Progress in Cardiovascular Diseases 63 (2020) 10–21

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Progress in Cardiovascular Diseases

journal homepage: www.onlinepcd.com

Left ventricular hypertrophy and hypertension☆

Mehmet Yildiz a, Ahmet Afşin Oktay b,⁎, Merrill H. Stewart c, Richard V. Milani c,
Hector O. Ventura c, Carl J. Lavie c
a
Department of Medicine, Southern Ohio Medical Center, Portsmouth, OH, United States of America
b
Department of Medicine, Division of Cardiology, Wentworth-Douglass Hospital, Partners HealthCare, Dover, NH, United States of America
c
Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School - The University of Queensland School of Medicine, New Orleans, LA, United
States of America

a r t i c l e i n f o a b s t r a c t

Article history: Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease (CVD) morbidity and mortality.
Received 17 November 2019 The left ventricle (LV) is a primary target for HTN end-organ damage. In addition to being a marker of HTN, LV
Accepted 17 November 2019 geometrical changes: concentric remodeling, concentric or eccentric LV hypertrophy (LVH) are major indepen-
dent risk factors for not only CVD morbidity and mortality but also for all-cause mortality and neurological pa-
Keywords:
thologies. Blood pressure control with lifestyle changes and antihypertensive agents has been demonstrated to
Hypertension
Left ventricular geometry
prevent and regress LVH. Herein, we provide a comprehensive review of literature on the relationship between
Left ventricular hypertrophy HTN and LV geometry abnormalities with a focus on diagnosis, prognosis, pathophysiological mechanisms, and
Remodeling treatment approaches.
Anti-hypertension therapy © 2019 Elsevier Inc. All rights reserved.

Contents

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Electrocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2D echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3D echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Speckle tracking echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cardiac magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Cardiovascular and all-cause mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Cerebrovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Abbreviations and acronyms: ACE, Angiotensin converting enzyme; ACC, American College of Cardiology; AF, Atrial fibrillation; AHA, American Heart Association; ALLHAT,
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack; ARBs, Angiotensin receptor blockers; ARIC, Atherosclerosis Risk in Communities; ASE, American Society of
Echocardiography; BP, Blood pressure; CAD, Coronary artery disease; CACS, Coronary artery calcium scoring; CCBs, Calcium channel blockers; CHIP, Chlorthalidone, indapamide, and
potassium-sparing diuretic/hydrochlorothiazide; CKD, Chronic kidney disease; CR, Concentric remodeling; CVD, Cardiovascular disease; DM, Diabetes mellitus; EACVI, European
Association of Cardiovascular Imaging; ECG, Electrocardiography; EF, Ejection fraction; ESC, European Society of Cardiology; ESH, European Society of Hypertension; HCM,
Hypertrophic cardiomyopathy; HF, Heart failure; HOPE, Heart Outcomes Prevention Evaluation; HTN, Hypertension or hypertensive; LIFE, Losartan Intervention for Endpoint
Reduction; LV, Left ventricle/ventricular; cLVH, Concentric left ventricular hypertrophy; eLVH, Eccentric left ventricular hypertrophy; LVH, Left ventricular hypertrophy; MESA,
Multiethnic Study of Atherosclerosis; MI, Myocardial infarction; MRI, Magnetic resonance imaging; RAAS, Renin-angiotensin-aldosterone system; RCT, Randomized clinical trial; RWT,
Relative wall thickness; SBP, Systolic blood pressure; SCD, Sudden cardiac death; SGLT2, Sodium-glucose cotransporter type2; STE, Speckle tracking echocardiography; 2D, Two-dimen-
sional; 3D, Three-dimensional.
☆ Statement of conflict of interest: see page 18.
⁎ Address reprint requests to: Ahmet Afşin Oktay, MD Department of Medicine, Division of Cardiology, Wentworth-Douglass Hospital, Partners HealthCare, 789 Central Ave, Dover, NH.
E-mail address: ahmet.oktay@wdhospital.org (A.A. Oktay).

https://doi.org/10.1016/j.pcad.2019.11.009
0033-0620/© 2019 Elsevier Inc. All rights reserved.
 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21 11

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Impact of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Non-pharmacological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Landmark studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Statement of conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Hypertension (HTN) is a major modifiable risk factor for cardiovas-
cular disease (CVD) morbidity and mortality.1,2 HTN frequently coexists
with other CVD risk factors, such as obesity, hyperlipidemia, diabetes
mellitus (DM), chronic kidney disease (CKD), and tobacco use.3 The
2017 American College of Cardiology (ACC)/American Heart Association
(AHA)/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline
for the Prevention, Detection, Evaluation, and Management of High
Blood Pressure in Adults has redefined the classification of HTN and pro-
posed novel treatment strategies. The guideline now defines HTN as a
systolic BP (SBP) of ≥130 mmHg or a diastolic BP of ≥80 mmHg, which
increases the prevalence of HTN among U.S. adults from 32% to 46%. In
diagnosing HTN, the emphasis is placed on the importance of out-of-
office BP measurements, which are better predictors of target organ
damage compared to in-office measurement and further discriminates
sustained HTN from white-coat or masked HTN. The guideline also rec-
ommends incorporation of the atherosclerotic CVD risk score in the de-
cision making to initiate pharmacological treatment with the aim of a
target BP of b130/80 mmHg.4
The left ventricle (LV) is a primary target for HTN end-organ dam-
age. HTN induced remodeling of the LV is often grouped into three dif-
ferent geometric patterns: concentric remodeling (CR), concentric LV
hypertrophy (LVH; cLVH), and eccentric LVH (eLVH).5 Electrocardiogra-
phy (ECG), echocardiography, and cardiac magnetic resonance imaging
(MRI) are the primary diagnostic modalities for the assessment of LV
geometric changes.6 In addition to being an end-organ response, LVH
is also an independent risk factor for CVD morbidity and mortality.7
The 2017 ACC/AHA high BP guideline noted the positive and negative
prognostic effects of LV geometric changes. However, the authors did
not recommend the routine use of echocardiography or cardiac MRI
for the assessment of LVH during the evaluation and management of
HTN due to a lack of data in cost-effectiveness.4 Numerous treatment
strategies from well-established thiazide diuretics, renin-angiotensin-
aldosterone system (RAAS) inhibitors and calcium channel blockers to
future promising sodium-glucose cotransporter type-2 (SGLT2) inhibi-
tors have been shown to regress LVH.8–11
Herein, we discuss the relationship between HTN and LV geometric
changes with a focus on diagnosis, epidemiology, pathophysiology,
prognosis, and treatment (Fig 1).
Diagnosis
Abnormalities of LV geometry can be evaluated by ECG, two-
dimensional (2D) and three-dimensional (3D) echocardiography,
speckle tracking echocardiography (STE), or cardiac MRI. The 2018
European Society of Hypertension (ESH)/European Society of Cardiol-
ogy (ESC) clinical practice guideline for the management of arterial
HTN defined LVH as a high-risk component in the Systematic Coronary
Risk Evaluation system and accepted LVH as a representative of diastolic
dysfunction. The guideline recommends (Grade IIB) 2D echocardiogra-
phy to detect LVH if the results are likely to influence treatment
decisions.12 According to the 2017 ACC/AHA high BP guideline, LVH as-
sessment “is most useful” in cases of young adults or adults with a his-
tory of secondary HTN or heart failure (HF) where the presence of
end-organ damage reinforces aggressive treatment in otherwise
healthy individuals.4
Electrocardiography
The 2018 ESH/ESC guideline for the management of arterial HTN
recognizes the most commonly used ECG criteria as: (1) SV1 + RV5 or
RV6 (Sokolow-Lyon) N35 mm, (2) R wave in aVL ≥11 mm, (3) SV3 + RaVL
(Cornell voltage) N28 mm for men and N20 mm for women, and (4) Cor-
nell product (Cornell voltage × QRS duration) N2440 mm × ms.12
Jiang et al. compared the diagnostic value of 18 different ECG criteria
to diagnose LVH among middle-aged subjects with HTN. Criteria of
SD + SV4, a combination of the deepest S-wave amplitude and the S-
wave amplitude of lead V4 ≥28 mm in males and ≥23 mm in females
had the highest sensitivity (29%) followed by Cornell product (24%).13
In a recent analysis from the MESA (Multi-Ethnic Study of Atherosclero-
sis) study, a new machine learning ECG technique, the Bayesian Addi-
tive Regression Trees, showed superior diagnostic and prognostic
ability compared to other traditional ECG techniques.14
Despite the low sensitivity and specificity in diagnosing LVH, elec-
trocardiographic LVH has a well-established prognostic value in CVD.
In the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Pre-
vent Heart Attack) study, baseline LVH by Cornell voltage was indepen-
dently associated with increased CVD morbidity and all-cause mortality
during a five-year follow-up among treated HTN participants.15 In the
LIFE (Losartan Intervention for Endpoint Reduction) study, persistence
or new development of LVH by both Cornell product and Sokolow-
Lyon was associated with markedly increased all-cause mortality.16
2D echocardiography
2D echocardiography remains the most commonly used imaging
modality for evaluation of LV geometry and its primary variables: LV
mass and relative wall thickness (RWT). Linear method and 2D based
formulas are the two main 2D echocardiographic methods for quantifi-
cation of LV mass. In linear method, LV mass is calculated as 0.8 × 1.04 x
[(interventricular septum + LV internal diameter + posterior wall
thickness)3 – LV internal diameter3] + 0.6 g. The linear method is a
widely used technique in clinical practice due to its ease of use and ac-
curacy in normally shaped ventricles. However, the linear method relies
on the assumption that the ventricle has a prolate ellipsoid shape, and it
does not consider the regional variations in LV thickness. Therefore, the
accuracy of the linear method is limited in the setting of asymmetric hy-
pertrophy, dilated LV, or other abnormalities of regional thickness. In
addition, even small measurement errors lead to an exaggeration of in-
accuracy due to the cubing of the parameters. 2D based formulas (trun-
cated ellipsoid and area-length methods) have the advantage of partial
correction for shape distortions. Therefore, they are less dependent on
geometric assumptions compared to linear methods. However, cumber-
some methodology, high measurement variability, and requirement of
good image quality make 2D based methods less attractive in routine
clinical practice.17
In addition to BP, LV mass correlates with several other variables
such as body size, age, sex, ethnicity, and physical activity level.18–24
12 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21

Fig 1. Central Illustration. Overview of left ventricular hypertrophy.

Therefore, it is difficult to define standard values for LV mass.17 LV mass
indexing to body surface area allows comparison among people with
different body sizes. However, in extremely obese individuals indexing
to height is more advantageous compared to body surface area.17,25
The 2015 American Society Echocardiography (ASE)/European As-
sociation of Cardiovascular Imaging (EACVI) chamber quantification
document defined increased LV mass index by body surface area as
N95 g/m2 in women and N115 g/m2 in men by linear methods; and
N88 g/m2 in women and N102 g/m2 in men by 2D formulas. RWT is cal-
culated as 2 x posterior wall thickness/LV end-diastolic diameter. Ac-
cording to LV mass and RWT, LV geometric patterns are classified into
four different types as follows: 1) normal LV geometry (normal LV
mass index and RWT ≤0.42); 2) cLVH (increased LV mass index and
RWT N0.42); 3) eLVH (increased LV mass index and RWT ≤0.42); and
4) CR (normal LV mass index and RWT N0.42).26 (Fig 2 and Fig 3)
3D echocardiography
3D echocardiography provides more accurate and reproducible
measurements in LV volumes and mass compared to 2D echocardiogra-
phy by not only relying on geometric modeling but also allowing for the
measurement of the non-foreshortened imaging.27,28 Despite its
strengths, 3D echocardiography can slightly underestimate LV mass as
compared to cardiac MRI.29
3D echocardiography technology is evolving rapidly. Several recent
studies confirmed the validity of automated techniques using artificial
 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21
Fig 2. Left ventricular geometric patterns determined by relative wall thickness and left ventricular mass index based on linear measurements. LVH, left ventricular hypertrophy. Adapted
from Konstam et al.151
intelligence for accurate quantification of chamber volumes.30–33 These
automated techniques are expected to help with the practical use of 3D
echocardiography in routine clinical practice as the application by un-
trained personnel can take additional time.
The 2015 ASE/EACVI document on cardiac chamber quantification
has not reported the normal reference values of LV mass by 3D echocar-
diography due to limited available data.17 Since the 2015 document,
several studies have been published validating the accuracy of LV
mass quantification by 3D echocardiography against cardiac MRI.
These studies have provided normal reference values for 3D echocardio-
graphic LV mass index in healthy subjects (Table 1).34–36 While these
studies have been helpful, owing to their comparatively small size, fur-
ther research is needed to determine normal reference values in 3D
echocardiography.
Speckle tracking echocardiography
LVH can develop secondary to pathological responses to pressure or
volume overload as in cLVH or eLVH, physiological responses to physical
exercise as in athletes, genetic disorders as in hypertrophic cardiomyop-
athy (HCM), or storage disorders as in amyloidosis (Table 2). The use of
STE technology helps substantially with understanding the etiology of
LVH and provides important prognostic information in patients with
LVH and preserved ejection fraction (EF).
Speckle tracking is a non-doppler and angle-independent quantita-
tive ultrasound technique which measures strain and strain rate by
tracking the motion of speckles during a cardiac cycle on both 2D and
3D echocardiograms. STE expands the measurements in three spatial
13
directions as longitudinal, radial, and circumferential. The STE technol-
ogy can also evaluate twisting, untwisting, and torsion of the LV
myocardium.37 Global longitudinal strain by STE is the most commonly
used strain parameter in clinical practice and it is a more sensitive
marker of LV dysfunction as compared to EF.38 Detection of subclinical
systolic dysfunction by STE provides diagnostic and prognostic insights
in HTN patients with preserved EF.39,40
Several studies have confirmed the utility of 2D STE in the differen-
tiation of an athlete's heart from HCM.41,42 For instance, Richand et al.
demonstrated that pathologic hypertrophic segments in patients with
HCM have significantly lower longitudinal strain compared to those of
an athlete's heart.41 Galderisi et al. compared the strain patterns of pro-
fessional athletes with young patients with HTN. They found that global
longitudinal strain was significantly lower in HTN patients compared to
that of professional athletes.43 The typical apical sparing pattern of lon-
gitudinal strain is a sensitive and specific STE finding for differentiation
of cardiac amyloidosis from LVH due to other pathologies.44
Cardiac magnetic resonance imaging
Cardiac MRI is generally considered the gold standard for quantifica-
tion and assessment of cardiac chambers.45,46 This technology does not
rely on geometric assumptions and provides superior delineation of the
endocardium and epicardium.47 Through its ability to provide repro-
ducible and unrestricted views, cardiac MRI has been used in clinical tri-
als to demonstrate subtle regression in LV mass after anti-HTN
treatment, e.g., LIFE sub-study.48
14 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21

Fig 3. Left ventricular geometric patterns determined by 2D echocardiography linear method. Parasternal long-axis view demonstrating end-diastolic linear measurements of left
ventricular (LV) internal diameter (LVID), LV septal wall (SW) thickness, LV posterior wall (PW) thickness. * interventricular septum, ∞ LV cavity, & LV inferolateral wall. Normal
Geometry: 23-year-old male, LVID of 5.31 cm, LV SW of 1.08 cm, LV PW of 1.01 cm, LV mass index of 112 g/m2, relative wall thickness (RWT): 0.38. Concentric Remodeling: 50 year-
old male, LVID of 4.19 cm, LV SW of 1.19 cm, LV PW of 1.26 cm, LV mass index of 88 g/m2, RWT: 0.60. Concentric LV hypertrophy (LVH): 57-year-old male, LVID of 4.79 cm, LV SW of
1.52 cm, LV PW of 1.53 cm, LV mass index of 144 g/m2, RWT: 0.64. Eccentric LVH: 40-year-old male, LVID of 7.48 cm, LV SW of 1.19 cm, LV PW of 1.21 cm, LV mass index of 222 g/m2,
RWT: 0.32.

Cardiac MRI is valuable in distinguishing different types of LVH, in-
cluding HTN heart disease, HCM, infiltrative cardiomyopathies, and ath-
letes' heart. By late gadolinium enhancement with T1 weighted
sequences, cardiac MRI can further detect and quantify myocardial fi-
brosis, a finding with significant prognostic importance. 49–53 Currently,
its availability, cost, and time-consuming nature limits the use of cardiac
MRI.45
Epidemiology
LV remodeling occurs in response to numerous modifiable and non-
modifiable risk factors, including age, gender, genetic factors, HTN, DM,
CKD, obesity, metabolic syndrome, obstructive sleep apnea, sedentary
lifestyle, and dietary salt intake. The reported prevalence of LV geomet-
ric patterns in patients with HTN varies depending on the population
studied, the imaging modalities utilized, and the way geometric pat-
terns are defined. A meta-analysis of 30 studies involving a total of
37,700 participants demonstrated that echocardiographic LVH was
present in 36% to 41% of all participants with HTN. This prevalence in-
creased to 58% to 77% in high-risk participants with HTN defined as
those with severe or refractory HTN or with history of DM or CVD.54 A
prospective cohort study (n = 6105) with a median follow up of 14-
years revealed ~2.5 times higher odds of developing ECG-LVH in the
presence of HTN. In this study, there was a 49% increase in the odds of
ECG-LVH for every 19 mmHg increase in SBP (p b .001).55
Pre-HTN has also been linked to cardiac remodeling. A meta-analysis
involving N73,000 subjects reported that patients with pre-HTN had an
Table 2
Differential diagnosis of left ventricular hypertrophy (LVH).

Physiological LVH
Table 1 ✓ Athlete's heart
3D echocardiography derived normal reference values of left ventricular mass index. Pathological LVH
Primary LVH
Fukuda et al. Muraru et al. Mizukoshi et al.
(2012) (2013) (2016) ✓ Hypertrophic cardiomyopathy
Secondary LVH
Study population ethnicity Japanese Caucasion Japanese / American
Number of subjects 410 226 230 (121/109) /160 ✓ Hypertensive heart disease
(Male/Female) (253/157) (101/125) (78/82) ✓ Infiltrative cardiomyopathy, i.e., amyloidosis or sarcoidosis
Mass index (g/m2) ✓ Valvular heart disease, i.e., aortic stenosis or regurgitation
Men (Mean ± SD) 64 ± 12 77 ± 10 69 ± 8 70 ± 9 ✓ Rare syndromes, i.e., Fabry disease, mitochondrial myopathy, glycogen storage
Women (Mean ± SD) 56 ± 11 74 ± 8 61 ± 8 60 ± 7 disorders
 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21
average LV mass and RWT higher than that of normotensive patients
but smaller than those with a history of HTN (p b .001).56 A large cohort
study among 52,111 Korean participants revealed a significant associa-
tion between HTN categories and the risk of LV remodeling defined with
increased RWT. They found a progressive increase in the odds ratio of LV
remodeling in the following order of HTN categories (from lowest to
highest): normotension, pre-HTN, controlled HTN, newly diagnosed
HTN, and uncontrolled HTN (OR: 1.00, 1.65, 2.02, 2.85, 3.31,
respectively).57 The recently published PAMELA (Pressioni Monitorate
E Loro Associazion) study reported a similar pattern of progressive in-
crease in the incidence of LVH from normotensive to pre-HTN and
HTN groups (9%, 23.2%, and 36.5%, respectively).58 Patients who
progressed from pre-HTN to sustained HTN over time had a significantly
higher incidence of LVH compared to those who had persistent pre-
HTN. These findings highlight the significance of early detection and
proper management of HTN to prevent end-organ damage.
Masked HTN is characterized by consistently elevated out-of-office
BP readings despite normal office BP readings.4 Masked HTN carries a
higher risk of CVD mortality compared to sustained HTN.59 A meta-
analysis of 13 studies with a total of 4884 untreated subjects revealed
a significantly higher LV mass index in patients with masked HTN com-
pared to normotensive individuals.60 Similarly, patients with white-
coat HTN have been shown to have higher LV mass index than those
with normotension.61
The presence of other comorbidities significantly contributes to the
risk of LV remodeling in patients with HTN. For instance, Palmieri
et al. reported a higher prevalence of LV geometric abnormalities
among DM patients with HTN compared to non-DM patients with
HTN.62 In a prospective study of 1160 subjects, the presence of meta-
bolic syndrome and CKD was shown to increase the risk of LVH by
2.4-fold among patients with HTN.63
Ambulatory BP measurements more closely correlate with LV geom-
etry abnormalities compared to office BP measurements.64,65 Abdalla
et al. reported a higher prevalence of LVH among blacks with a reverse
dipping pattern defined as an increase in BP at night assessed by ambu-
latory BP measurement.66 White coat HTN has an effect comparable to
ambulatory HTN as attended and unattended BP measurements corre-
late similarly with LV mass (r = 0.205 and r = 0.194, respectively).67
Pathophysiology
LV remodeling in response to HTN involves a complex interaction of
cardiomyocytes and cardiac non-myocytes, such as endothelial cells, fi-
broblasts, and the immune system.68
The mechanical stretch activates intracellular signaling cascades and
leads to gene expression and synthesis of proteins (e.g., actin, myosin),
which organize in the sarcomere. In general, LV wall stress is reduced by
increasing the size of cardiomyocyte by addition of sarcomeres in paral-
lel, in the case of pressure overload; whereas, in series, in the case of vol-
ume overload.26 This adaptive response is also mediated by several
neurohumoral mechanisms involving expression of catecholamines, an-
giotensin II, and growth factors from cardiac non-myocytes.68,69
The adaptive and innate immune systems play a vital role in the
pathogenesis of HTN and HTN-induced end-organ damage.70 In clinical
trials, an imbalance of adaptive immunity and elevated levels of pro-
inflammatory markers was shown to contribute to end-organ damage
in subjects with HTN.71,72 Mechanical stretch and upregulation of in-
flammation can trigger fibroblasts to differentiate into myofibroblasts
which build up myocardial fibrosis with increased production of colla-
gen type I and type II fibers. Myocardial fibrosis contributes to a variety
of clinical presentations in HTN heart disease including HF with pre-
served or reduced EF, reduced coronary flow reserve, and cardiac
arrhythmias.73–75
Another important pathophysiologic link between HTN and cardiac
remodeling is the upregulation of the sympathetic nervous system.
This finding is supported by the fact that in spontaneously HTN rat
15
models, sympathectomy leads to a reduction in BP and normalization
in LV mass.76
Prognosis
LVH is not only an adaptive response to hemodynamic changes but
also a significant risk factor for adverse CVD outcomes. Echocardio-
graphic LVH was associated with CVD morbidity and mortality, and
all-cause mortality in the Framingham Heart Study three decades
ago.77 Similarly, a recently published analysis on ALLHAT study partici-
pants (n = 26,384) with treated HTN showed a significant association
between electrocardiographic LVH and increased risk of myocardial in-
farction (MI), stroke, HF, and all-cause mortality.15
Prognostic impact of LVH has been reported in different ethnic
groups. A sub-group analysis of the ARIC (Atherosclerosis Risk In Com-
munities) prospective cohort study reported a significantly increased
risk of CVD in African-American subjects with LVH.78 A prospective co-
hort study, The Northern Manhattan Study, confirmed a similar pattern
among Hispanic-Americans by showing a significant association be-
tween LV mass and CVD morbidity.79
Women, in general, have a lower incidence of CVD morbidity com-
pared to men as in ischemic heart disease, HF, atrial fibrillation (AF),
or stroke.80–82 A community-based prospective cohort study, including
12,329 subjects with HTN, investigated the impact of LVH on gender-
specific CVD morbidity profile. In this study, LVH was more commonly
reported in women than men (43.4% vs. 32.1%; p b .001). The presence
of obesity and diabetes put both men and women at risk for LVH; how-
ever, women had a higher risk of LVH. Lower risk for major CVD events
(composite of acute coronary syndrome, stroke, decompensated HF,
and incident AF) was seen in HTN women compared to men in the ab-
sence of LVH (HR: 0.65; 95% CI: 0.44 to 0.96; p = .031). However, this
gender difference was erased in the setting of LVH. Women with HTN
had a comparable major CVD event risk compared to men in the pres-
ence of LVH (HR: 0.94; 95% CI: 0.69 to 1.30; p = .720).83
Cardiovascular and all-cause mortality
In a large retrospective study on a clinical population (n = 35,602)
referred for echocardiography, Milani et al. found a significant associa-
tion between CR or LVH (concentric or eccentric) and increased risk of
all-cause mortality (RR: 1.99; 95% CI: 1.88 to 2.18; p b .0001 and RR:
2.13; 95% CI: 1.89 to 2.40; p b .0001, respectively). Compared to the
other geometric patterns, cLVH carried a higher mortality risk. They fur-
ther showed that prognosis was dynamic in response to changes in LV
geometry, as the reversal of CR to a normal geometric pattern improved
survival (RR: 0.64; 95% CI: 0.42 to 0.97; p = .03).84
Several studies have indicated a link between abnormalities in LV
geometry and the risk of sudden cardiac death (SCD). A report from Or-
egon Sudden Unexpected Death Study, a population-based case-control
study, showed a significant association between abnormal LV geometric
patterns by echocardiography and increased risk of SCD (OR: 3.20, 2.47,
1.76 for cLVH, eLVH, and CR; respectively).85 A prospective cohort study
from Italy evaluated SCD risk factors in relatively young and untreated
HTN patients (n = 3242) without established CVD over an average
10-year follow up. Despite an overall low SCD event rate (~0.1%) in
the study population, electrocardiographic LVH almost tripled the risk
of SCD even after adjustment for sex, age, DM, and 24-h ambulatory
BP (HR: 2.99; 95% CI: 1.47 to 6.09; p = .002).86
Heart failure
To emphasize the progressive nature of HF and the importance of
prevention, the 2013 ACC Foundation/AHA guideline for the manage-
ment of heart failure considers HTN and LVH as stage A and stage B
HF, respectively.87 This staging also highlights the importance of these
risk factors in the pathophysiology of HF.
16 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21
Traditional models of HF include one whereby sustained pressure
overload results in an increased LV mass and RWT with consequent im-
pairment of LV compliance and elevated filling pressures. In contrast,
sustained volume overload remodels the heart by dilation in the LV
with a RWT in the normal range.88 However, a new line of evidence
has challenged this understanding. Sustained BP overload can cause dis-
tinct LV remodeling patterns at different parts of the heart (e.g., cLVH in
the septum and eLVH in the lateral wall).89 Further, some epidemiolog-
ical studies reported a higher prevalence of eLVH compared with cLVH
in patients with HTN. 90
The most recent ASE document on the evaluation of LV diastolic dys-
function considers LVH as an indicator of diastolic dysfunction.91 More-
over, LVH has also been associated with the risk of development of
systolic dysfunction.92 A retrospective study by Milani et al. found that
13% of HTN subjects with cLVH (n = 1024) developed systolic dysfunc-
tion after an average of 33 ± 24 months follow-up. Variables associated
with this progression were interval MI, prolonged QRS duration
(N120 ms), and elevated arterial impedance (N4.0 mmHg/ml/m2).93 Sim-
ilar results were observed in a retrospective study by Krishnamoorthy
et al. In their study, progression from LVH to systolic dysfunction oc-
curred in 20% patients (over ~7.5-year of follow-up), but noted that
was particularly rare in the absence of interval MI.94
Detectable troponin-T or elevated N-terminal pro-B type natriuretic
peptide have been shown to predict future risk of HF among subjects
with LVH (20.6% vs. 5.8% for detectable vs. undetectable troponin-T;
20.2% vs. 6.5% for elevated vs. normal N-terminal pro-B).95
Coronary artery disease
The population-based Dallas Heart Study (n = 2633) investigated
the relationship between LVH by cardiac MRI and coronary artery cal-
cium score (CACS) by computerized tomography. In a multivariable lin-
ear regression analysis, LV mass remained significantly associated with
the quantity of CACS (β 0.32; p b .001).96 A recent small cohort study
among 132 subjects with stable angina, who underwent myocardial
contrast stress echocardiography to measure the extent of myocardial
ischemia, reported a significant association between LVH and the risk
of myocardial ischemia (OR: 3.27; 95% CI: 1.11 to 9.60; p = .031).97
Furthermore, LVH was associated with increased CVD mortality after
percutaneous coronary interventions. This finding highlights the prog-
nostic impact of LVH in patients with established CAD.98 A retrospective
observational study investigated the long-term prognostic effects of
LVH in patients with ST-segment elevation MI (n = 481) managed
with successful primary percutaneous coronary intervention. The inves-
tigators reported a significant association between LVH and increased
risk of all-cause mortality (OR:2.37; 95% CI: 1.09 to 5.12; p = .028). Fur-
thermore, severe LVH (defined as ≥149 g/m2 in male and ≥122 g/m2 in
female) was associated with an even higher risk of mortality (OR:
5.11; 95% CI: 1.45 to 17.9; p = .001).99 A sub-study of the DANAMI-3
(DANish Study of Optimal Acute Treatment of Patients With ST-
elevation Myocardial Infarction) trial involving ST-segment elevation
MI patients (n = 764) managed with successful primary percutaneous
coronary intervention reported that LVH by cardiac MRI was signifi-
cantly associated with larger final infarct size, smaller final myocardial
salvage index, and higher incidence of microvascular obstruction.100
Arrhythmias
LVH increases the risk of cardiac arrhythmias. In a retrospective
study among subjects with untreated HTN (n = 2482), each standard
deviation increase in LV mass was associated with a 20% increase in
the risk of AF (95% CI; 1.07 to 1.34; p = .001).101 Hypertensive LVH
was also significantly associated with the progression of AF from parox-
ysmal to persistent and permanent (OR: 4.84; 95% CI: 1.70 to 13.78; p =
.003).102 Fortunately, in a small prospective study by Hennersdorf et al.,
regression in LV mass with anti-HTN treatment led to a significant de-
crease in the prevalence of AF from 12.5% to 1.5% (p = .05).103
Other than AF, LVH has been associated with ventricular and supra-
ventricular arrhythmias. A meta-analysis involving 27,141 subjects re-
vealed a 2.8-fold higher odds of developing ventricular tachycardia or
fibrillation and 3.4-fold higher odds of developing supraventricular
tachycardia in the presence of LVH.104
Cerebrovascular disease
An analysis on Framingham Heart Study participants (n = 1230,
age N 58 years, ~8-year follow-up) found that subjects in the highest
quartile of LV mass to height ratio had a 2.7 times higher risk of cerebro-
vascular disease when compared to those in the lowest quartile after
adjustment for other variables.105 A retrospective cohort study, which
included young ischemic stroke survivors (b60-year-old) reported ab-
normal LV geometry in 37% of study subjects (21% had CR, and 16%
had LVH).106 Bluemke et al. examined the association between LV
mass by cardiac MRI and the future stroke risk in 5098 subjects enrolled
in the prospective MESA study. Their analysis revealed a significant as-
sociation between LV mass index and stroke risk after adjustment for
other variables (HR: 1.2; 95% CI: 1.0 to 1.4; p = .01).107
Dementia
There exists a link between LVH and increased risk of impaired cog-
nitive performance. In a population-based study of subjects age N 74 years
old, echocardiographic LVH was a predictor of cognitive decline over a 5-
year follow-up.108 In the ARIC study (n = 12,665), electrocardiographic
LVH was associated with a markedly higher risk of dementia during a
median of 18-year follow-up (HR: 1.90; 95% CI: 1.47 to 2.44).109 Simi-
larly, a report on 4999 MESA study participants (median follow-up of
12-years) revealed that LV mass index and LV mass to volume ratio (in-
dicator of cLVH) by cardiac MRI were independently associated with in-
creased risk of dementia (HR: 1.01; 95% CI: 1.00 to 1.02 and HR: 2.37;
95% CI 1.25 to 4.43, respectively).110
Treatment
Impact of treatment
In the 1990s, an investigation of Framingham Heart Study subjects
demonstrated a significant improvement in CVD morbidity in correla-
tion with regression of electrocardiographic LVH over time (OR: 0.46;
95% CI: 0.26 to 0.84).111 Subsequent landmark trials in the early 2000s
such as MRFIT (Multiple Risk-Factor Intervention Trial), HOPE (Heart
Outcomes Prevention Evaluation), and LIFE confirmed the possibility
of LV regression in response to anti-HTN therapy and related CVD prog-
nostic benefits.8,9,112 A recent report from SPRINT (Systolic Blood Pres-
sure Intervention Trial) demonstrated that, compared to standard SBP
control (b140 mmHg), intensive SBP control (b120 mmHg) was associ-
ated with a 46% lower risk of developing ECG-LVH in participants with-
out baseline LVH and 66% higher likelihood of regression/improvement
of LVH in participants with baseline LVH.113
The ratio of regression in LV mass with anti-HTN therapy varies sig-
nificantly depending on the population studied.114 The predictors of
persistent LVH and lack of LVH regression with anti-HTN therapy are
older age, central obesity, higher body mass index, kidney disease, sub-
optimal BP control, and longer duration of HTN.115,116 Therefore, to
avoid irreversible LVH, anti-HTN therapy should be started early with
an appropriate BP goal and simultaneous management of related co-
morbidities such as obesity.
The 2018 ESH/ESC guideline for the management of arterial HTN
recommend (Grade 1A and Grade IIA) that all patients with HTN and
LVH should be treated with RAAS inhibitors in addition to calcium
 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21
channel blockers (CCBs) or diuretics with a target SBP goal of
120–130 mmHg.12
Non-pharmacological
In the early 1980s, a small randomized clinical trial (RCT) which en-
rolled overweight participants with HTN, revealed a significant regres-
sion in LV mass (up to 24%) in response to weight reduction with
lifestyle changes. This significant association between LV mass and
weight reduction was independent of change in BP.117 Furthermore, in
a meta-analysis of 1022 obese subjects, bariatric procedures were asso-
ciated with a significant decrease in LV mass, RWT, and left atrial diam-
eter, with a corresponding improvement in diastolic dysfunction.118
Lifestyle changes can also decrease the future risk of incident LVH in
patients with HTN. In a prospective study of HTN subjects (n = 454)
without baseline LVH, regular aerobic exercise was shown to improve
BP and reduce the risk of LVH development during 8.3 years of follow-
up (10.3% for sedentary; 1.7% for active; p b .001).119
Landmark studies
All major anti-HTN drug classes, including diuretics, CCBs, β-
blockers, angiotensin-converting enzyme (ACE) inhibitors, and angio-
tensin receptor blockers (ARBs) have been shown to regress LVH sec-
ondary to HTN.
In the early 2000s, the HOPE trial showed that compared to placebo,
treatment with ramipril led to regression or prevention of LVH and re-
duction of the risk of CVD mortality, MI, and stroke (12.3% vs. 15.8%
for regression/prevention of LVH vs. development/persistence of LVH;
p = .006).8 Losartan was compared to atenolol in the randomized LIFE
trial, which enrolled 9193 HTN participants with electrocardiographic
LVH. Losartan reduced the severity of LVH and prevented adverse CVD
outcomes better than did atenolol (HR: 0.87; 95% CI: 0.77 to 0.98;
p = .021). In addition, losartan use was associated with a 25% lower
risk of new-onset DM (HR: 0.75; 95% CI: 0.63 to 0.88; p = .001).9 Subse-
quent analysis from the LIFE study by Okin et al. reported a 12.2% lower
rate of new-onset AF proportional to electrocardiographic LVH regres-
sion (for every 1050 mm x msec (per 1-SD) lower Cornell product) in-
dependent of BP reduction or medication arm (HR: 0.88; 95% CI: 0.80 to
0.97; p = .007).120 In the PRESERVE (Prospective Randomized Enalapril
Study Evaluating Regression of Ventricular Enlargement) trial, enalapril
was compared to long-acting nifedipine among HTN participants with
LVH (n = 202). Treatment with both medications led to a similar mod-
erate degree of regression in LV mass (26 g vs. 32 g; p = .36).121
Pitt et al. compared eplerenone, a selective aldosterone blocker, to
enalapril in a double-blind RCT among HTN patients with LVH and re-
ported similar degrees of LVH regression with both drugs.122 They also
found that compared to eplerenone alone, the combination of enalapril
and eplerenone was more effective in reducing LV mass. Other trials
have explored the idea of combination therapy. The ADVANCE (Action
in Diabetes and Vascular Disease Study) trial showed that a fixed com-
bination of long-acting ACE inhibitor -perindopril- and a thiazide-like
diuretic -indapamide- had additive CVD morbidity and mortality bene-
fits. An echocardiographic sub-study of the ADVANCE trial also showed
a reduction in LV mass index by 2.7 g/m2 (95% CI: −5.0 to −0.1; p =
.04) among those treated with this fixed combination.123 The landmark
ALLHAT trial and subsequent ALLHAT-HF validation study endorsed the
superiority of chlorthalidone over amlodipine, lisinopril, or doxazosin in
preventing HF.124,125 Subsequent posthoc analysis of ALLHAT revealed
that reduction in LVH along with a reduction in BP by chlorthalidone ex-
plained up to 13% of its HF prevention effect compared to other anti-
HTN drug classes in the study.126
The landmark PARADIGM-HF (Prospective Comparison of Angioten-
sin Receptor-Neprilysin Inhibitors with an ACE inhibitor to Determine
Impact on Global Mortality and Morbidity in Heart Failure) trial showed
a more substantial reduction in CVD morbidity and mortality for
17
sacubitril/valsartan treatment compared to enalapril.127 Vasodilation
and anti-proliferative effects of sacubitril might explain some aspects
of this superiority. Schmieder et al., in a double-blind, multicenter RCT
involving participants with HTN, reported that sacubitril/valsartan pro-
vided a more significant reduction in LV mass compared to olmesartan
which might contribute to the superiority of sacubitril in terms of its fa-
vorable outcomes.128 Furthermore, a recently published meta-analysis
of 20 studies (16 non-RCTs and 4 RCTs) revealed a significant regression
in LV mass with sacubitril/valsartan treatment compared to ACE inhib-
itors or ARBs among subjects with HF with reduced EF.129
Meta-analyses
A meta-analysis involving 80 double-blind RCTs, including all major
drug classes and echocardiographic assessment of LV mass, showed a
significant reduction in the LV mass index by 13% with ARBs, 11% with
CCBs, 10% with ACE inhibitors, 8% with diuretics, and 6% with β-
blockers. The pairwise comparison analysis reported ARBs, CCBs, and
ACE inhibitors to be more effective compared to β-blockers; however,
diuretics were not included in the pairwise comparison analysis.130
The design of this meta-analysis was criticized because each treatment
arm of the included studies was considered as a separate observation
despite original comparative designs. Fagard et al. conducted a meta-
analysis of 75 RCTs using a pooled pairwise comparison of each drug
class versus other classes along with meta-regression analysis. In this
analysis, β-blockers reduced LV mass significantly less than ARBs
(9.8% vs. 12.5%; p = .01) and were found to be a significant negative
predictor of the regression (−3.6%; p b .01). Overall, the inferiority of
β-blockers was more prominent than the superiority of ARBs.114 The
mechanism behind the marked decrease in LV mass by ARBs, ACE inhib-
itors, or CCBs might be explained by; 1) activation of RAAS stimulates
myocardial cells growth, 2) increase in plasma angiotensin II level is in-
dependently associated with LVH, and 3) sympathetic nerve activity is
stimulated through N-type calcium channels.131–133 On the other
hand, the minimal decrease by β-blockers might be explained by a
smaller reduction in central aortic BP and a more significant reduction
in heart rate. Both of these factors result in a relatively increased LV
end-diastolic diameter with subsequently higher LV wall stress.134
A meta-analysis by Roush et al. which combined the data of diuretic
arms in 38 RCTs compared the efficacy of hydrochlorothiazide and
“CHIP” diuretics (CHlorthalidone, Indapamide, and Potassium-sparing
diuretic/hydrochlorothiazide). Their results revealed that “CHIP” di-
uretics reduced LV mass 2-fold more than hydrochlorothiazide.135 A
subsequent head-to-head systematic review involving 12 double-
blind RCTs reported that “CHIP” diuretics were better than RAAS inhib-
itors in the reduction of LV mass.136
Future directions
DM is a major risk factor for cardiac remodeling and LVH. SGLT2 in-
hibitors are relatively novel anti-diabetic agents with added benefits of
BP and weight reduction.137,138 Landmark trials, EMPA-REG Outcomes
(Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabe-
tes) and CANVAS (The Canagliflozin Cardiovascular Assessment Study)
demonstrated beneficial effects of empagliflozin and canagliflozin on
CVD morbidity and mortality.139,140 To assess whether regression of LV
mass could explain the potential mechanism behind the benefit in CVD
morbidity and mortality with SGLT2 inhibitors, various small trials are
still in progress, such as DAPA-LVH, EMPATROPHY, EMPA-HEART, and
NCT0295691.141 Potential mechanisms for LV mass reduction by SGLT2
inhibitors include 1) decrease in LV wall stress secondary to diuresis
and natriuresis; and 2) suppression of sodium‑hydrogen exchange in
cardiomyocytes which impacts cardiac remodeling.142,143 In a non-
diabetic rodent model of HF with preserved EF, Empagliflozin was
shown to reduce the LV mass without affecting BP, which led to im-
provement of diastolic dysfunction.11
18 M. Yildiz et al. / Progress in Cardiovascular Diseases 63 (2020) 10–21
Animal model studies have shown regression of LVH by xanthine ox-
idase inhibitors by reducing oxidative tissue stress, which mediates
myocardial hypertrophy.144,145 RCTs showed that allopurinol, a xan-
thine oxidase inhibitor, was associated with a significant regression in
LVH without a change in BP in adult patients with CAD, CKD, or
DM.146–148
Renal sympathetic denervation was an exciting innovation for the
treatment of resistant HTN until the single-blind Symplicity HTN-3
RCT failed to show a significant reduction in BP in the therapeutic
arm.149 However, a recent meta-analysis involving 12 observational,
but no RCTs, reported a significant decrease in LV mass index by cardiac
MRI with renal sympathetic denervation (−5.43 g/m2; 95% CI: −10.1 to
−0.35 g/m2).150
Conclusions
LVH is a leading risk factor for CVD morbidity and mortality, stroke,
cognitive impairment, and all-cause mortality. Elevated BP, at pre-HTN
and HTN stages, is a major contributor to LV remodeling, including CR,
cLVH, and eLVH. ECG and 2D echocardiography are the primary diag-
nostic tools for the diagnosis and quantification of LVH. Evolving 3D
echocardiography technologies provide more accurate and reproduc-
ible measurements but are still relatively new, and ongoing studies to
determine standard reference values are underway. Cardiac MRI is not
only superior to other techniques in the quantification of LVH, but also
helpful with distinguishing different types of LVH, yet can be costly
and time-consuming. BP control with lifestyle changes and anti-HTN
agents can lead to the prevention or regression of LVH. Diuretics,
RAAS inhibitors, and CCBs are the guideline-directed treatment options
with well-known survival benefits through the regression of LVH. Mul-
tiple clinical trials are currently underway to understand the impact of
SGLT2 inhibitors on LV mass in DM patients with or without HTN.
Statement of conflict of interest
None of the authors have any conflicts of interests with regard to this
publication.
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