessment of LV mass is

documented to be closer to that found with MRI, and may be particularly more accurate in
Expert Review of Cardiovascular Therapy

subjects with asymmetric LVH or coronary artery disease [41]. However, the superiority of

3D echocardiography assessment of LVH has not been validated in larger clinical outcome

studies.

5.3 Magnetic resonance imaging

When diagnosing LVH by MRI typically myocardial volume from end-diastolic LV shortaxis

slices are summed up and multiplied by 1.05 g/mL to derive the LV mass [57]. Although this

may be done by manual planimetry, automated segmentation is used for more rapid

quantitation of LV mass. In many studies, MRI found systematically lower LV mass

compared to echocardiography [58]. Although this difference was initially explained by the

many geometric assumptions and other factors related to echocardiographic calculation of LV

mass, also MRI related factors may have contributed to these differences in earlier studies.

After development of automated partial voxel segmentation for MRI, estimation of LV mass

has proved much closer to LVM derived from autopsy studies and echocardiography

performed by experts [59]. The Multi-ethnic Study of Atherosclerosis (MESA) using MRI

compared the prognostic relevance of different allometric exponents to normalize LV mass,

13
 and suggested indexation of LV mass to height1.7 as optimal. MESA confirmed that ethnicity,

sex and obesity were main confounders of LVH by MRI, in consistence with previous

echocardiographic studies.

5.4 Biomarkers

Cardiac troponins (TnT) and the N-terminal fragment of the prohormone of B-type

natriuretic peptide (NT-proBNP) are released from cardiomyocytes in response to increased

LV wall stress and hypertrophy. The interaction between LVH, TnT and NT pro- BNP on

outcome was tested in the Dallas Heart Study [60]. Patients with LVH and either detectable

TnT or elevated NT-proBNP had a 4-fold increased risk for heart failure or death during 8

years follow-up. In the Cardiovascular Health Study, risk for new-onset heart failure
Expert Review of Cardiovascular Therapy

increased in parallel with higher level of TnT or NT-proBNP in patients with LVH [61]. Thus

biomarkers of subclinical cardiac injury and hemodynamic stress like TnT or NT-proBNP

may be useful for further risk classification among patients with LVH. However, a diagnostic

cut-off value in NT-proBNP level to be used for identification of LVH is still not established.

6. LVH and systolic function

In LVH, reduced myocardial contractility may be present despite normal EF (Figure

3), since EF primarily reflects endocardial displacement, which may be exaggerated in such

patients (Figure 4) [62]. In pressure overload conditions, low EF occurs when myocardial

compensatory mechanisms are exhausted [63], or as a consequence of coronary artery disease.

Previous data from patients with hypertension or aortic stenosis have demonstrated that

myocardial systolic dysfunction is detectable at an earlier stage of disease [64, 65].

Myocardial dysfunction is common in LVH, even in asymptomatic patients, and may be

detected by conventional echocardiography using midwall shortening (Figure 4) [65, 66].

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 Myocardial dysfunction despite normal EF is particularly common in patients with

exaggerated hypertrophic response to pressure overload [67, 68], and associated with

impaired prognosis and new-onset heart failure [69].

Sex differences in LV systolic function have been reported [12], and cut-off values for

normal EF and midwall shortening are higher for women than for men, as reflected in the

guidelines [41]. In patients with severe aortic stenosis, men had more myocardial fibrosis than

women in endomyocardial biopsies [70]. LV myocardial dysfunction is also common in

patients with diabetes [67, 71], probably reflecting increased myocardial inflammation and

interstitial reactive fibrosis in these patients.

Reduced LV strain is an early marker of LV systolic dysfunction, and may be present

Expert Review of Cardiovascular Therapy

despite normal EF in patients with LVH. LV strain may be assessed by speckle tracking

echocardiography (Figure 5), or by tissue Doppler imaging. Presence of reduced LV strain

has been associated with impaired CV prognosis [72, 73]. In patients with LVH due to

hypertension or aortic stenosis, lower LV strain is typically associated with presence of

concentric geometry [74, 75, 76]. Reduction of strain is more pronounced in the basal LV

segments [76], reflecting more myocardial fibrosis at the base of the LV [77]. Lower LV

global longitudinal strain is associated with reduced survival in aortic stenosis patients, also in

presence of normal EF [78]. In hypertension, lower LV global longitudinal strain has been

associated with reduced peak O 2 uptake and decompensated LVH [79, 80].

The myocardium has three myocardial layers: the subendocardial and subepicardial

layers with primarily longitudinal fibers, and the midmyocardial layer with primarily

circumferential fibers. Patients with LVH have progressive changes in individual layer

geometry and their functional interaction, leading to changes in the regional function.

Myocardial layer function may be visualized by tissue Doppler (Figure 6). Hypertension and

aortic stenosis may have different influence on myocardial function in individual layers [81].

15
 In this study using radial tissue Doppler strain, aortic stenosis influenced myocardial function

both in the midwall and subendocardial layers, while hypertension primarily influenced

myocardial function in the midwall layer [81]. These changes may reflect LVH associated

microvascular dysfunction and fibrosis particularly found in the midwall layer [23]. These

new techniques are promising new tools for detection of very subtle LV systolic dysfunction

in LVH [82].

7. LVH and diastolic function

Enlarged left atrium is a common finding in hypertensive LVH, reported in 56% of

women and 38% of men based upon measurement of its anterior-posterior diameter [83]. An
Expert Review of Cardiovascular Therapy

enlarged left atrial diameter is associated with increased risk for cardiovascular events in

hypertensive patients with LVH [84]. A left atrial volume e 34 ml/m² is considered a better

measure of enlarged left atrium, and has been associated with higher risk of atrial fibrillation,

recurrent stroke, and silent cerebrovascular disease which may be detected by MRI [85, 86,

87]. Changes in left atrial size and function may contribute to the observed higher risk for

atrial fibrillation, congestive heart failure and cerebrovascular events in hypertension [84, 88].

Hypertensive LVH is associated with abnormal diastolic LV filling pattern and timing [89].

Presence of normal LV filling pattern in hypertensive subjects is associated with low risk of

heart failure [90]. In elderly patients operated for aortic stenosis, residual LVH is common in

subjects with hypertension, and associated with reduced diastolic function and less relief of

symptoms [91]. Antihypertensive treatments improve diastolic dysfunction as part of effective

reduction in LVH [92]. Measurement of mitral annular velocities is recommended as part of a

standard echocardiographic examination in hypertension [3]. Several studies have

16
 documented that higher LV filling pressure measured by the E/e’ ratio, is associated with

worse CV outcome in hypertensive patients both with and without LVH [93, 94].

Myocardial diastolic strain and strain rate are promising new modalities for more

detailed assessment of diastolic function. By MRI higher extracellular volume, reflecting

diffuse fibrosis, and a reduction in early diastolic strain have been found in hypertensive

patients with LVH compared to those without LVH [95]. Lower early diastolic strain rate in

both longitudinal and circumferential direction, as well as lower diastolic untwist rate, all by

speckle tracking echocardiography were found in hypertensive patients with LVH compared

to those without LVH [96].

Expert Review of Cardiovascular Therapy

8. LVH and arrhythmias

In the Framingham Heart Study, presence of LVH was associated with a 5-9 fold increased

rate of sudden cardiac death during 36 years follow-up [44]. A recent meta-analysis based

upon 10 studies with 27,000 patients found that LVH was associated with increased risk for

both supraventricular and ventricular arrhythmias [97]. The incidence of supraventricular

tachycardia was 11.1% in patients with LVH compared to 1.1% among patients without LVH.

The incidence of ventricular arrhythmias (tachycardia and fibrillation) was 5.5% in patients

with LVH compared to 1.2% in patients without LVH.

The association of LVH with increased risk for atrial fibrillation has been documented

from many studies. As demonstrated in the Framingham Heart Study, patients with atrial

fibrillation are 5 times more likely to suffer from stroke, and have a 1.5-1.9 increased

mortality. In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA)

registry, the annular rates of incident atrial fibrillation and chronic atrial fibrillation were

0.46% and 0.15%, respectively. Higher age and LV mass were the only independent

predictors of atrial fibrillation. In the LIFE study, ECG LVH was a strong predictor of

17
 newonset atrial fibrillation, and LVH regression was associated with reduced incidence of

atrial fibrillation [98]. In the MESA study, LVH both diagnosed by Sokolow Lyon criterion

and by MRI were associated with a 2-fold increased hazard rate for new onset atrial

fibrillation during 6.9 years follow-up [99]. The prevalence of LVH was 52% in an Italian

registry for patients with non-valvular atrial fibrillation [100]. In particular LVH was

associated with female sex, older age, hypertension and history of myocardial infarction in

this registry. The cause of increase arrhythmogenicity in LVH is not completely understood,

but may be related to myocardial ischemia, scar tissue, neuroendocrine factors and elevated

LV wall stress, all factors leading to slow and non-uniform propagation of the action potential

in the myocardium.
Expert Review of Cardiovascular Therapy

9. Management of patient with LVH

Clinical trials in hypertension have confirmed the impact on RAS inhibition on LVH

regression from blood pressure lowering treatment [6, 101]. In metaanalysis, the angiotensin

converting enzyme inhibitors (ACEI) were more potent than calcium channel blockers (CCB)

in inducing LVH regression, while beta-blockers and diuretics were less effective [102]. The

LIFE study documented that treatment with the angiotensin receptor blocker (ARB) losartan

reduced LVH more than treatment with the beta blocker atenolol despite similar blood

pressure reduction, indicating that inhibition of the RAS system added benefits beyond blood

pressure control [6]. Overall LVH was reduced from 70% at baseline to 20% after 5 years,

and the LVH regression was better with losartan-based than atenolol-based treatment [6]. In

particular African race, female sex, arterial stiffness, renal dysfunction and obesity have been

identified as factors associated with persistent concentric LVH in hypertension [6, 40].

Aldosterone inhibitors are effective in reducing LVH in patients with primary

hyperaldosteronism. During long-term antihypertensive treatment with ACEI or ARB, the

18
 suppression of aldosterone reverses with time in response to non-angiotensin II regulators of

aldosterone production. In essential hypertension, aldosterone inhibitors have been mostly

tested in resistant hypertension studies focusing on blood pressure control. However,

eplerenone/enalapril in combination proved more efficient in reducing LVH diagnosed by

magnetic resonance imaging compared to either agent used alone in a small series of 202

patients with essential hypertension [101]. The results may be explained by the aldosterone

escape during RAS inhibition, as pointed out above, or possibly improved effect on

myocardial fibrosis. Also antihypertensive treatment with the direct renin inhibitor aliskiren

induces LVH regression in essential hypertension. However, results from the Aliskiren Trial

in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) study demonstrated that

Expert Review of Cardiovascular Therapy

aliskiren did not improve outcome in such patients, and dual RAS inhibition with combined

aliskiren and ARB was less safe with increased adverse events, renal complications,

hyperkalemia and hypotension [103]. Dual RAS inhibition was also tested in the Ongoing

Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)

which did not show any advantages of combining treatment with ACEI and ARB [104].

Based upon this documentation, current European guidelines on management of arterial

hypertension do not recommend combined treatment with ACEI, ARB and direct renin

inhibitor.

A recent meta-analysis documented that despite LVH regression in hypertensive

patients, the CV risk remained higher in these subjects compared to those persistently without

LVH [50]. In subjects with LVH, current guidelines recommend ARB, ACEI and CCB as

first line drugs. In most patients combination of 3-4 drug classes are necessary to achieve the

treatment goal for these patients, i.e. a blood pressure < 140/90 mmHg.

19
 10. Expert commentary

LVH is a common complication in hypertension which profoundly impairs the prognosis of

the patient. LVH may be diagnosed by ECG, echocardiography or MRI. Although ECG is

recommended as the first line diagnostic test in hypertension, ECG has low sensitivity for

detection of LVH. Widely use of echocardiography is therefore highly recommended. Since a

number of hemodynamic and non-hemodynamic factors beyond clinic blood pressure

influence LV mass, LVH is common even in mild hypertension, in particular if obesity

concurs. Current European Society of Hypertension/European Society of Cardiology

guidelines for management of arterial hypertension recommend systematic search for organ

damage, in particular in subjects with moderately elevated risk [37]. For diagnosis of LVH
Expert Review of Cardiovascular Therapy

well validated criteria should be used. In subjects with LVH, current guidelines recommend

ARB, ACEI and CCB as first line drugs. In most patients combination of drug classes is

necessary to achieve the treatment goal for these patients, i.e. a blood pressure < 140/90

mmHg. Combination of ARB/ACEI and CCB with hydrochlorothiazide diuretics is potent

and the effect well studied. If a 4th drug is necessary, an aldosterone antagonist would be

preferred. LVH regresses slowly, and may take >2 years in many patients, as demonstrated in

the LIFE study. In subjects with LVH and body mass index > 35 kg/m2, LVH regression is

unlikely [105]. A second echocardiography 1 year after blood pressure control has been

established is recommended to identify subjects in whom LVH regression is not induced and

that may be suspected to have LVH of other etiologies.

11. Five-year view

Further development of 3D echocardiography is expected in the next years. This will likely

lead to more accurate assessment of LVH and EF compared to today’s standard. Reduction of

inter-vendor variability in deformation methods and further documentation of normal strain

20
 values will facilitate development of standardization and quality assurance of these important

new methods for the routine use in diagnosis of subclinical myocardial dysfunction at an

earlier stage. Further research and improved non-invasive cardiac imaging methods including

echocardiography, MRI and positron emission tomography-MRI is necessary to improve

prediction and understanding of progression from compensated hypertensive LVH to HFPEF,

a major cause of cardiovascular morbidity and mortality and high health care costs related to

repeated hospitalizations all over Europe today.

12. Key issues

• LVH is a common complication in hypertension and associated with increased CV

Expert Review of Cardiovascular Therapy

morbidity and mortality.

• LVH may be diagnosed by ECG, echocardiography or MRI and is traditionally

divided into eccentric and concentric types. Accurate methods and prognostically

validated cut-off values should be used for identification of LVH irrespective of the

chosen imaging modality.

• Although most patients with hypertensive LVH have normal EF, reduced LV

myocardial function is common and may be unmasked by assessment of midwall

function or global longitudinal strain.

• Reduced LV myocardial function is associated with impaired prognosis independent

of presence of a normal EF.

• LV diastolic dysfunction is present in most patients with LVH, and a comprehensive

assessment of LV filling, E/E’ ratio and left atrial volume is recommended.

• Combined assessment of structural and functional abnormalities is recommended for

more optimal identification of hypertensive heart disease.

21
 Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or pending, or royalties.

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35
 Figure 1.Overview of hemodynamic and non-hemodynamic factors influencing LV mass
Expert Review of Cardiovascular Therapy
 Figure 2.Traditional classification of LVH into eccentric and concentric groups. The newly

proposed 4-group classification of LVH also takes LV end-diastolic volume into account.
Expert Review of Cardiovascular Therapy
 Figure 3. Changes in LV function during development and progression of LVH. A series of

triggers (A) stimulate cardiomyocyte hypertrophy and growth of extracellular matrix,

resulting in LVH (B). This causes changes in the functional interaction between the

subendocardial, midmyocardial and subepicardial layers of the LV wall that can be measured

by deformation analysis (C). Functional changes at the layer level are early changes in

systolic function (D) and changes in diastolic function (E).

Expert Review of Cardiovascular Therapy
 Figure 4. Due to the cross-fiber shortening phenomenon, EF is often preserved in LVH. In

this example, a patient with concentric LVH has normal biplane EF (73%) due to good

endocardial movement, but significantly reduced midwall fractional shortening (13.4%).

Expert Review of Cardiovascular Therapy
 Figure 5. Lower global longitudinal strain (-15%) by speckle tracking echocardiography in a

patient with hypertensive LVH. Top left panel: Bmode apical 4-chamber image with selection

of LV myocardium to be analyzed; bottom left panel: segmental peak longitudinal systolic

strain in

6 LV segments; top right panel: corresponding peak longitudinal strain curves for the 6 LV

segments; bottom right panel: color curved anatomical M-mode of longitudinal strain.
Expert Review of Cardiovascular Therapy
 Figure 6. Measurement of peak systolic radial strain in three layers in the left ventricular

inferior wall of a hypertensive LV due to A) severe aortic stenosis in a normotensive patient;

B) hypertension in a patient with moderate aortic stenosis. Each panel: left side–colour TDI

image in parasternal short-axis view of the inferior left ventricular wall and B-mode image

with a region of interest placed in each layers of the inferior LV wall; right side:

corresponding peak systolic radial strain curves for the three regions of interest: red curve for

subendocardium, blue curve for mid-myocardium, and yellow curve for subepicardium.
Expert Review of Cardiovascular Therapy
 36

Table 1. Calculation, diagnostic cut-off value, and performance of selected ECG criteria for
diagnosis of LVH

Criterion Calculation Diagnostic Sensitivity Specificity

cut-off value
Sokolow- SV1 + RV5/V6 e 35 mV 43% 96%
Lyon
R in aVL RaVL >1.1 mV 20% 96%

Cornell (SV3 + RaVL + 0.6 mV added in e 244 mV 27% 96%

product women) * QRS duration
Romhilt- 3 points: R or S in any limb e 5 points 50% 95%

Estes lead >0.2 mV or SV1-2 or RV5-

3 points: LV strain without

Expert Review of Cardiovascular Therapy

score 6

digitalis

1 point: LV strain with digitalis

3 points: Terminal negativity of

P wave in V1 and 0.04 s wide 2

LV strain STi segment

f depression
i d i ie 0.1 mV
30º + Present
asymmetric T wave

inversion in lead V2-V6 and in