Sudhir Gupta

Isolated Myocyte Contractile Function Is Normal in Postinfarct Remodeled Rat Heart With Systolic Dysfunction

BACKGROUND Postinfarction ventricular remodeling is associated with lengthening and contractile dysfunction of the remote noninfarcted myocardium. Mechanisms underlying this phenomenon remain unclear. METHODS AND RESULTS We studied serial changes in global left ventricular (LV) structure and function in infarcted (1, 2, 4, and 6 weeks after myocardial infarction) and sham-operated rat hearts and correlated them with structural and functional changes in myocytes isolated from the remote LV myocardium in the same hearts. Rats with myocardial infarction developed significant remodeling. The heart weight-to-body weight ratios were increased. LV volumes at filling pressure of 10 mm Hg were higher (305+/-28 versus 215+/-12 microL, P<.01). This was accompanied by global LV dysfunction (in vivo LV end-diastolic pressure, 4+/-1 versus 23+/-1.6 mm Hg; Langendorff LV developed pressure, 105+/-4 versus 62+/-9 mm Hg, P<.001 for both). Myocytes isolated from these hearts showed significant structural remodeling (LV myocytes, 24% longer and 15% wider; right ventricular myocytes, 38% longer and 31% wider, all P<.05). LV myocyte length correlated with changes in LV volume (r=.79) and function (LV developed pressure, r=-.81). However, LV myocytes from the same hearts showed normal contractile function and intracellular Ca2+ transients at baseline and during inotropic stimulation with increasing extracellular Ca2+ (1 to 6 mmol/L). The shortening-frequency relationship was also similar in myocytes from sham and myocardial infarction rats. CONCLUSIONS Postinfarct LV remodeling occurs predominantly by myocyte lengthening rather than by myocyte slippage. However, contractile function of the unloaded myocytes from the remote noninfarcted LV myocardium of the remodeled heart is normal. Therefore, myocyte contractile abnormalities may not contribute to global dysfunction of the remodeled heart. Reduced myocyte mass and nonmyocyte factors like increased wall stress, altered LV geometry, and changes in the myocardial interstitium may be more important in the genesis of postinfarct LV dysfunction in this model.

Myocyte contractile function is intact in the post-infarct remodeled rat heart despite molecular alterations

OBJECTIVE To investigate the cellular mechanisms underlying global and regional LV dysfunction in the post-infarct (MI) remodeled rat hearts. METHODS LV remodeling and function were quantified by echocardiography, morphometry, in vivo hemodynamics, and isolated perfused heart studies in 6 weeks post-MI and sham-operated rats. LV myocytes from sham and MI hearts were used for morphometric and functional studies. Myocyte contractile function and intracellular calcium kinetics were measured at different stimulation frequencies (0.2-2 Hz), temperatures (30 and 37 degrees C), and external viscous load (1, 15, 200 and 300 centipoise). Myocyte apoptosis was measured by DNA laddering; BCL-2, BAX, Na(+)-Ca(2+) exchanger, and SERCA-2 proteins by western blot; and brain natriuretic peptide (BNP), SERCA-2 mRNA by RT-PCR. RESULTS MI hearts were remodeled (Echo LV diameter 7.3+/-0.38 vs. 5.9+/-0.16 mm, P<0.03), and showed global (Echo % fractional shortening 30+/-2.4 vs. 58+/-3, P<0.001), and regional contractile dysfunction of non-infarcted myocardium (Echo % systolic posterior wall thickening 36+/-2 vs. 57+/-1.7, P<0.001). In vivo hemodynamic and isolated heart function studies confirmed depressed LV systolic and diastolic function and increased volumes. Whereas, myocytes isolated from infarcted hearts were remodeled (40% longer and 10% wider), their contractile function and calcium kinetics under basal conditions and at high stimulation frequency, temperature and viscous load were similar to sham myocytes. The mRNA for BNP was increased whereas that for SERCA-2 decreased, but the SERCA-2 protein was normal. Despite myocyte hypertrophy, ventricular septal thickness was reduced in infarcted hearts (2.2+/-0.1 vs. 2. 6+/-0.07 mm, P<0.01), and showed increased apoptosis. CONCLUSIONS Myocytes from remote non-infarcted myocardium of the remodeled hearts have normal contractile function, despite structural remodeling and altered gene expression. Non-myocyte factors may be more important in genesis of contractile dysfunction in the remodeled heart, for up to 6 weeks after MI.

The role of arginine vasopressin and its receptors in the normal and failing rat heart

OBJECTIVE To evaluate the role of arginine vasopressin (AVP) in the normal and post-myocardial infarction (post-MI) hearts, and to investigate whether chronic AVP receptor antagonism can attenuate post-infarct ventricular remodeling. BACKGROUND A number of neurohormones, like norepinephrine and angiotensin II, have detrimental effects in heart failure (HF) and inhibiting them is beneficial. AVP shares some important properties with these hormones and is activated in HF. However, its role in the syndrome of HF, especially the effect of AVP inhibition, is largely undefined. METHODS AND RESULTS Effects of AVP-V1a and AVP-V2 receptor stimulation on normal rat cardiomyocyte contractile function, intracellular calcium [Ca2+]i, inositol 3 phosphate (IP3) generation and cell survival were studied. In post-MI rats, AVP receptor function was assessed in cardiomyocytes as well as isolated working hearts. AVP receptor total number (ligand binding) and mRNA levels (RT-PCR) were measured in myocytes. Finally, the effects of chronic AVP-V1a blockade were assessed in post-MI rats using echo and morphometry to measure ventricular remodeling. Normal cardiomyocytes showed a dose-dependent increase in myocyte contractile function, [Ca2+]i, and IP3 generation in response to AVP-V1a receptor stimulation. AVP-V2 agonists had no effect. Cells from MI hearts showed reduced inotropic response to AVP-V1a stimulation. Myocyte AVP-V1a receptor number and receptor mRNA were decreased. Prolonged exposure to AVP reduced cellular viability. However, chronic AVP-V1a blockade did not attenuate structural remodeling or improve function in post-MI hearts. CONCLUSIONS Isolated adult rat cardiomyocytes bear AVP-V1a receptors that mediate inotropic effects through the IP3 pathway. These receptors are functionally and numerically downregulated in the post-MI remodeled hearts. Despite evidence that AVP is cytotoxic to cells, chronic AVP-V1a receptor blockade does not attenuate post-MI ventricular remodeling in this model. Thus, AVP may not play a major role in the structural progression of HF.

Myocyte Response to β-Adrenergic Stimulation Is Preserved in the Noninfarcted Myocardium of Globally Dysfunctional Rat Hearts After Myocardial Infarction

Background—Cellular mechanisms underlying the diminished inotropic response of remodeled hearts after myocardial infarction (MI) remain unclear. Methods and Results—Left ventricular (LV) remodeling and function were assessed by 2D echocardiography and isolated perfused heart studies in 6-week post-MI and sham-operated rats. LV myocytes from sham and noninfarcted MI hearts were used for morphometric and functional studies. β-Adrenergic receptor (β-AR) agonist isoproterenol (ISO)-induced contractile response was measured in isolated hearts. The effects of ISO and forskolin on contractile function and calcium transients of isolated myocytes were recorded. ISO-induced cAMP generation was compared in sham and MI myocytes. β-AR density was measured by radioligand binding. MI hearts were remodeled (LV diameter 8.5±0.3 versus 5.7±0.3 mm, P<0.001) and showed global (% fractional shortening 19.1±2.5 versus 55.3±2.2, P<0.01) and regional contractile dysfunction of noninfarcted myocardium (% systolic posterior wall t...