The transition from hypertensive hypertrophy to left ventricular systolic chamber decompensation
Date
2014-04-08
Authors
Veliotes, Demetri George Alexander
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Hypertensive left ventricular hypertrophy (LVH) increases the risk for the development of heart failure with systolic chamber dysfunction. However, the exact mechanisms and hence best therapeutic approach to prevent this transition process is uncertain. One potential mechanism is through excessive β-adrenergic receptor (-AR) activation, but the risks of β-AR blocker therapy may outweigh the benefits. Since activation of -AR augments function of the renin-angiotensin-aldosterone system, I therefore explored whether mineralocorticoid receptor (MR) blockade prevents the transition from hypertensive LVH to systolic chamber decompensation produced by excessive β-AR activation, and the mechanisms thereof. The role of hypertensive LVH as a predisposing factor to systolic chamber decompensation post-myocardial infarction (MI) is controversial. In the present thesis I therefore also evaluated this question.
The effect of spironolactone (SPIRO, 80 mg.kg-1.day-1), an MR blocker, on LV chamber remodelling and function was evaluated in spontaneously hypertensive rats (SHR) in whom decompensation was induced by administering a low dose of the -AR agonist, isoproterenol (ISO) for 4.5 months. ISO administration resulted in an increased urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, and a decreased LV relative wall thickness without further enhancing an increased myocardial norepinephrine (NE) release in SHR. ISO reduced LV systolic chamber function (decreased LV endocardial fractional shortening and the slope of the LV systolic pressure-
volume relationship) without modifying intrinsic myocardial systolic function (as assessed from LV midwall fractional shortening and the slope of systolic stress-strain relationship). SPIRO abolished ISO-induced chamber dilatation, wall thinning and systolic dysfunction, but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, or myocardial NE release. These results suggest that MR activation, through load-independent effects, may be critical in mediating the transition from compensated hypertensive LVH to dilatation and LV systolic chamber dysfunction.
In SHR, ISO increased myocardial matrix metalloproteinase (MMP)-2 activity (zymography) after only 4-5 days of administration, a change that was associated with MMP-2, but not TIMP expression. The increased MMP-2 activity persisted until 4.5 months of the study and these changes were prevented by SPIRO. At 4.5 months, ISO resulted in increased non-cross-linked, but not cross-linked myocardial collagen concentrations in SHR, an effect that was abolished by SPIRO. Although at 4.5 months ISO administration was not associated with an increased cardiomyocyte apoptosis (TUNEL), an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Neither ISO nor SPIRO influenced cardiomyocyte length (image analysis and flow cytometry) in SHR. Thus MR blockade may prevent the adverse effects of β-AR activation in hypertensive LVH through alterations in the cardiac interstitium and cardiomyocyte apoptosis.
Six-to-seven months after ligation of the left anterior descending coronary artery, LV myocardial systolic function as assessed from % shortening of the non-infarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and % thickening of the posterior wall (echocardiography) was reduced in infarcted SHR (SHR-MI) (p<0.05), but not in normotensive Wistar Kyoto (WKY-MI) animals as compared to corresponding controls (SHR-Sham, WKY-Sham). This change in regional myocardial function in SHR-MI, but not in WKY- MI, occurred despite a similar degree of LV dilatation in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis (TUNEL) or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in resting global LV chamber systolic function (endocardial fractional shortening-FSend and end-systolic elastance [LV Ees] determined in the absence of an adrenergic stimulus), in the presence of an ISO challenge a reduction in LV Ees in SHR-MI compared to WKY-MI and SHR and WKY-Sham rats was noted (p<0.04). These data suggest that with chronic MI, the hypertensive heart is susceptible to development of viable tissue myocardial dysfunction, a change which cannot be attributed to excessive chamber dilatation, apoptosis or necrosis, but which in-turn, contributes toward a reduced cardiac adrenergic-inotropic reserve.
The present thesis therefore suggests that MR blockade may prevent the transition from hypertensive LVH to systolic chamber decompensation, and that pre-existing hypertensive LVH increases the susceptibility to a depressed LV regional myocardial systolic function in the non-infarcted LV myocardium subsequent to MI, an effect that translates into a reduced inotropic reserve.