Left Ventricular Hypertrophy New Insights

Transcription

1 Left Ventricular Hypertrophy New Insights Athanasios J. Manolis MD, FACC, FESC, FAHA Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece

2 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

3 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?

4 Differences Between Physiological And Pathological Manifestations Of Left Ventricular Hypertrophy Conditions Physiological Pregnancy Postnatal growth Regular physical activity Pathological 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 Noncardiomyocyte changes Extracellular matrix Intramyocardial vessels Clinical aspects Cardiac function Association with HF Incidence of arrythmia Coronary flow reserve Association with increased mortality Complete regression RTK GPCR PI3K-Akt Preserved Relatively normal Normal Normal Normal Normal or enhanced No Normal Normal or increased No Usually Gαq/PLC Disturbed Usually upregulated Stimulated Fibrosis Arteriolar remodelling Capillary rarefanction Depressed over time Yes Increased Reduced Yes Not usually

5 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 studies, 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

6 Patterns of LV Remodelling Based on EDV, Wall Mass, and RWT Gaasch WH et al. J Am Coll Cardiol 2011;58:1753

7 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 Altered Impaired systolic contraction Impaired diastolic filling Conduction and focal re-entry machanisms Impaired coronary Flow reserve Left ventricular dysfunction Arrythmias Myocardial ischemia

8 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

9 New Take on the Role of Ang II in Cardiac Hypertrophy and Fibrosis Sodium and aldosterone Angiotensinogen Angiotensin I Angiotensin II Renin ACE Oxidative stress Cardiac fibrosis Electrical remodeling Cardiac Hypertrophy Hypertension Atrial Pressure and stretch Sympathetic overactivity Pro-inflammatory effects

10 The Relationship Between Renal Impairment And Left Ventricular Structure, Function, And Ventricular-erterial Interaction In Hypertension Echocardiogaraphic parameters by urine albumin-to-creatinine ratio category 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/m 2 ) PWT(cm) ASWT(cm) LVEDV(ml) < LVESV(ml) < Left ventricular systolic function LVEF (%) < Left ventricular diastolic function LAVI (ml/m 2 ) E (cm/s) E/E IVRT NT-proBNP (PG/ML)* (52-72) (61-78) (82-128) Shah A et al J Hypertens 2011;29:1829

11 Early Cardiac Gene Transcript Levels in Peripheral Blood Mononuclear Cells in Patients with Untreated HTN Kontaraki J et al. J Hypertens 2011;29:791

12 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

13 2007 ESH/ESC Guidelines and Search for Subclinical Organ Damage 2003 GLs SCr (> mg/dl) EKG LVH (Echo) CA thickening / plaques MA Routine Recommended Search for multiorgan OD OD assessed before and during T 2007 GLs SCr (> mg/dl) ecrcl / GFR MA EKG LVH (Echo) Concentric LVH LA enlargement CA thickening / plaques Ankle/Brachial ratio Arterial stiffening (PWV)* * Depending on availability / also shown by high SBP / low DBP LVH / MI-ischemia / Arrhythmias

14 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: 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

15 Normal range and Cut-off Values for ECG and Echo According to ESH/ESC Guidelines ECG: Sokolow-Lyon>38 mm Cornell voltage duration product >2240 mm*ms ECHO Parameter Normal range Pathologic cut-off point LV mass index (g/ m 2 ) LV mass index (g/m 2.7 ) Relative wall thickness in women in men in women in men in women in men E/ average e ratio <8 13 LAVi (ml/m 2 ) LAVi = Left atrial volume index, LV = Left ventricular

16 Predictive Value, Availability, and Cost- Effectiveness of ECG and ECHO Parameter CV predictive value Availability Reproducibility Costeffectiveness Electrocardiography Echocardiography

17 Assessment Of Left Ventricular Function In Hypertensive Patients With 2-dimensional Strain E. Hamodraka,, MS Kallistratos, V Lezos, LE Poulimenos,, I Zacharopoulou, K Kifnidis, A Giannakopoulos, N Kouremenos, AJ Manolis Two- dimensional strain can be used to identify latent left ventricular dysfunction in hypertensive patients. ESC 2012 Abs

18 3 D echocardiography global systolic function

19 Regional systolic function

20 Hemodynamic and Humoral Correlates in Essential HTN: Relationship Between Patterns of LVH and Myocardial Ischemia ETT (-) ETT(+), Th(+), CA(-) Overweight, Hyperlipidemia, Holter: (+), HRV: (+), LPs: (+) NE: p:ns Manolis AJ et al. Hypertension. 1997

21 3D CONTRAST ECHOCARDIOGRAPHY

22 ECG For The Diagnosis Of LVH: Revisiting An Old Friend In Times Of Austerity 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 Manolis AJ et al. J Hypertens 2012; 30:

23 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

24 Muiesan ML et al, Hypertension 2004 CV Events According To LV Geometry Changes 40 CV ev (%) 30 1 tertile (LVMI < 91 g/m2) 2 tertile (LVMI g/m2) 3 tertile (LVMI > 117 g/m2) * RWT < RWT > * * g/m g/m g/m g/m g/m g/m2

25 Subclinical Organ Damage as a Marker of High CV Risk Condition Study Condition Organ damage 10 yr CVD 20% Tsioufis Mihani CASE-J trial CV Health Study ELSA Laurent Fowkes De Buyzere Koren Tsioufis HOT INSIGHT Jensen Hypertension Outpatients Hypertension Elderly Hypertension Hypertension Outpatients Outpatients Hypertension Hypertension Hypertension Hypertension Hypertension 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 Yes Yes Yes Yes Yes Yes Yes (men) Yes (men) Yes Yes Yes Yes Yes (CHD)

26 LVH vs CKD as predictors of CV events in HTN : a Greek 6-year-follow-up study 1652 hypertensives free of CV disease were enrolled within a period of 3 yrs ( ) 3.2 Fold Tsioufis C, et al. J Hypertension 2009

27 The Many Aspects of Left Ventricular Hypertrophy

28 Percent Percent LVH And Abdominal Aorta Size In Essential HTN: The ETODH Study (a) 70 (b) * 50 * I II III IV Quartiles of abdominal aorta diameter 0 I II III IV Quartiles of abdominal aorta diameter 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 Cuspidi C et al. J Hypertens 2011;29:1213

29 Age-adjusted odds ratio Risk Factor for the Development of AF 38-year follow-up of the Framingham study Cigarettes Diabetes ECG LVH Hypertension BMI Alcohol Risk factors

30 Left Atrial Size In Hypertension And Stroke Logistic regression model for cavariates of stroke 95% CI Predictor OR Lower Upper P LAVi Left ventricular mass index Significant stenosis in ica Atherosclerotic changes in ica History of PAF CI, confidence interval; ica, internal and common carotid artery; LAVi, left atrial volume index; OR, odds ratio; PAF, paroxysmal atrial fibrillation. a More than 50% stenosis in at least one CA. Piotrowski G et al. J Hypertens 2011;29:1988

31 Quantification of LA volume

32 Assessment Of Left Atrial Function In Hypertensive Patients With 2-dimensional Strain E. Hamodraka, V Lezos, MS Kallistratos, LE Poulimenos,, I Zacharopoulou, T. Zamfir,K Kifnidis, N Kouremenos, AJ Manolis Two- dimensional strain can be used to identify latent left atrial dysfunction in hypertensive patients. ESC 2012

33 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

34 LVMI at Baseline and 16 Weeks 170 * p< Baseline 16 weeks Kokkinos et al. N Engl J Med 1995;333:1462-7

35 2007 ESH/ESC Guidelines Preferred Drugs Condition Subclinical OD Clinical Event ISH (elderly) D / CA MS (or risk of incident DM) ACEI / ARB (+CA / low dose D) DM ACEI / ARB Pregnancy CA / MD / BB Blacks D / CA LVH Asympt. atherosclerosis MA Renal dysfunction Previous stroke Previous MI Angina pectoris CHF AF (recurrent) AF (permanent) ESRF/proteinuria PAD 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

36 Proportion of patients with first event (%) LIFE Study Primary Composite Endpoint Intention-to-treat Adjusted risk reduction 13 0%, P=0 021 Unadjusted risk reduction 14 6%, P= Atenolol Losartan Study Month Losartan (n) Atenolol (n)

37 Change in E/A (%) Change in E (%) Change in LVMI(%) Change in RWT(%) Role Of Plasma Aldosterone Concentration In Regression Of LVM Following Antihypertension Medication AE(-) AE(+) AE(-) AE(+) P<0.01 P=n.s P=n.s. AE(-) AE(+) AE(-) AE(+) P<0.05 Yoshida C et al. J Hypertens 2011;29:357

38 Role of Plasma Aldosterone Concentration in Regression of LVM Following Antihypertensive Treatment Yoshida C et al. J Hypertens 2011;29:357

39 Perindopril and Indapamide Reverse Coronary Microvascular Remodelling and Improve Flow in HTN Neglia D et al. J Hypertens 2011;29:364

40 Effects Of Perindopril-indapamide On Left Ventricular Diastolic Function And Mass In Patients With Type 2 Diabetes:the ADVANCE Echocardiography Substudy 10 No LVH LVH BL-6M BL-4yrs BL-6M BL-4yrs Placebo Perindopril-Indapamide ADVANCE Collaborative Group J Hypertens 2011;29:1439

41 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

42 RSD Reduces LVH and Improves cardiac Function in Patients with Resistant HTN Brandt MC et al. J Am Coll Cardiol 2011;59:901

43 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

44 Heart 2008;94: D ECHOCARDIOGRAPHY- LV mass 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

45 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

46 Take Home Message New therapeutic targets and strategies 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