Left Ventricular Hypertrophy

“New Insights”

Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece

Athanasios J. Manolis MD, FACC, FESC, FAHA

Overview

Introduction and Factors promoting LVH

Diagnostic approach

LVH: a CV risk factor

Pharmacologic strategies for prevention

and regression of LVH

Future novel approaches

Take home message

Left Ventricular Hypertrophy: Definition

LVH represents the heart’s response

to increased biomechanical stress

such as HTN.

LVH has traditionally considered a

compensatory mechanism required

to normalize wall tension and to

maintain CO in the face of increased

afterload, and increased

perivascular and interstitial fibrosis

Why an adaptive response increase CV risk in hypertensive patients with LVH?

Physiological Pathological

Conditions Pregnancy

Postnatal growth

Regular physical activity

Pressure overload

Volume overload

Direct myocardial injury

Stimuli Peptidic growth factors Physical stretch

Neurohumoral agents

Cardiomyocyte changes

Receptor

Signalling pathway

Calcium homeostasis

Fetal gene expression

Apoptosis

RTK GPCR

PI3K-Akt

Preserved

Relatively normal

Normal

Gαq/PLC

Disturbed

Usually upregulated

Stimulated

Noncardiomyocyte changes

Extracellular matrix

Intramyocardial vessels

Normal

Normal

Fibrosis

Arteriolar remodelling

Capillary rarefanction

Clinical aspects

Cardiac function

Association with HF

Incidence of arrythmia

Coronary flow reserve

Association with increased mortality

Complete regression

Normal or enhanced

No

Normal

Normal or increased

No

Usually

Depressed over time

Yes

Increased

Reduced

Yes

Not usually

Differences Between Physiological And Pathological

Manifestations Of Left Ventricular Hypertrophy

Prevalence of LVH

Prevalence varies widely depending on different diagnostic

modalities and criteria used, severity and duration of HTN,

intensity of treatment, patients compliance etc.

Electrocardiographic LVH: 1 to 8%

Echocardiographic LVH is about 20-30% in mild-moderate

HTN and 50-60% in severe HTN

Manolis AJ et al. J Hypertens 2012

30 studies, 37700 untreated and treated HTN patients

Prevalence: 36% - 41%, similar men and women

Eccentric vs Concentric 22% vs 15% (p<0.05)

Cuspidi C et al. J Hum Hypertens 2011

Patterns of LV Remodelling Based on EDV, Wall

Mass, and RWT

Gaasch WH et al. J Am Coll Cardiol 2011;58:1753

Left Ventricular Hypertrophy:

Risk factors and Consequences

Background

Age

Gender

Race

Obesity

Salt

Alcohol

Other disease

Hemodynamic

Blood pressure

Volume load

Arterial stiffness

Blood viscosity

Nonhemodynamic

Sympathetic nervous system

Renin-angiotensin-aldosterone system

Insulin

Humoral stimulatory factors

Hymoral inhibitory factors

Genetic factors and other intracellular signals

Cardiomyocyte

apoptosis Cardiomyocyte

hypertrophy

Myocardial

fibrosis

Microcirculatory

alterations

Impaired systolic

contraction

Impaired

diastolic filling

Altered

Conduction and

focal re-entry

machanisms

Impaired coronary

Flow reserve

Left ventricular

dysfunction Arrythmias Myocardial

ischemia

Exercise Capacity and BP Associations with LVM

in Prehypertensive Individuals

SBP at the workload of 5 METs is a strong an practical

predictor of LVH in prehypertensive individuals

A 4-fold increase in the risk of LVH was noted for every

10 mm Hg rise in SBP beyond the threshold of 150

mm Hg at this exercise level of 5 METs

Also we found an inverse association between LVM and

exercise capacity. For every 1 MET increase in the

workload we noted a 42% reduction in the risk for

LVH

Prehypertensive individuals with low exercise capacity

are identified as a high risk subgroup for developing

LVH.

Kokkinos P, A. Pittaras, Manolis AJ et al. Hypertension 2007

Angiotensinogen

Angiotensin I

Angiotensin II

Cardiac

fibrosis

Electrical

remodeling

Cardiac

Hypertrophy

Hypertension

Atrial Pressure

and stretch

Sympathetic

overactivity

Pro-inflammatory

effects

Renin

ACE

New Take on the Role of Ang II in Cardiac

Hypertrophy and Fibrosis

Sodium and

aldosterone

Oxidative

stress

The Relationship Between Renal Impairment And Left Ventricular Structure, Function, And Ventricular-erterial Interaction In

Hypertension

Undetectable (n=148)

Normal or low (n=292)

High or very high (n=100)

P for trend Adjusted P for trend

Left ventricular structure

LVMI (g/m2)

PWT(cm)

ASWT(cm)

LVEDV(ml)

LVESV(ml)

68.5 9.5

0.86 0.08

0.86 0.09

89.5 14.9

38.5 8.0

71.8 13

0.88 0.11

0.89 0.12

96.5 20.0

42.8 10.8

73.8 13.

0.90 0.10

0.91 0.11

99.7 18.5

45.0 10.0

0.0009

0.0001

0.0003

<0.0001

<0.0001

0.13

0.011

0.019

0.16

0.54

Left ventricular systolic function

LVEF (%)

57.2 3.3

56.0 3.2

55.1 2.9

<0.0001

0.12

Left ventricular diastolic function

LAVI (ml/m2)

E’ (cm/s)

E/E’

IVRT

NT-proBNP (PG/ML)*

30.9 4.7

7.73 1.16

9.2 2.2

102 18

61 (52-72)

29.1 5.2

7.56 1.28

9.6 2.7

106 18

69 (61-78)

28.7 5.4

7.26 1.15

9.6 2.9

110 20

103 (82-128)

0.0003

0.0033

0.21

0.0017

0.0002

0.21

0.0107

0.0028

0.82

0.0025

Echocardiogaraphic parameters by urine albumin-to-creatinine ratio category

Shah A et al J Hypertens 2011;29:1829

Kontaraki J et al. J Hypertens 2011;29:791

Early Cardiac Gene Transcript Levels in Peripheral

Blood Mononuclear Cells in Patients with Untreated HTN

Overview

Introduction and Factors promoting LVH

Diagnostic approach

LVH: a CV risk factor

Pharmacologic strategies for prevention

and regression of LVH

Future novel approaches

Take home message

2007 ESH/ESC Guidelines and Search

for Subclinical Organ Damage

2003

GLs

2007

GLs SCr (> 1.4-1.5 mg/dl)

eCrCl / GFR

MA

EKG †

SCr (> 1.4-1.5 mg/dl)

EKG †

LVH (Echo)

Concentric LVH

LA enlargement

CA thickening / plaques

Ankle/Brachial ratio

Arterial stiffening (PWV)*

LVH (Echo)

CA thickening / plaques

MA

Routine Recommended

Search for

multiorgan OD

OD assessed before

and during T

* Depending on availability / also shown by high SBP / low DBP

† LVH / MI-ischemia / Arrhythmias

New Data in the Area of the ECG Diagnosis

IKARIA Study: 570 pts, using ECG and Echo in elderly participants,

Cornell voltage, its product and Framingham criteria

were associated with Echo detection of LVH,

and Cornell product in younger ones.

Tsiachris D et al. J Hypertens 2011;29:1624

HERMEX Study: 2564 pts using ECG, … the best prevalence ratio

between hypertensives and normotensives was

achieved with Lewis, Dalfo and Perugia criteria.

Felix-Redondo F et al. J Hypertens 2012;30:1460

958 hypertensives using ECG and Echo, …. The single measurement

of the R wave in aVL gives results at least as good as those of

more complicated indices

Gosse P et al. J Hypertens 2012;30:990

Normal range and Cut-off Values for ECG and Echo

According to ESH/ESC Guidelines

Parameter Normal range Pathologic cut-off point

LV mass index (g/ m 2) 43-95 in women

49-115 in men

≥ 110

≥ 116

LV mass index (g/m 2.7) 18-44 in women

20-48 in men

≥45

≥ 49

Relative wall thickness 0.22-0.42 in women

0.24-0.42 in men

≥ 0.42

≥ 0.42

E/ average e’ ratio <8 ≥ 13

LAVi (ml/m 2 ) 22-33 ≥ 34

ECG: Sokolow-Lyon>38 mm

Cornell voltage duration product >2240 mm*ms

ECHO

LAVi = Left atrial volume index, LV = Left ventricular

Predictive Value, Availability, and Cost-

Effectiveness of ECG and ECHO

Parameter CV predictive

value

Availability Reproducibility Cost-effectiveness

Electrocardiography +++ ++++ ++++ ++++

Echocardiography ++++ +++

++ +++

E. Hamodraka,, MS Kallistratos, V Lezos, LE Poulimenos,, I Zacharopoulou, K Kifnidis, A

Giannakopoulos, N Kouremenos, AJ Manolis

ESC 2012 Abs

Two- dimensional strain can be used

to identify latent left ventricular

dysfunction in hypertensive patients .

Assessment Of Left Ventricular Function In

Hypertensive Patients With 2-dimensional Strain

3 D – echocardiography global systolic function

Regional systolic function

Hemodynamic and Humoral Correlates in Essential HTN:

Relationship Between Patterns of LVH and Myocardial

Ischemia

Manolis AJ et al. Hypertension. 1997

ETT (-) ETT(+), Th(+), CA(-)

Overweight, Hyperlipidemia, Holter: (+), HRV: (+), LPs: (+)

NE: p:NS

3D CONTRAST ECHOCARDIOGRAPHY

Manolis AJ et al. J Hypertens 2012; 30:1325–1327

It would be useful to develop a model in which

ECG LVH criteria could be combined with

additional clinical variables and/or biomarkers to

improve risk stratification and may obviate the

need for echocardiography at least when, in these

times of austerity, cost has to be considered

ECG For The Diagnosis Of LVH:

Revisiting An Old Friend In Times Of Austerity

Overview

Introduction and Factors promoting LVH

Diagnostic approach

LVH: a CV risk factor

Pharmacologic strategies for prevention

and regression of LVH

Future novel approaches

Take home message

0

40

10

20

30

1 tertile

(LVMI < 91 g/m2)

2 tertile

(LVMI 91-117 g/m2)

3 tertile

(LVMI > 117 g/m2)

149+32 g/m2

75+11 g/m2

79+9 g/m2

104 + 7 g/m2

104 + 8 g/m2

141+21 g/m2

CV ev (%)

RWT < 0.44

RWT > 0.44

*

* §

Muiesan ML et al, Hypertension 2004

*

§

§

CV Events According To LV Geometry Changes

Study

Tsioufis

Mihani

CASE-J trial

CV Health Study

ELSA

Laurent

Fowkes

De Buyzere

Koren

Tsioufis

HOT

INSIGHT

Jensen

Condition

Hypertension

Outpatients

Hypertension

Elderly

Hypertension

Hypertension

Outpatients

Outpatients

Hypertension

Hypertension

Hypertension

Hypertension

Hypertension

10 yr CVD

≥ 20%

Yes

Yes

Yes

Yes

Yes

Yes

Yes (men)

Yes (men)

Yes

Yes

Yes

Yes

Yes (CHD)

Organ damage

LVH (echo)

LVH (echo)

LVH (echo)

Ca IMT (highest quintile)

Ca IMT (2 highest quintiles)

PWV (highest quintile)

Ankle / brachial ratio

Ankle / brachial ratio

LVH (echo)

Low eGFR

Low eGFR or high SCR (≥ 1.5 mg/dl)

Low eGFR or high SCR (≥ 1.5 mg/dl)

MA

Subclinical Organ Damage as a Marker of

High CV Risk Condition

LVH vs CKD as predictors of CV events in HTN

: a Greek 6-year-follow-up study

3.2 Fold

1652 hypertensives free of CV disease were enrolled within a period of

3 yrs (1998-2000)

Tsioufis C, et al. J Hypertension 2009

The Many Aspects of Left Ventricular Hypertrophy

LVH And Abdominal Aorta Size In Essential HTN: The ETODH Study

Quartiles of abdominal aorta diameter

10

20

30

40

0

50

Pe

rce

nt

(a)

Prevalence of LVH in hypertensive men (red bars) and women (yellow bars) according to quartiles

of abdominal aortic diameter indexed to body surface area. * P < 0.01

70

60

*

I II III IV Quartiles of abdominal aorta diameter

10

20

30

40

0

50

Pe

rce

nt

(b) 70

60

*

I II III IV

Cuspidi C et al. J Hypertens 2011;29:1213

Risk Factor for the Development of AF

38-year follow-up of the Framingham study

Risk factors

Ag

e-a

dju

ste

d o

dd

s r

ati

o

Cigarettes

1

2

3

4

0

Diabetes ECG LVH Hypertension BMI Alcohol

Left Atrial Size In Hypertension And Stroke

Predictor OR Lower Upper P

LAVi 1.73 1.06 2.65 0.001

Left ventricular mass index 1.11 1.03 1.21 0.012

Significant stenosis in iCA 1.09 1.03 1.24 0.033

Atherosclerotic changes in iCA

1.07 1.03 1.14 0.042

History of PAF 1.02 0.92 1.16 0.421

CI, confidence interval; iCA, internal and common carotid artery; LAVi, left atrial volume index; OR, odds ratio; PAF, paroxysmal atrial fibrillation. aMore than 50% stenosis in at least one CA.

Logistic regression model for cavariates of stroke

95% CI

Piotrowski G et al. J Hypertens 2011;29:1988

Quantification of LA volume

Assessment Of Left Atrial Function In Hypertensive

Patients With 2-dimensional Strain

Two- dimensional strain can be used to

identify latent left atrial dysfunction in

hypertensive patients .

ESC 2012

E. Hamodraka, V Lezos, MS Kallistratos, LE Poulimenos,, I Zacharopoulou, T.

Zamfir,K Kifnidis, N Kouremenos, AJ Manolis

Overview

Introduction andFactors promoting LVH

Diagnostic approach

LVH: a CV risk factor

Pharmacologic strategies for prevention

and regression of LVH

Future novel approaches

Take home message

LVMI at Baseline and 16 Weeks

Kokkinos et al. N Engl J Med 1995;333:1462-7

* p<0.05

Baseline

125

140

155

170

163

143

16 weeks

2007 ESH/ESC Guidelines

Preferred Drugs

ISH (elderly) MS (or risk of incident DM) DM Pregnancy Blacks

LVH Asympt. atherosclerosis MA Renal dysfunction Previous stroke Previous MI Angina pectoris CHF

AF (recurrent) AF (permanent) ESRF/proteinuria PAD

D / CA ACEI / ARB (+CA / low dose D) ACEI / ARB CA / MD / BB D / CA

ACEI / CA / ARB CA / ACEI ACEI / ARB ACEI / ARB

any BP lowering agent BB / ACEI / ARB BB / CA D / BB / ACEI / ARB / antialdo agents

ARB / ACEI BB / nonDHCA ACEI / ARB / loop D CA

Condition

Subclinical OD

Clinical Event

LIFE Study Primary Composite Endpoint

0 6 12 18 24 30 36 42 48 54 60 66

Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901

Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Study Month

Pro

po

rtio

n o

f p

ati

en

ts

wit

h f

irs

t e

ve

nt

(%)

Intention-to-treat

Losartan

Atenolol

2

4

6

8

10

12

14

16

Adjusted risk reduction 13·0%, P=0·021

Unadjusted risk reduction 14·6%, P=0·009

Role Of Plasma Aldosterone Concentration In Regression Of LVM Following Antihypertension Medication

-4

-8

-10

-6

Ch

an

ge

in

LV

MI(

%)

AE(-)

0

-2

P<0.01

15

0

5

10

25

15

5

0

10

20

AE(+)

-4

-8

-6

Ch

an

ge

in

RW

T(%

)

AE(-)

0

-2

P=n.s.

AE(+)

P=n.s.

Ch

an

ge

in

E/A

(%

)

Ch

an

ge

in

E’ (%

)

AE(-) AE(+) AE(-) AE(+)

P<0.05

Yoshida C et al. J Hypertens 2011;29:357

Role of Plasma Aldosterone Concentration in Regression

of LVM Following Antihypertensive Treatment

Yoshida C et al. J Hypertens 2011;29:357

Perindopril and Indapamide Reverse Coronary Microvascular Remodelling and Improve Flow in HTN

Neglia D et al. J Hypertens 2011;29:364

Effects Of Perindopril-indapamide On Left Ventricular

Diastolic Function And Mass In Patients With Type 2

Diabetes:the ADVANCE Echocardiography Substudy

Placebo -15

-10

-5

0

-20

Perindopril-Indapamide

5

10 No LVH LVH

BL-6M BL-4yrs BL-6M BL-4yrs

ADVANCE Collaborative Group J Hypertens 2011;29:1439

Overview

Introduction and Factors promoting LVH

Diagnostic approach

LVH: a CV risk factor

Pharmacologic strategies for prevention

and regression of LVH

Future novel approaches

Take home message

RSD Reduces LVH and Improves cardiac Function

in Patients with Resistant HTN

Brandt MC et al. J Am Coll Cardiol 2011;59:901

Cardiovascular Magnetic Resonance in HTN

Measurement of ventricular

volume, mass, function

and hemodynamics

Tissue characterization of

diffuse and local fibrosis

Exclude secondary HTN

Maceira AM et al. J Cardiovasc MR 2012;14:28

Assessment of left ventricular mass and volumes by three-dimensional

echocardiography in patients with or without wall motion abnormalities:

comparison against cine magnetic resonance imaging

3-D ECHOCARDIOGRAPHY- LV mass

Heart 2008;94:1050–1057

Take Home Message

The clinical burden of LVH is great, as is the

opportunity to develop new treatment options.

Innovation will require investigations that consider

hypertrophy, fibrosis, ischemia, altered metabolism,

aortopathy, and atrial myopathy as interconnected

mechanisms along the LVH spectrum

Take Home Message

Strategies to optimize the use of available

pharmacological agents

Strategies to blunt or reverse pathological

cardiomyocyte growth

Strategies to induce physiological cardiomyocyte

growth

Strategies to repair myocardial remodelling

New therapeutic targets and strategies