State-of-the-Art Prevention of Heart Failure: Maladaptive versus Adaptive Hypertrophy.

Hypertrophy is the response of cardiac muscle to altered hemodynamic loads. The increase in ventricular wall thickness normalizes increased wall stress and, therefore, hypertrophy is initially beneficial. However, progressive hypertrophy is associated with deleterious long-term consequences that significantly increase the risk of mortality. This review outlines the events associated with hypertrophy and discusses how strategies can be aimed at preventing pathological hypertrophy. The fact that heart failure is one of the leading causes of death in the West demands a detailed understanding of the complexities underlying this response. Complete dissection of hypertrophy will aid the development of novel therapeutic approaches that could take advantage of its beneficial features while removing the deleterious consequences caused by hypertrophic growth of the heart. Heart Fail Monit 2008;5(4):112-8.

Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature.

OBJECTIVE: Hypercholesterolemia (HC) and hypertension (HT) are both major risk factors for the development and progression of atherosclerotic heart disease, and their co-existence has been associated with an increased incidence of cardiac events in clinical studies. HC and HT are individually associated with abnormal myocardial vascular function, but whether HT exacerbates the HC-induced myocardial vascular dysfunction remains unclear. METHODS: We studied in pigs the effect of renovascular HT superimposed on diet-induced HC (HC+HT) on myocardial perfusion and microvascular permeability in vivo (using electron-beam computed tomography) in response to cardiac challenge (i.v. adenosine and dobutamine). The involvement of systemic and myocardial tissue oxidative stress in vitro was assessed by oxidizability of LDL, levels of endogenous antioxidants, and tissue activities of radical-scavenger systems. RESULTS: While in normal animals myocardial perfusion increased in response to i.v. adenosine (+36+/-13%, P<0.05), in HC and HT alone the increase was blunted. In HC+HT myocardial perfusion response was further attenuated and significantly lower than normal, and myocardial vascular resistance failed to decrease (+7.6+/-8.8 vs. -21.0+/-5.8%, P=0.02 versus normal). HC+HT also showed blunted response to dobutamine, and augmented increases in microvascular permeability in vivo. These functional abnormalities were associated with increased systemic and myocardial tissue oxidative stress compared to HC or HT alone, and a synergistic decrease in endogenous antioxidant defenses in myocardial tissue. Furthermore, chronic antioxidant vitamin supplementation in combined HC and HT improved myocardial vascular responses. CONCLUSION: HT amplifies the HC-induced myocardial microvascular dysfunction in vivo and increased oxidative stress in vitro. These alterations may potentially play a role in the increased incidence of cardiac events observed when HC and HT co-exist.

Body mass index and preinfarction angina in elderly patients with acute myocardial infarction.

BACKGROUND: Preinfarction angina, a clinical equivalent of ischemic preconditioning, seems to protect against in-hospital death, cardiogenic shock, and the combined endpoints in adult but not in elderly patients with acute myocardial infarction. Experimental evidence indicates that caloric restriction may restore ischemic preconditioning in aged animals. OBJECTIVE: The objective was to verify whether body mass index (BMI) influences the cardioprotective effect of preinfarction angina in the elderly. DESIGN: We retrospectively studied 820 patients aged >/= 65 y with acute myocardial infarction by evaluating BMI and major (death and cardiogenic shock) and minor in-hospital outcomes. RESULTS: In-hospital death, cardiogenic shock, and the combined endpoints were not significantly different between elderly patients with and without preinfarction angina. Interestingly, in-hospital death, cardiogenic shock, and the combined endpoints were significantly fewer in elderly patients with than without preinfarction angina in the subset of patients with the lowest BMI (P < 0.01, < 0.01, and < 0.01, respectively). Regression analysis showed that preinfarction angina did not protect against in-hospital death when analyzed in all patients independently of BMI, whereas it was protective in the subset of patients with the lowest BMI (odds ratio: 0.06; 95% CI: 0.00, 0.54). CONCLUSIONS: Preinfarction angina does not protect against in-hospital death, cardiogenic shock, or the combined endpoints in elderly patients with acute myocardial infarction. With stratification by quartiles of BMI, the protective effect of preinfarction angina is preserved in elderly patients with the lowest BMI.

Losartan treatment and left ventricular filling during volume loading in patients with dilated cardiomyopathy.

BACKGROUND: Patients with mild heart failure show a reduction in preload reserve mechanism during volume expansion. At this time, the effects of volume expansion on left ventricular (LV) diastolic filling in this subset of patients have not been well characterized. METHODS: We evaluated the effects of acute volume loading on Doppler parameters of LV filling in 10 healthy control subjects and in 12 patients with idiopathic dilated cardiomyopathy (DCM). In patients with DCM, the effects of losartan on diastolic adaptation to volume load were also investigated. RESULTS: During volume loading, the healthy control subjects showed a decrease in isovolumic relaxation time (F = 5.3, P <.05) but an increase in the LV peak filling rate (F = 52.9, P <.001) and velocity time integral of both systolic (F = 72.8, P <.001) and diastolic (F = 4.6, P <.05) pulmonary venous flow. In patients with DCM, isovolumic relaxation time decreased more than in control subjects (F = 8.1, P <.01), and the deceleration time of the early mitral wave was reduced (F = 26.3, P <.001). Furthermore, the duration of pulmonary venous flow reversal exceeded that of mitral flow at atrial contraction (F = 28.5, P <.001). After treatment with losartan, the deceleration time of early mitral wave remained unchanged, and the duration of pulmonary venous flow reversal at atrial contraction did not exceed that of mitral flow; thus, a significant treatment effect was detectable (F = 5.6, P <.05; and F = 6.6, P <.05, respectively). CONCLUSIONS: Control subjects respond to volume load with enhancement in early LV filling, whereas patients with DCM show an increase of LV filling pressure. Diastolic adaptation to volume load improves in patients with DCM after treatment with losartan.

Combined effect of the force-frequency and length-tension mechanisms on left ventricular function in patients with dilated cardiomyopathy.

BACKGROUND: The myocardial length-tension and the force-frequency relations are important mechanisms that regulate the contractile strength of the heart. AIMS: To evaluate in humans the effect on left ventricular function of the interaction between the myocardial length-tension and force-frequency relations. METHODS AND RESULTS: Eight patients with dilated cardiomyopathy (DCM) and 6 control subjects underwent radionuclide monitoring of left ventricular function during atrial pacing, saline loading and atrial pacing at the end of saline loading. In controls, atrial pacing reduced left ventricular end-diastolic (P < 0.001) and end-systolic volumes (P < 0.001) with no change in ejection fraction whereas after volume expansion end-diastolic volume (P < 0.001) and ejection fraction (P < 0.001) increased. Atrial pacing after volume expansion increased ejection fraction (P < 0.05). In patients with DCM, ejection fraction was reduced during atrial pacing (P < 0.001) and volume expansion (P < 0.05) due to an increase in left ventricular end-systolic volume (P < 0.001). Pacing tachycardia after volume expansion further increased end-systolic volume and reduced ejection fraction with a significant 'pacing by load' interaction (P < 0.001). Peak filling rate increased at each step in controls while it remained unchanged in patients with DCM. CONCLUSION: The heart rate increase during left ventricular distension improves ventricular function in normals and has detrimental effects in patients with DCM.

Efficacy of thrombolysis in younger and older adult patients suffering their first acute q-wave myocardial infarction.

OBJECTIVES: Advancing age is an independent predictor of increased mortality after acute myocardial infarction (AMI). Several hypotheses have been developed to try to explain this phenomenon, but data available about the efficacy of thrombolytic therapy in older patients are still not conclusive. The goal of this study was to investigate the efficacy of thrombolysis in adult and older patients who suffered their first AMI. DESIGN: Retrospective cohort study. SETTING: A coronary care unit. PARTICIPANTS: The sample included 244 younger (aged <65, n = 166) and older (age 65, n = 78) adult patients suffering their first Q-wave AMI, all receiving thrombolysis with human-recombinant tissue-type plasmin-ogen activator (100 mg total dose within 2.5 hours of the onset of AMI. MEASUREMENTS: Infarct size was estimated by isoenzyme creatine kinase-myoglobin (CK-MB) release, measuring the area under the curve as a function of time. ST elevation, the sum of ST elevation above the baseline, and the sum of R wave height in precordial leads V1-V6 were evaluated using 12-lead electrocardiograms. Myocardial reperfusion was calculated when ST-segment elevation decreased more than 60 with respect to the most abnormal peak detected. RESULTS: CK-MB peak level was significantly smaller in younger patients than in older ones (P< .01) and was significantly correlated with increasing age (P< .0001). Area under the 36-hour CK-MB curve was lower in younger patients than in older ones (P< .0001) and was well correlated with increasing age (P< .01). Reperfusion time was significantly shorter in younger patients (P< .05), and age was significantly correlated with reperfusion time (P< .001). CONCLUSIONS: Infarct size was greater and reperfusion time was longer in older patients than in younger ones with first Q-wave AMI treated with thrombolysis. Infarct size and reperfusion time were linearly correlated with increasing age. These findings may help explain the increase in mortality due to AMI observed with advancing age.

Glycoxidation of low-density lipoprotein increases TUNEL positivity and CPP32 activation in human coronary cells.

Apoptosis of arterial cells induced by oxidized low-density lipoprotein (oxLDL) is thought to contribute to the progression of vascular dysfunction and atherogenesis. It is well established that diabetes mellitus is accompanied by both glycosylation and oxidation of LDL (glc-oxLDL), but the biological effects of these modified lipoproteins are poorly understood. We demonstrate here for the first time that glc-oxLDL increases TUNEL positivity and caspase-3 activation (by Western blot and immunocytochemistry) of human coronary smooth muscle cells. Overall, these effects induced by glc-oxLDL were greater than those achieved with oxLDL. Thus, glc-oxLDL activated downstream apoptotic signaling. This may influence the evolution of atherogenesis and vascular complications in diabetes.

Prediction of long-term survival in chronic heart failure by multiple biomarker assessment: a 15-year prospective follow-up study.

BACKGROUND: In chronic heart failure (CHF), several plasma biomarkers identify subjects at risk of death over the midterm. However, their long-term predictive value in the context of other candidate predictors has never been assessed. This information may prove valuable in the management of a chronic disease with a long natural history, as CHF is today. HYPOTHESIS: We aimed to assess the very-long-term prognostic power of a set of biomarkers to identify CHF patients at highest risk for all-cause mortality. METHODS: A group of 106 consecutive outpatients with CHF (85 male and 21 female, median age 56 y) was followed for 15 years. Echocardiographic tracings and blood samples were collected at study entry to evaluate cardiac function, plasma atrial natriuretic peptide (ANP), aldosterone, and erythropoietin, and plasma renin activity. The relationships between biomarkers, clinical and echocardiographic variables, and mortality were assessed. RESULTS: After 15 years, 86 of the 106 patients (81%) had died. Multivariate analysis showed that ANP was the best independent predictor of survival over several clinical, echocardiographic, and humoral variables (hazard ratio: 5.62, 95% confidence interval: 3.37-9.39, P < 0.001 for plasma levels < median value of 71 pg/mL). Plasma renin activity and erythropoietin provided prognostic information in univariate analysis, but lost their predictive power when adjusted for covariates. CONCLUSIONS: The present study represents the longest available follow-up of patients with CHF evaluating the prognostic power of multiple biomarkers. It shows that a simple assessment of plasma ANP levels is the strongest long-term predictor of death in all stages of heart failure.

Programmed electrical stimulation and Amiodarone therapy for the control of persistent junctional tachycardia.

The use of radiofrequency as a means of synchronization and stimulation does not necessitate an external lead, and thus has allowed the construction of an implantable device for long-term treatment of reentry tachycardias. The device is used along with Amiodarone therapy and can be triggered by the patient himself.

Protease-activated receptor-2 activation improves efficiency of experimental ischemic preconditioning.

Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage. PAR-2 is involved in inflammatory events and cardiac ischemic reperfusion injury. The objective of this study was to investigate the effects of PAR-2 in experimental myocardial ischemic preconditioning. To monitor the effects of PAR-2, Langendorff-perfused rat hearts were used. These hearts were treated with PAR-2-activating peptide (PAR-2AP) in various protocols. Hemodynamic parameters (left ventricular developed pressure, left ventricular diastolic pressure, coronary flow rate, and heart rate), several indexes of oxidative injury, and neutrophil accumulation were evaluated. We show for the first time that enhanced PAR-2 activation improves efficiency of ischemic preconditioning and reduces cardiac inflammation in the rat heart. Indeed, after PAR-2AP infusion we found that hemodynamic parameters, oxidative injury, infarct size, and neutrophil accumulation were involved. These data support the concept that PAR-2-dependent cell trafficking may regulate signaling responses to cardiac ischemia and inflammation.

Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats.

Ischemic preconditioning (PC) has been proposed as an endogenous form of protection against-ischemia reperfusion injury. We have shown that PC does not prevent postischemic dysfunction in the aging heart. This phenomenon could be due to the reduction of cardiac norepinephrine release, and it has also been previously demonstrated that age-related decrease of norepinephrine release from cardiac adrenergic nerves may be restored by caloric restriction. We investigated the effects on mechanical parameters of PC against 20 min of global ischemia followed by 40 min of reperfusion in isolated hearts from adult (6 mo) and "ad libitum"-fed and food-restricted senescent (24 mo) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. Final recovery of percent developed pressure was significantly improved after PC in adult hearts versus unconditioned controls (85.2 +/- 19% vs. 51.5 +/- 10%, P < 0.01). The effect of PC on developed pressure recovery was absent in ad libitum-fed rats, but it was restored in food-restricted senescent hearts (66.6 +/- 13% vs. 38.3 +/- 11%, P < 0.05). Accordingly, norepinephrine release significantly increased after PC in both adult and in food-restricted senescent hearts, and depletion of myocardial norepinephrine stores by reserpine abolished the PC effect in both adult and in food-restricted senescent hearts. We conclude that PC reduces postischemic dysfunction in the hearts from adult and food-restricted but not in ad libitum-fed senescent rats. Despite the possibility of multiple age-related mechanisms, the protection afforded by PC was correlated with increased norepinephrine release, and it was blocked by reserpine in both adult and food-restricted senescent hearts. Thus caloric restriction may restore PC in the aging heart probably via increased norepinephrine release.

Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet.

Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66(Shc-/-) and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66(Shc-/-) mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% high-fat treatment increased the aortic cumulative early lesion area by approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice. Early lesions from p66(Shc-/-) mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66(Shc-/-) may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66(Shc) might represent a molecular target for therapies against vascular diseases.

Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice.

The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 +/- 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (-5.1 +/- 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages-derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.

The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial.

We investigated whether intervention with antioxidant vitamins C and E in enteral feeding influenced oxidative stress and clinical outcome in critically ill patients. Two-hundred-sixteen patients expected to require at least 10 days of enteral feeding completed the study. One-hundred-five patients received enteral feeding supplemented with antioxidants, and 111 control patients received an isocaloric formula. Plasma lipoperoxidation (by thiobarbituric acid reactive substances [TBARS] and prostaglandin F(2alpha) isoprostane levels), low-density lipoprotein (LDL) oxidizability, and LDL tocopherol content were determined at baseline and at the end of the 10-day period. The clinical 28-day outcome was also assessed. Plasma TBARS and isoprostanes were 5.33 +/- 1.26 nM/mL and 312 +/- 68 pg/mL, respectively, before treatment and 2.42 +/- 0.61 nM/mL and 198 +/- 42 pg/mL after intervention (P < 0.01 for both comparisons). Antioxidants improved LDL resistance to oxidative stress by approximately 30% (the lag time before treatment was 87 +/- 23 min and was 118 +/- 20 min after treatment; P < 0.04). There was a significantly reduced 28-day mortality after antioxidant intervention (45.7% in the antioxidant group and 67.5% in the regular-feeding group; P < 0.05). Isoprostanes may provide a sensitive biochemical marker for dose selection in studies involving antioxidants.

Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis.

Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague-Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S-nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA. NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.