Pathological Left Ventricular Remodeling Research Articles

The mitochondrial permeability transition pore as a target of cardioprotective signaling

it is has been over two decades since Murry and colleagues ([15][1]) published their seminal study describing ischemic preconditioning, a phenomenon whereby brief antecedent periods of ischemia-reperfusion profoundly protect the heart against a subsequent lethal period of ischemia and reperfusion.

Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1beta was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Selective Targeting of Matrix Metalloproteinase Inhibition in Post-Infarction Myocardial Remodeling

A cause-effect relationship has been established between MMP activation and left ventricular (LV) remodeling following myocardial infarction. The goal of the present study was to examine a selective MMP inhibitor (sMMPi) strategy that effectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction. Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg TID) begun 3 days prior to myocardial infarction. Ten weight-matched noninstrumented pigs served as reference controls. Left ventricular end-diastolic volume in the myocardial infarction-only group was increased from baseline (81 +/- 3 mL versus 55 +/- 4 mL, respectively, P < 0.05) but was attenuated with sMMPi (67 +/- 3 mL, P < 0.05). Fractional area of shortening of marker area was decreased in the myocardial infarction-only group (change from baseline -63 +/- 10%, P < 0.05) but this effect was attenuated with sMMPi (-28 +/- 14%, P < 0.05), indicative of less dyskinesis of the infarct region with sMMPi. Wall stress was reduced within both the septal and posterior wall regions with sMMPi. Myocardial MMP-2 activity was decreased in both remote and border areas of sMMPi-treated samples compared with myocardial infarction-only values, consistent with pharmacologic MMP inhibition. Selective MMP inhibition favorably affected regional myocardial geometry and decreased left ventricular dilation post-myocardial infarction. This study suggests that a strategy of selective MMP inhibition of a limited array of MMPs may be an achievable goal in preventing pathologic left ventricular remodeling post-myocardial infarction.

Arginase: a modulator of myocardial function

when nitric oxide (NO) donors were first administered to isolated, normal cardiomyocytes, a negative, cGMP-dependent inotropic effect was observed, whereas inhibitors of NO synthases (NOS) had no effect. Further studies then demonstrated a biphasic contractile response to exogenous NO and cGMP,

Chronic Recurrent Myocardial Ischemic Injury Is Significantly Attenuated by Pre-Emptive Adeno-Associated Virus Heme Oxygenase-1 Gene Delivery

We assessed the hypothesis that overexpression of the antioxidant enzyme heme oxygenase (HO)-1 may protect against chronic recurrent ischemia/reperfusion injury. Multiple and recurring episodes of myocardial ischemia can result in significant myocardial damage, including myocyte death, fibrosis, and wall thinning, leading to impaired ventricular function and cardiac failure. In this study we used a closed-chest rodent model of chronic recurring myocardial ischemia and reperfusion to investigate the efficacy of pre-emptive gene therapy in overexpressing the antioxidant enzyme HO-1, using adeno-associated virus (AAV)-2 as the delivery vector. We show that constitutive overexpression of HO-1 can prevent myocardial wall thinning, inflammation, fibrosis, and deterioration of cardiac function (as measured by echocardiography, histology, and immunohistochemistry) induced by repeated transient myocardial ischemia and reperfusion injury. With HO-1 therapy, there was a significant reduction in apoptosis as determined by levels of markers of survival proteins and terminal deoxynucleotidyltransferase dUTP nick end-labeling staining. This prevention of tissue damage was also associated with reduction in superoxide generation. Taken together we provide the first evidence of the therapeutic efficacy of pre-emptive AAV-HO-1 delivery for prevention against multiple ischemic injury. This approach protects myocytes by simultaneously activating protective response and inhibiting pathological left ventricular remodeling and, therefore, may be a useful cardio-protective strategy for patients with coronary artery disease at a high risk for recurrent myocardial ischemia.

DURATION-OUTCOMES RELATIONSHIPS IN NONPHAR-MACOLOGICAL THERAPY OF CHRONIC CARDIAC FAILURE WHICH HAS DEVELOPED AFTER ACUTE MYOCARDIAL INFARCTION

Left-ventricular (LV) systolic-diastolic function and cardiac rhythm variability, the rate of pathological LV remodeling and outcomes of the disease for 18 months were studied in 394 males at the age 35-68 years suffering from chronic cardiac failure (CCF) of NY-HA functional class I-I I consequent to myocardial infarction occurring 9.6-4.2 months before. It was found that long-term (12-24 weeks) taking sauna, underwater dousch-massage, general effervescent baths and exercise in combination with drug therapy in patients with asymptomatic CCF inhibit the rate of LV remodeling, decrease LV hypertrophy, improve diastolic function of the heart. This results in lowering a cumulative risk of unfavourable outcomes of the disease by 42% (p = 0.006). The best of effect of the combined therapy is not achieved in angina of effort, massive myocardial hypoperfusion zones, no viable myocardium in the zones of the lesion, marked LV hypertrophy.

Belastung und Belastbarkeit bei chronischer Herzinsuffizienz

Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.

Importance of an intact growth hormone/insulin-like growth factor 1 axis for normal post-infarction healing: studies in dwarf rats.

Treatment with GH attenuates remodeling and improves left ventricular function in the setting of experimental heart failure following coronary ligation. This study was designed to test the hypothesis that an intact GH/insulin-like growth factor 1 (IGF-1) axis is required for normal myocardial infarction healing. Myocardial infarction was induced by coronary ligation in GH-deficient dwarf rats and in age-matched controls. In dwarf rats, serum IGF-1 levels were reduced by 50%, and grow rate was 50% less than normal littermates, although no differences in myocardial IGF-1 messenger RNA levels were observed compared with controls. All rats underwent transthoracic echocardiography at baseline, 2 weeks, and 6 weeks after myocardial infarction. Left ventricular end-diastolic pressure was obtained by in vivo closed chest catheterization. At 6 weeks, both infarcted groups exhibited similar myocardial infarction size at transthoracic echocardiography and at morphometric histology. In both groups with myocardial infarction, there was significant left ventricular dilation and reduced systolic function. However, the extent of remodeling as assessed by the increase in end-diastolic dimension (%Delta + 36 +/- 5 vs. +19 +/- 4; P: < 0.01) and depression of function (%Delta fractional shortening -12 +/- 2 vs. -7 +/- 1; P: < 0.01) were both greater in the dwarf group. Furthermore, dwarf rats failed to develop compensatory hypertrophy of noninfarcted posterior wall (%Delta posterior wall +5 +/- 1 vs. +15 +/- 3; P: < 0.01). Therefore, pathologic left ventricular remodeling and functional loss following myocardial infarction is more marked in conditions of GH deficiency. An intact GH/IGF-1 axis appears necessary for a normal response to myocardial infarction injury in the rat.

The effects of neurohormonal antagonism on pathologic left ventricular remodeling in heart failure.

The effects of neurohormonal antagonism on pathologic left ventricular remodeling in heart failure.

Growth Hormone Attenuates Early Left Ventricular Remodeling and Improves Cardiac Function in Rats With Large Myocardial Infarction

Objectives. We sought to investigate the cardiac effects of growth hormone (GH) administration during the early phase of pathologic remodeling in a rat model of large myocardial infarction (MI).Background. Recent evidence suggests that exogenous administration of GH evokes a hypertrophic response and increases left ventricular (LV) function in vivo in rats with normal or chronically failing hearts. We hypothesized that these effects would attenuate ventricular remodeling early after MI.Methods. Fifty-eight male rats underwent sham operation (n = 19) or had induced MI (n = 39). The day after the operation, the infarcted rats were randomized to receive 3 weeks of treatment with GH, 3 mg/kg body weight per day (n = 19) or placebo (n = 20). Echocardiography, catheterization and isolated whole heart preparations were used to define cardiac structure and function.Results. Growth hormone caused hypertrophy of the noninfarcted myocardium in a concentric pattern, as noted by higher echocardiographic relative wall thickness at 3 weeks and by morphometric histologic examination. Left ventricular dilation was reduced in the GH-treated versus placebo group (echocardiographic LV diastolic diameter to body weight ratio 2.9 ± 0.1 vs. 3.5 ± 0.2 cm/kg; p < 0.05). In vivo and in vitro cardiac function was improved after GH treatment. Despite elevated insulin-like growth factor-1 (IGF-1) serum levels in GH-treated rats, myocardial IGF-1 messenger ribonucleic acid was not different among the three groups, suggesting that an increase in its local expression does not appear necessary to yield the observed effects.Conclusions. These data demonstrate that early treatment of large MI with GH attenuates the early pathologic LV remodeling and improves LV function.(J Am Coll Cardiol 1997;29:1109–16)© 1997 by the American College of Cardiology

Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat.

The development of heart failure after acute myocardial infarction (MI) may be related to alterations of left ventricular (LV) structure and function. Pathological LV remodeling may exacerbate systolic and diastolic dysfunction because increased cavity dimensions tend to increase LV wall stress. Unfortunately, many complicating factors have made it difficult to clearly define the time course of LV remodeling after myocardial infarction in patients, and the contribution of structural changes to altered function has not been fully explored. To determine the type, magnitude, and time course of changes in LV geometry and function, we performed transthoracic Doppler echocardiographic examinations in rats before and 1 and 6 weeks after transmural MI induced by coronary ligation. LV internal diastolic dimension was greater in infarcted than in sham-operated rats at 1 and 6 weeks after MI (9.4 +/- 0.6 versus 8.0 +/- 0.5 and 10.1 +/- 0.9 versus 8.5 +/- 0.9 mm, respectively; P < .05 compared with sham-operated rats). There was significant thinning of the infarcted anterior wall at 1 and 6 weeks (0.99 +/- 0.2 versus 1.33 +/- 0.19 and 0.96 +/- 0.22 versus 1.51 +/- 0.18 mm, P < .05), while the thickness of the noninfarcted posterior wall increased but was not different from normal growth in sham-operated rats. Six weeks after surgery, fractional shortening was impaired (11 +/- 5% versus 35 +/- 5%, P < .05), and systolic thickening of the noninfarcted posterior wall was depressed (38 +/- 9% versus 67 +/- 18%, P < .05) in infarcted rats compared with shams. These changes in structure and systolic function were accompanied by progressive alterations in LV diastolic filling. Peak early filling velocity increased at 1 and 6 weeks in MI rats (91 +/- 9 versus 79 +/- 9 and 100 +/- 14 versus 74 +/- 11 cm/s, P < .05), and the deceleration rate of the early filling wave was more rapid in rats with MI (21.6 +/- 5.0 versus 15.6 +/- 3.1 and 26.1 +/- 9.8 versus 11.2 +/- 2.7 m/s2, P < .05). Late filling velocity was decreased (16 +/- 15 versus 33 +/- 7 and 15 +/- 18 versus 34 +/- 5 cm/s, P < .05), resulting in a marked increase in the ratio of early to late filling. The peak velocity and the velocity-time integral of LV outflow did not change after MI. Postinfarction LV remodeling in the rat is characterized by progressive cavity dilatation, inadequate hypertrophy of the surviving myocardium, the gradual development of regional contractile dysfunction in noninfarcted segments, and marked abnormalities of diastolic filling. These changes can be tracked longitudinally with transthoracic echocardiography.

Induction of myocardial hypertrophy after coronary ligation in rats decreases ventricular dilatation and improves systolic function.

Previous studies have shown that hypertrophy of surviving myocytes after myocardial infarction (MI) is limited. Progressive ventricular dilatation after MI may occur when compensatory hypertrophy cannot restore left ventricular (LV) wall stress to normal. To test whether induction of additional myocyte hypertrophy might prevent pathological LV remodeling after large MI, we administered 2-tetradecylglycidic acid (TDGA) 20 mg/kg/day to sham-operated (n = 12) and MI (n = 10) rats for 10 days, beginning the third day after infarction. We have previously shown that chronic inhibition of long-chain fatty acid oxidation with TDGA in rats results in myocardial hypertrophy without any apparent impairment of LV systolic function. When compared with untreated MI rats (n = 9), we found that TDGA-treated MI rats had increases in LV weight/body wt, myocyte cross-sectional area, and peak developed LV pressure during abrupt aortic occlusion. MI rats treated with TDGA had lower LV end-diastolic pressures and smaller end-diastolic volumes, whereas stroke volume was maintained. The ex vivo passive LV pressure-volume relation was shifted toward the pressure axis compared with untreated infarct rats. In sham-operated rats, TDGA caused increases in LV weight/body wt, myocyte size, peak developed LV pressure, cardiac index, and stroke volume index, and a shift of the passive LV pressure-volume relation toward the pressure axis. Induction of myocardial hypertrophy with an inhibitor of long-chain fatty acid oxidation retarded the process of LV dilatation and produced beneficial effects on systolic function after large myocardial infarction. These data support the hypothesis that inadequate hypertrophy of residual myocardium after infarction may contribute to LV dilatation and the development of congestive heart failure.