Myocardial Stress and Hypertrophy: a Complex Interface Between Biophysics and Cardiac Remodeling

Myocardial stress and hypertrophy: a complex interface between biophysics and cardiac remodeling

William Grossman, Walter J. Paulus

J Clin Invest. 2013;123(9):3701-3703. https://doi.org/10.1172/JCI69830.

Hindsight

Pressure and volume overload results in concentric and eccentric hypertrophy of cardiac ventricular chambers with, respectively, parallel and series replication of sarcomeres. These divergent patterns of hypertrophy were related 40 years ago to disparate wall stresses in both conditions, with systolic wall stress eliciting parallel replication of sarcomeres and diastolic wall stress, series replication. These observations are relevant to clinical practice, as they relate to the excessive hypertrophy and contractile dysfunction regularly observed in patients with aortic stenosis. Stress-sensing mechanisms in cardiomyocytes and activation of cardiomyocyte death by elevated wall stress continue to intrigue cardiovascular scientists.

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Center for Prevention of Heart and Vascular Disease, UCSF, San Francisco, California, USA. Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Pressure and volume overload results in concentric and eccentric hypertro- catheters (1). This allowed matching of phy of cardiac ventricular chambers with, respectively, parallel and series instantaneous LV pressure, radius, and wall replication of sarcomeres. These divergent patterns of hypertrophy were thickness throughout the cardiac cycle, related 40 years ago to disparate wall stresses in both conditions, with sys- something not possible using only imag- tolic wall stress eliciting parallel replication of sarcomeres and diastolic wall ing and measured blood pressure (4, 5). stress, series replication. These observations are relevant to clinical practice, The ability to match these measurements as they relate to the excessive hypertrophy and contractile dysfunction reg- turns out to be important because of the ularly observed in patients with aortic stenosis. Stress-sensing mechanisms wide variation in the LV pressure contour, in cardiomyocytes and activation of cardiomyocyte death by elevated wall in which the rate of rise, the duration of stress continue to intrigue cardiovascular scientists. peak (spiky or broad), and the rate of fall have enormous influence on calculated Pattern recognition in left ventricular wall stress suggested that maladaptive stress or the presumed force at the level of hypertrophy hypertrophy develops insidiously during individual myocytes. Pressure and volume overload result in volume overload. divergent patterns of LV hypertrophy. Based on the development of concen- Cardiac remodeling and disease The presence of LV hypertrophy implies tric hypertrophy in pressure overload and In concentric LV remodeling, the contri- a higher-than-normal myocardial mass. eccentric hypertrophy in volume overload, bution of LV hypertrophy to the prevailing Pressure overload usually elicits con- peak systolic wall stress was proposed as a LV wall stress remains clinically relevant. centric hypertrophy, with a high ratio stimulus for parallel replication of sarcom- It is still debated whether asymptomatic of LV wall thickness to radius (h/R). In eres in concentric hypertrophy and end-di- patients with extensive LV hypertrophy contrast, volume overload triggers eccen- astolic wall stress as a stimulus for series should undergo aortic valve replacement tric hypertrophy with a normal h/R ratio replication of cardiomyocytes in eccentric to prevent progression of LV hypertrophy (Figure 1). Nearly 40 years ago, an article hypertrophy (1). A reflection of LV remod- or whether they should be managed con- in these pages related the divergent pat- eling in cardiomyocyte remodeling was servatively until symptoms develop (6, 7). terns of LV hypertrophy to disparate LV confirmed more than two decades later Knowledge of LV wall stress helps to solve wall stresses in both conditions (1). In by detailed histomorphometric measure- this clinical dilemma. When LV wall stress patients with aortic stenosis, both sys- ments in concentric and eccentric human is lower than normal, LV hypertrophy tolic and diastolic LV wall stresses were or animal LV hypertrophy (2). In concen- is excessive. This probably results from normal because concentric hypertrophy tric LV hypertrophy, cardiomyocytes only comorbidities such as diabetes mellitus had succeeded in nicely counterbalancing grow in a transverse direction while keep- (8) or from a genetic predisposition such the effect on LV wall stress of elevated ing cell length constant, whereas in eccen- as the DD genotype of the ACE gene (9). In systolic and diastolic LV pressures. tric LV hypertrophy, cardiomyocytes grow both conditions, excessive LV hypertrophy Concentric hypertrophy was therefore proportionally in both longitudinal and is accompanied by prominent LV fibrosis labeled an adaptive mechanism, which transverse directions. The difference in car- (10), which predisposes patients to ventric- avoids afterload excess to hinder myo- diomyocyte remodeling is also reflected in ular arrhythmias or sudden death. Under cardial shortening. In contrast, eccentric distinct patterns of peptide growth factor these circumstances, early aortic valve hypertrophy, as observed in patients with induction in concentric and eccentric LV replacement, even in the absence of symp- mitral or aortic regurgitation, corrected hypertrophy (3). toms, could be the more favorable option. systolic LV wall stress but failed to nor- This 1975 assessment of cardiac remod- The appropriateness of LV hypertro- malize diastolic LV wall stress. Although eling continues to stand out because of phy to LV wall stress is also relevant in the eccentric hypertrophy resembled phys- its unique methodology: LV remodeling reverse situation in which patients with iological growth, its effect on diastolic of the human heart was assessed using an aortic stenosis present with higher-than- integrated, multimodality approach with normal LV wall stress (11, 12). Excessive simultaneous measurement of LV dimen- LV wall stress results from insufficient LV Conflict of interest: The authors have declared that no conflict of interest exists. sion, septal and posterior wall thickness hypertrophy with a low h/R ratio and is Citation for this article: J Clin Invest. 2013; by echocardiography, and LV pressures accompanied by depressed LV contractile 123(9):3701–3703. doi:10.1172/JCI69830. by high-fidelity micromanometer-tipped performance (11). In the majority of these

The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 9 September 2013 3701 hindsight

Figure 1 Schematic overview of the development of concentric hypertrophy with the parallel addition of sarcomeres in pressure overload and of eccentric hypertrophy with a series addition of sarcomeres in volume overload. Chamber enlargement increases systolic wall stress in volume overload (dashed black arrow indicates positive feedback). Wall thickening induces concentric hypertrophy in pressure overload and contributes to eccentric hypertrophy in volume overload (blue arrow). Concentric hypertrophy reduces systolic wall stress in pressure overload, and eccentric hypertrophy reduces diastolic wall stress in volume overload (dashed red lines indicate negative feedback).

patients, the depressed LV contractile per- from ubiquitin-related autophagy and induced pulmonary hypertension sup- formance merely reflects afterload mis- ischemic cell death or oncosis, i.e., swell- ports this explanation (14). When rats were match and does not jeopardize postopera- ing of cardiomyocytes. In patients with a given low-dose monocrotaline, they devel- tive outcome (12). Occasionally, however, greatly reduced LVEF (<30%), myocardial oped slow-onset pulmonary hypertension the depressed LV contractile performance degeneration was 32 times more frequent and adaptive RV hypertrophy, but when is worse than predicted by the high LV wall than in control myocardium, and all of rats were given high-dose monocrotaline, stress, and in these patients it heralds a these patients failed to improve postop- they developed rapid-onset pulmonary poor postoperative outcome (12, 13). eratively. Myocardial fibrosis increased hypertension accompanied by RV failure A histopathological study of patients concordantly with cardiomyocyte degener- and premature death. Fourteen days after with aortic stenosis and varying degrees of ation and resulted in replacement fibrosis monocrotaline administration, the extent LV systolic dysfunction nicely confirmed being superimposed on reactive interstitial of RV hypertrophy was still identical in the concept of insufficient LV hypertro- fibrosis, with a greater likelihood of reentry both groups, but microarray analysis of RV phy underlying depressed LV contractile arrhythmias and poor outcome. myocardium revealed that 63 of the 3,010 performance (13). In this study, markers The cause of cardiomyocyte degeneration cardiac genes screened were differentially of cardiomyocyte hypertrophy, such as an in aortic stenosis patients with a low EF is expressed between both groups. The dif- elevated cardiomyocyte cross-sectional area unclear. The severity of aortic stenosis does ferentially expressed genes included those and increased nuclear DNA content, were not seem to be involved because the aortic responsible for the activation of proapop- present in all patients, irrespective of their valve orifice area was similar in patients totic pathways. This study implies that the LV ejection fraction (EF). In patients with with a normal or low EF (13). A poten- initial rate of rise of the pressure overload a reduced LVEF (LVEF <50%), cardiomyo- tial explanation could be the rate of pro- stimulus predestines the myocardium to cyte hypertrophy was paralleled by cardio- gression of aortic valve narrowing, which the development of an adaptive or mal- myocyte degeneration, which was evident determines the speed at which a higher wall adaptive phenotype. This conclusion was from the disappearance of myofilaments. stress is imposed on the myocardium. RV reinforced by a study in which both groups Cardiomyocyte degeneration resulted remodeling as a result of monocrotaline- were subjected to an exercise training pro-

3702 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 9 September 2013 hindsight gram (15). Low-dose monocrotaline rats Address correspondence to: Walter J. Pau- should not be operated on before symptom onset. Circulation. 2012;126(1):118–125. fared better with regular exercise because lus, Department of Physiology, Institute 8. Falcão-Pires I, et al. Diabetes mellitus worsens of a higher RV myocardial capillary density, for Cardiovascular Research VU (ICaR- diastolic left ventricular dysfunction in aortic but high-dose monocrotaline rats fared VU), VU University Medical Center Amster- stenosis through altered myocardial structure worse because of myocardial leukocyte dam, Van der Boechorststraat 7, 1081 BT and cardiomyocyte stiffness. Circulation. 2011; 124(10):1151–1159. infiltration. The latter probably resulted Amsterdam, The Netherlands. Phone: 9. Dellgren G, Eriksson MJ, Blange I, Brodin LA, from excessive elevation of RV wall stress 31.20.444.8110; Fax: 31.20.444.8255; Rådegran K, Sylvén C. Angiotensin-converting related to repetitive episodes of exercise at E-mail: [email protected]. enzyme gene polymorphism influences degree of left ventricular hypertrophy and its regression in a higher pulmonary artery (PA) pressure patients undergoing operation for aortic stenosis. and was reactive to the activation of cardio- 1. Grossman W, Jones D, McLaurin LP. Wall stress Am J Cardiol. 1999;84(8):909–913. myocyte death pathways. A similar leuko- and patterns of hypertrophy in the human left ven- 10. Fielitz J, et al. Activation of the cardiac renin-angi- tricle. J Clin Invest. 1975;56(1):56–64. otensin system and increased myocardial collagen cyte infiltration was also observed in aortic 2. Gerdes AM. Cardiac myocyte remodeling in hyper- expression in human aortic valve disease. J Am Coll stenosis patients with a reduced LVEF (13). trophy and progression to failure. J Card Fail. Cardiol. 2001;37(5):1443–1449. 2002;8(6 suppl):S264–S268. 11. Gunther S, Grossman W. Determinants of ventric- 3. Calderone A, Takahashi N, Izzo NJ, Thaik CM, ular function in pressure-overload hypertrophy in Conclusions Colucci WS. Pressure- and volume-induced left man. Circulation. 1979;59(4):679–688. The 1975 study by Grossman et al. (1) ventricular hypertrophies are associated with dis- 12. Carabello BA, Green LH, Grossman W, Cohn LH, continues to raise more questions than it tinct myocyte phenotypes and differential induc- Koster JK, Collins JJ Jr. Hemodynamic determi- tion of peptide growth factor mRNAs. Circulation. nants of prognosis of aortic valve replacement in answers. We still do not know the precise 1995;92(9):2385–2390. critical aortic stenosis and advanced congestive mechanisms whereby individual myocytes 4. Ganau A, et al. Patterns of left ventricular hypertro- heart failure. Circulation. 1980;62(1):42–48. sense the force patterns imposed by LV pres- phy and geometric remodeling in essential hyper- 13. Hein S, et al. Progression from compensated sure or volume overload and transduce the tension. J Am Coll Cardiol. 1992;19(7):1550–1558. hypertrophy to failure in the pressure-over- 5. Khouri MG, Peshock RM, Ayers CR, de Lemos loaded human heart: structural deterioration force into sarcomerogenesis that results in JA, Drazner MH. A 4-tiered classification of left and compensatory mechanisms. Circulation. 2003; cell thickening, lengthening, or both. Also, ventricular hypertrophy based on left ventricular 107(7):984–991. when does elevated myocardial wall stress geometry: the Dallas heart study. Circ Cardiovasc 14. Buermans HP, et al. Microarray analysis reveals Imaging. 2010;3(2):164–171. pivotal divergent mRNA expression profiles early activate cardiomyocyte death pathways, 6. Carabello BA. Should severe aortic stenosis be in the development of either compensated ventric- which may well be the critical factor under- operated on before symptom onset? Aortic valve ular hypertrophy or heart failure. Physiol Genomics. lying the distinction between adaptive and replacement should be operated on before symp- 2005;21(3):314–323. tom onset. Circulation. 2012;126(1):112–117. 15. Handoko ML, et al. Opposite effects of training in maladaptive hypertrophy? Hopefully, the 7. Shah PK. Should severe aortic stenosis be operated rats with stable and progressive pulmonary hyper- next 40 years will answer these questions. on before symptom onset? Severe aortic stenosis tension. Circulation. 2009;120(1):42–49.

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