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
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