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PubMed2004

Pharmacological prevention of reperfusion injury in acute myocardial infarction. A potential role for adenosine as a therapeutic agent.

The concept of reperfusion injury, although first recognized from animal studies, is now recognized as a clinical phenomenon that may result in microvascular damage, no-reflow phenomenon, myocardial stunning, myocardial hibernation and ischemic preconditioning. The final consequence of this event is left ventricular (LV) systolic dysfunction leading to increased morbidity and mortality. The typical clinical case of reperfusion injury occurs in acute myocardial infarction (MI) with ST segment elevation in which an occlusion of a major epicardial coronary artery is followed by recanalization of the artery. This may occur either spontaneously or by means of thrombolysis and/or by primary percutaneous coronary intervention (PCI) with efficient platelet inhibition by aspirin (acetylsalicylic acid), clopidogrel and glycoprotein IIb/IIIa inhibitors. Although the pathophysiology of reperfusion injury is complex, the major role that neutrophils play in this process is well known. Neutrophils generate free radicals, degranulation products, arachidonic acid metabolites and platelet-activating factors that interact with endothelial cells, inducing endothelial injury and neutralization of nitrous oxide vasodilator capacity. Adenosine, through its multi-targeted pharmacological actions, is able to inhibit some of the above-mentioned detrimental effects. The net protective of adenosine in in vivo models of reperfusion injury is the reduction of the infarct size, the improvement of the regional myocardial blood flow and of the regional function of the ischemic area. Additionally, adenosine preserves the post-ischemic coronary flow reserve, coronary blood flow and the post-ischemic regional contractility. In small-scale studies in patients with acute MI, treatment with adenosine has been associated with smaller infarcts, less no-reflow phenomenon and improved LV function. During elective PCI adenosine reduced ST segment shifts, lactate production and ischemic symptoms. During the last years, three relatively large placebo-controlled clinical trials have been conducted: Acute Myocardial Infarction Study of Adenosine Trial (AMISTAD) I and II and Attenuation by Adenosine of Cardiac Complications (ATTACC). In the AMISTAD trials, the final infarct size was reduced and the LV systolic function was improved by adenosine treatment, mainly in patients with anterior MI localization. However, morbidity and mortality were not affected. In the ATTACC study, the LV systolic function was not affected by adenosine, however, trends towards improved survival were observed in patients with anterior MI localization. The possibility of obtaining a Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the infarct-related artery in up to 95% of patients with acute MI (increasing the occurrence of reperfusion injury) has turned back the interest towards the protection of myocardial cells from the impending ischemic and reperfusion injury in which adenosine alone or together with other cardio-protective agents may exert important clinical effects.

Adenosine↗
PubMed1994

Renal adaptation to the failing heart. Understanding the cascade of responses.

Progressive systolic dysfunction of the heart results in a broad array of physiologic compensatory mechanisms within the kidney. These mechanisms are primarily stimulated by diminution of the effective arterial blood volume and resultant activation of a biochemical cascade of neurohormonal responses, including activation of the renin-angiotensin-aldosterone system and enhanced release of norepinephrine, arginine vasopressin, prostaglandins, endothelin, and atrial natriuretic peptide. The interaction of these neurohormonal systems within the kidney is complex. Vasoconstriction induced by angiotensin II, arginine vasopressin, and catecholamines may decrease renal perfusion by both endocrine and neural actions. In contrast, systemic pressures may rise, which may facilitate perfusion.

Adaptation, Physiological↗
PubMed1997

Myocardial damage does not occur in untreated hyperthyroidism unless associated with congestive heart failure.

Even in the absence of underlying cardiac disease, hyperthyroidism has seldom been reported to be associated with left ventricular dysfunction and congestive heart failure. The left ventricular function invariably improves with achievement of euthyroid status. Anecdotal autopsy reports have suggested that myocardial necrosis associated with hyperthyroidism may be responsible for congestive heart failure. This study prospectively evaluates the role of myocardial necrosis in untreated hyperthyroidism by imaging with Indium-111 antimyosin antibody. Thirteen consecutive patients (7 men and 6 women, mean age 36 +/- 11 years) with hyperthyroidism and Graves' disease (10 patients), subacute thyroiditis (2 patients), or multinodular goiter (1 patient) formed the basis of the study. The T4 levels ranged from 33 to 183 pmol/L (mean 103 +/- 47 pmol/L) and cardiac output from 5.47 to 11.0 L/min (mean 7.17 +/- 1.75 L/min). Two patients had clinical congestive heart failure and mildly depressed left ventricular ejection fraction. Both patients had scintigraphic evidence of myocardial damage with abnormal antimyosin scans. In the remaining 11 patients with normal left ventricular ejection fraction, no antimyosin uptake was observed. The reevaluation of two patients with abnormal initial scans 6 to 8 months after treatment revealed euthyroid status, resolution of antimyosin uptake, and normalization of left ventricular function. This study indicates that myocardial necrosis may be detected in a small proportion of patients with hyperthyroidism, which could contribute to left ventricular systolic dysfunction.

Adult↗
PubMed2001

Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.

BACKGROUND: The beneficial effects of beta-blockers on long-term outcome after acute myocardial infarction were shown before the introduction of thrombolysis and angiotensin-converting-enzyme (ACE) inhibitors. Generally, the patients recruited to these trials were at low risk: few had heart failure, and none had measurements of left-ventricular function taken. We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with left-ventricular dysfunction after acute myocardial infarction treated according to current evidence-based practice. METHODS: In a multicentre, randomised, placebo-controlled trial, 1959 patients with a proven acute myocardial infarction and a left-ventricular ejection fraction of </=40% were randomly assigned 6.25 mg carvedilol (n=975) or placebo (n=984). Study medication was progressively increased to a maximum of 25 mg twice daily during the next 4-6 weeks, and patients were followed up until the requisite number of primary endpoints had occurred. The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems. Analysis was by intention to treat. FINDINGS: Although there was no difference between the carvedilol and placebo groups in the number of patients with the primary endpoint (340 [35%] vs 367 [37%], hazard ratio 0.92 [95% CI 0.80-1.07]), all-cause mortality alone was lower in the carvedilol group than in the placebo group (116 [12%] vs 151 [15%], 0.77 [0.60-0.98], p=0.03). Cardiovascular mortality, non-fatal myocardial infarctions, and all-cause mortality or non-fatal myocardial infarction were also lower on carvedilol than on placebo. INTERPRETATION: In patients treated long-term after an acute myocardial infarction complicated by left-ventricular systolic dysfunction, carvedilol reduced the frequency of all-cause and cardiovascular mortality, and recurrent, non-fatal myocardial infarctions. These beneficial effects are additional to those of evidence-based treatments for acute myocardial infarction including ACE inhibitors.

Adrenergic beta-Antagonists↗
PubMed2000

Clinical diagnosis and management strategies in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease, often familial, that is characterized by fibro-fatty replacement of the right ventricular (RV) myocardium. The most common clinical manifestations of ARVC consists of ventricular arrhythmias of RV origin, which may lead to sudden death mostly in young people and athletes, electrocardiograph depolarization/repolarization changes mostly localized to right precordial leads, and global and/or regional dysfunction and structural alterations of the RV. The diagnosis of ARVC may be difficult due to several problems with the specificity of the electrocardiograph abnormalities, the different potential etiologies of ventricular arrhythmias with a left bundle branch morphology, the assessment of the RV structure and function, and the interpretation of endomyocardial biopsy findings. Therefore, standardized diagnostic criteria have been proposed by the Study Group on ARVC of the European Society of Cardiology. According to these guidelines, the diagnosis of ARVC is based on the presence of major and minor criteria encompassing electrocardiograph, arrhythmic, morphofunctional, histopathologic, and genetic factors. Because the assessment of sudden death risk in patients with ARVC is still not well established, there are no precise guidelines to determine which are the patients who need to be treated and which is the best management approach. The therapeutic options include beta blockers, antiarrhythmic drugs, catheter ablation, and implantable cardioverter defibrillator. The implantable defibrillator is the most effective safe-guard against arrhythmic sudden death. However, its precise role in changing natural history of ARVC by preventing sudden and nonsudden death needs to be evaluated by a prospective study of a large series of patients. In patients in whom ARVC has progressed to severe RV or biventricular systolic dysfunction with risk of thromboembolic complications, treatment consists of current therapy for heart failure including anticoagulant therapy. In case of refractory congestive heart failure, the patients may become candidates for heart transplantation.

Anti-Arrhythmia Agents↗
PubMed1991

[Reperfusion injury in the myocardium--significance of the oxygen-derived free radicals].

Convincing proof is now available that reperfusion of the ischaemic myocardium results in release of oxygen-derived free radicals (ODFR). Experimental data support the hypothesis that ODFR play a pathological physiological role in the development of post-ischaemic systolic dysfunction (stunning), microcirculatory disturbances and reperfusion arrhythmias. In addition, the free radicals appear to modify the energy metabolic conditions after reperfusion. The results from investigations of the effects of ODFR on the extent of myocardial infarction are difficult to interpret as, in various experimental series in which formation of ODFR is reduced to a minimum, the infarct reducing effect has not been found to be in agreement with similar durations of ischaemia. The varying results concerning the extent of the infarcts suggests that other factors e.g. collateral circulation and balance between oxygen supply and oxygen requirements play a dominating role in these problems. It has not yet been elucidated whether ODFR are of significance in man in connection with reperfusion of the ischaemic myocardium.

Animals↗
PubMed2001

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure.

OBJECTIVES: This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND: Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS: Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS: During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS: Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Blood Flow Velocity↗
PubMed1999

Molecular mechanisms of myocardial remodeling.

"Remodeling" implies changes that result in rearrangement of normally existing structures. This review focuses only on permanent modifications in relation to clinical dysfunction in cardiac remodeling (CR) secondary to myocardial infarction (MI) and/or arterial hypertension and includes a special section on the senescent heart, since CR is mainly a disease of the elderly. From a biological point of view, CR is determined by 1 ) the general process of adaptation which allows both the myocyte and the collagen network to adapt to new working conditions; 2) ventricular fibrosis, i.e., increased collagen concentration, which is multifactorial and caused by senescence, ischemia, various hormones, and/or inflammatory processes; 3) cell death, a parameter linked to fibrosis, which is usually due to necrosis and apoptosis and occurs in nearly all models of CR. The process of adaptation is associated with various changes in genetic expression, including a general activation that causes hypertrophy, isogenic shifts which result in the appearance of a slow isomyosin, and a new Na+-K+-ATPase with a low affinity for sodium, reactivation of genes encoding for atrial natriuretic factor and the renin-angiotensin system, and a diminished concentration of sarcoplasmic reticulum Ca2+-ATPase, beta-adrenergic receptors, and the potassium channel responsible for transient outward current. From a clinical point of view, fibrosis is for the moment a major marker for cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, and the propensity for reentry arrhythmias. In addition, systolic dysfunction is facilitated by slowing of the calcium transient and the downregulation of the entire adrenergic system. Modifications of intracellular calcium movements are the main determinants of the triggered activity and automaticity that cause arrhythmias and alterations in relaxation.

Animals↗
PubMed2004

Expression of cardiac troponin T with COOH-terminal truncation accelerates cross-bridge interaction kinetics in mouse myocardium.

Transgenic mice expressing an allele of cardiac troponin T (cTnT) with a COOH-terminal truncation (cTnT(trunc)) exhibit severe diastolic and mild systolic dysfunction. We tested the hypothesis that contractile dysfunction in myocardium expressing low levels of cTnT(trunc) (i.e., <5%) is due to slowed cross-bridge kinetics and reduced thin filament activation as a consequence of reduced cross-bridge binding. We measured the Ca(2+) sensitivity of force development [pCa for half-maximal tension generation (pCa(50))] and the rate constant of force redevelopment (k(tr)) in cTnT(trunc) and wild-type (WT) skinned myocardium both in the absence and in the presence of a strong-binding, non-force-generating derivative of myosin subfragment-1 (NEM-S1). Compared with WT mice, cTnT(trunc) mice exhibited greater pCa(50), reduced steepness of the force-pCa relationship [Hill coefficient (n(H))], and faster k(tr) at submaximal Ca(2+) concentration ([Ca(2+)]), i.e., reduced activation dependence of k(tr). Treatment with NEM-S1 elicited similar increases in pCa(50) and similar reductions in n(H) in WT and cTnT(trunc) myocardium but elicited greater increases in k(tr) at submaximal activation in cTnT(trunc) myocardium. Contrary to our initial hypothesis, cTnT(trunc) appears to enhance thin filament activation in myocardium, which is manifested as significant increases in Ca(2+)-activated force and the rate of cross-bridge attachment at submaximal [Ca(2+)]. Although these mechanisms would not be expected to depress systolic function per se in cTnT(trunc) hearts, they would account for slowed rates of myocardial relaxation during early diastole.

Actin Cytoskeleton↗
PubMed2006

Neurohumoral, immunoinflammatory and cardiovascular profile of patients with severe tetanus: a prospective study.

INTRODUCTION: Autonomic disturbances in tetanus are traditionally associated with adrenergic variations and/or cardiac dysfunction, based on case report data. The objective of this study was to measure catecholamines, (TNF)-alpha and troponin T relative to and left ventricular ejection fraction (LVEF) in patients with severe tetanus. METHODS: This prospective study was carried out at two general Intensive Care Units and included 21 patients consecutively admitted with severe tetanus. Catecholamines (dopamine, norepinephrine, epinephrine and total catecholamines), tumor necrosis factor (TNF)-alpha and LVEF were assessed during the first week of autonomic instability and following tetanus recovery. Troponin T was measured during autonomic instability only. RESULTS: Mean age of patients was 46 +/- 17 years, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 8 (range 1-23). All patients had both blood pressure and heart rate instability. Two patients were recuperated from cardiac arrest. Intensive Care Unit mortality was 14% (3 cases). No increase in total catecholamines or in TNF-alpha levels was observed during autonomic instability or in the recovery period. Six patients had troponin T > 0.01 ng/ml and six had > 0.1 ng/ml. Mean LVEF was similar during autonomic instability and after tetanus recovery, 67 +/- 7% and 65 +/- 7%, respectively. Troponin T levels correlated with pressoric instability during autonomic instability. CONCLUSION: Our study demonstrated that in patients with severe tetanus no significant increased levels of catecholamines or TNF-alpha or evidence of cardiac systolic dysfunction was observed either during autonomic instability or in the recovery period. Elevated values of troponin T detected during autonomic instability were not associated with left ventricular dysfunction. Our data do not support the hypothesis that autonomic disturbances in tetanus are associated with adrenergic variations or cardiac dysfunction.

Adult↗
PubMed2005

[Impaired endothelium-dependent forearm vasodilation in idiopathic dilated cardiomyopathy is related to severe left ventricular dysfunction and elevated serum tumor necrosis factor levels].

INTRODUCTION AND OBJECTIVES: Endothelial dysfunction has been found in patients with idiopathic dilated cardiomyopathy (IDC), but its mechanism remains unknown. Our aim was to investigate whether forearm endothelium-dependent vasoreactivity correlates with cardiac disease severity or neurohormonal activation. PATIENTS AND METHOD: We studied 23 patients with IDC and 10 healthy sex- and age-matched controls using brachial artery ultrasound to assess flow-mediated dilation (FMD) and nitroglycerin-induced vasodilation (NIV). In the IDC group, we determined plasma neurohormone and cytokine levels at the same time. RESULTS: FMD was significantly less in the IDC group compared with the control group [--0.06 (2.8)% vs 4.4 (4.6)%, respectively; P<.01], whereas NIV was similar in both groups [15.0 (6.4)% vs 14.0 (7.4)%, respectively; P=NS]. FMD was significantly less in patients with poorer left ventricular (LV) function and more severe LV dilatation, and in those with a higher tumor necrosis factor-alpha (TNF-alpha) level. NIV was similar in all patient subgroups. There was a significant inverse correlation between the TNF-alpha plasma level and FMD (r=-0.75; P<.01). No correlation was found between the plasma levels of other neurohormones and FMD. CONCLUSIONS: FMD, but not NIV, was impaired in patients with IDC compared with control subjects. In patients, there were significant associations between FMD impairment and the severity of LV dilatation, the severity of LV systolic dysfunction, and the plasma TNF-alpha level. The strongest correlation was observed between TNF-alpha plasma level and FMD. These data suggest that TNF-alpha may be implicated in endothelial dysfunction in patients with IDC.

Arm↗
PubMedDate not supplied

Mechanism of physiologic and pathologic S3 gallop sounds.

Although the S3 gallop sound has long been used clinically as an indicator of left ventricular systolic dysfunction, the mechanism responsible for its production remains controversial. The same sound is often found in young healthy individuals, and whether a similar mechanism is responsible is also unknown. The relationship of the S3 gallop sound to the dynamics of left ventricular filling was compared in 18 healthy young triathletes and 15 older subjects with cardiac disease. Twenty healthy normal subjects without an S3 were included as controls. Phonocardiographic, two-dimensional echocardiographic, and Doppler echocardiographic analysis of left ventricular inflow were evaluated. The S3 in both groups always occurred close to peak early filling velocity (E), during early flow deceleration. Mean E deceleration rate was higher in the subjects with S3 (726 +/- 153 cm/sec2 in the triathletes and 819 +/- 274 cm/sec2 in those with cardiac disease) than in control subjects (563 +/- 131 cm/sec2, p less than 0.001 in both cases). Ten triathletes underwent examination both before and immediately after 30 degrees head-up tilt. E deceleration rate dropped significantly with head-up tilt (720 +/- 137 vs 590 +/- 174 cm/sec2, p less than 0.01), while concurrently the S3 disappeared or was diminished in amplitude. Similar changes were seen in subjects with cardiac disease. We conclude that both the "pathologic" and "physiologic" S3 are related to abnormally rapid deceleration of early diastolic left ventricular inflow. Although the presence of the S3 is not dependent on the state of left ventricular systolic function, diastolic filling is characterized by a predominance of early inflow with a rapid flow deceleration rate.

Adult↗
PubMed1997

Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure.

OBJECTIVES: Cognitive impairment has been reported in middle aged patients with end stage heart failure. This cross sectional study assessed the prevalence and determinants of cognitive dysfunction in older patients with mild to moderate heart failure. METHODS: 57 consecutive patients (mean age 76.7 years) with chronic heart failure underwent physical examination, blood chemistry, urinalysis, chest radiography ECG, Doppler echocardiography, and the mini mental state examination (MMSE), mental deterioration battery, depression scale of the Center for Epidemiological Studies (CES-D), Katz activities of daily living, and instrumental activities of daily living 24 hours before hospital discharge. RESULTS: MMSE scores <24 were found in 53% of participants. The MMSE score was associated with left ventricular ejection fraction according to a non-linear correlation, so that cognitive performance was significantly lower in subjects with left ventricular ejection fraction < or =30%. The same pattern of correlation was evidenced between left ventricular ejection fraction and both the attention sub-item of MMSE and the Raven test score. In a multivariate linear regression model, after adjusting for age, sex, and a series of clinical data and objective tests, both age (beta=-0.30; P=0.038) and the natural log of left ventricular ejection fraction (beta=0.58; P=0.001) were associated with the MMSE score. CONCLUSION: Cognitive impairment in older patients with chronic heart failure is common, and independently associated with lower left ventricular ejection fraction. Given the overwhelming incidence and prevalence of heart failure in older populations, early detection of cognitive impairment in these subjects with prompt, intensive treatment of left ventricular systolic dysfunction may prevent or delay a remarkable proportion of dementia in advanced age.

Aged↗
PubMed1991

Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens.

Cyclophosphamide (CY) cardiotoxicity may be a lethal complication of bone marrow transplantation. Previous echocardiographic studies have reported that left ventricular dysfunction due to CY occurs in over 50% of patients undergoing transplantation. To evaluate the cardiotoxicity of new dosing protocols that included twice-daily rather than once-daily CY, 44 bone marrow transplantation patients were prospectively evaluated with serial ECGs and echocardiograms. Twenty-six patients received a once-daily lower-dose protocol (mean total 87 +/- 11 mg/kg), and 18 patients received a twice-daily higher-dose (mean total 174 +/- 34 mg/kg) CY regimen. In the higher-dose CY group, significant reductions in summed ECG voltage (-20%) (P less than .01) and increases in left ventricular mass index (LVMI) (+10%) (P less than .05) were detected in the first week following therapy. These changes resolved by the third week following CY and were significantly greater than the changes noted in the lower-dose group. However, left ventricular ejection fraction (EF) did not change significantly in either group. Five patients developed clinical cardiotoxicity (four, pericarditis; one, congestive heart failure); four of the five patients were in the higher-dose group (P = .14). Only a prior history of congestive heart failure or a baseline EF less than 50% was an independent correlate of clinical cardiotoxicity (P less than .05). Thus, dose-dependent cardiotoxicity following the use of CY for bone marrow transplantation is evident as reversible decreases in ECG voltage and increases in left ventricular mass, possibly reflecting myocardial edema or hemorrhage. However, systolic dysfunction is much less common with these new twice-daily dosing regimens when compared with earlier studies of high-dose once-daily CY.

Adult↗
PubMed2000

Myocardial effects of repeated electrical defibrillations in the isolated fibrillating rat heart.

OBJECTIVE: Although substantial myocardial cell injury has been reported after high-energy electrical defibrillation, only minimal injury with transient functional defects seems to develop at energy levels not exceeding those required to reverse ventricular fibrillation. Because multiple electrical shocks are often delivered in clinical settings during attempts to reverse ventricular fibrillation, we investigated the effects of repetitive shocks on postresuscitation myocardial dysfunction by using an isolated rat heart model of ventricular fibrillation. DESIGN: Prospective and randomized. SETTING: Cardiopulmonary resuscitation research laboratory. SUBJECTS: Twenty-seven Sprague-Dawley rats. INTERVENTIONS: Hearts were harvested and perfused at a constant flow of 10 mL/min by using a modified Krebs-Henseleit solution equilibrated with 95% oxygen and 5% CO2. Ventricular fibrillation (VF) was induced by a 0.05-mA current delivered to the right ventricular endocardium and the perfusate flow was stopped. After 10 mins, the perfusate flow was resumed at 20% of baseline flow and maintained for 15 additional minutes before returning to baseline flow after 25 mins of VF (VF25 mins). Twenty-seven hearts were randomized to receive from VF22 mins to VF25 mins either 0 epicardial shocks, 6 epicardial shocks, or 12 epicardial shocks. MEASUREMENTS AND MAIN RESULTS: Isovolumic indices of left ventricular function were obtained by using a latex balloon advanced through the mitral valve into the ventricular cavity. After defibrillation, indices of contractile function rapidly returned to baseline without differences among groups. The isovolumic end-diastolic pressure, however, remained elevated throughout the postresuscitation interval. A left shift of the diastolic pressure-volume curves without changes in their slope was observed at 10 mins after resuscitation with partial return to baseline by 30 mins postresuscitation. The shifts were significantly greater in hearts that received 12 shocks. CONCLUSIONS: These findings indicate that repetitive low-energy electrical shocks do not accentuate postischemic systolic dysfunction in the isolated fibrillating rat heart but adversely affect postischemic diastolic dysfunction by reducing the unstressed left ventricular end-diastolic volume.

Animals↗
PubMed2000

Metoprolol: a review of its use in chronic heart failure.

UNLABELLED: Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure. The effects of metoprolol controlled-release/extended-release (CR/XL) in patients with stable, predominantly mild to moderate (NYHA functional class II to III) chronic heart failure have been evaluated in the large Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial and the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25 mg once daily and gradually increased at 2-weekly intervals until the target dosage (200 mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure. At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial. The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL. Similarly, a trend towards decreased mortality in the metoprolol CR/XL group compared with placebo was observed in the RESOLVD trial. Data from small numbers of patients with severe (NYHA functional class IV) heart failure indicate that metoprolol CR/XL is effective in this subset of patients. However, no firm conclusions can yet be drawn. Improvement from baseline values in NYHA functional class, exercise capacity and some measures of quality of life with metoprolol CR/XL or immediate-release metoprolol were significantly greater than those with placebo. The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks. CONCLUSIONS: Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy. Although limited data indicate that metoprolol CR/XL is effective in patients with severe (NYHA functional class IV) chronic heart failure, more data are needed to confirm these findings. Treatment with metoprolol CR/XL significantly reduced the incidence of sudden death and death due to progressive heart failure.

Adrenergic beta-Antagonists↗
PubMed2006

Pharmacologic treatment of heart failure due to ventricular dysfunction by myocardial stunning: potential role of levosimendan.

The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. Myocardial stunning is mainly due to calcium overload in the cytosol of myocardial cells, the loss of myofilaments and their reduced sensitivity to calcium. Enhanced immune activation with inflammatory phenomena also plays an important role in the pathophysiology of cardiac dysfunction. Increasing evidence has shown that the myocardial ATP-dependent potassium channel (K(ATP)) plays an important role in many myocardial cell functions and that it is involved in ischemia-reperfusion injury and myocardial stunning. K(ATP) is thus considered a therapeutic target in this setting. Currently used inotropic drugs improve contractility by increasing intracellular concentrations of free calcium, but they increase myocardial consumption of energy and even produce arrhythmia; therefore, in this clinical context, they do not seem to be 'pathophysiologically correct' drugs. Levosimendan, a new calcium-sensitizing agent, increases contractility by enhancing the sensitivity of myofilaments to calcium by binding to the C cardiac troponin in cardiac muscle in a calcium-dependent way. Levosimendan also exerts a coronary and systemic vasodilatory effect through its K(ATP) channel-opening properties and may exert other cardioprotective actions through this mechanism. Levosimendan produces positive hemodynamic effects without increasing myocardial oxygen demand or causing arrhythmias. Intravenous levosimendan is generally well tolerated and has been approved by several European countries, and recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe decompensated heart failure in adults. Randomized, double-blind trials have shown that levosimendan is not only more clinically and hemodynamically effective but also that it significantly reduces morbidity and mortality when compared with dobutamine or placebo. Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.

Adenosine Triphosphate↗
PubMed2001

Tumour necrosis factor-alpha soluble receptors type I are related to symptoms and left ventricular function in hypertrophic cardiomyopathy.

BACKGROUND: High circulating levels of tumour necrosis factor-alpha (TNF-alpha) and its soluble receptors (sTNFRI, sTNFRII) are involved in the pathogenesis of congestive heart failure due to left ventricular (LV) systolic dysfunction. However, their role in hypertrophic cardiomyopathy (HCM) has not been elucidated. OBJECTIVES: To determine the circulating serum levels of sTNFRI in a wide spectrum of patients with HCM, and to study in detail their relationship with symptom severity and various echocardiographic disease characteristics. PATIENTS AND METHODS: sTNFRI serum levels were measured in 66 patients with HCM and 30 age-matched healthy subjects using enzyme linked immunosorbent assay for serum levels of soluble TNF-a receptor type I at rest and at 1, 3 (sTNFRI-3e) and 6 h after dobutamine stress echocardiography (DSE). RESULTS: sTNFRI-r levels were significantly higher in patients with HCM than in control subjects (2.8+/-0.8 compared with 1.4+/-0.5 ng/mL, P<0.002). In patients with HCM, there was a significant difference in sTNFRI-r levels between mildly (New York Heart Association [NYHA] functional class I and II) and severely (NYHA functional class III and IV) symptomatic patients (1.4+/-0.9 compared with 4.8+/-1.0 ng/mL, p<0.001). Higher sTNFRI-r and sTNFRI-3e levels were found in patients with an LV restrictive filling pattern during DSE compared with sustained abnormal relaxation (p<0.052, p<0.004, respectively), and in patients with reduced compared with normal increments in LV fractional shortening during DSE (p<0.02, p<0.003, respectively). CONCLUSIONS: Significant differences in sTNFRI serum levels between patients with HCM and healthy subjects were shown. In patients with HCM, sTNFRI levels were higher in severely symptomatic patients, and in patients with reduced LV systolic and diastolic reserve during DSE. These data suggest that TNF may be involved in the pathogenesis of HCM.

Adult↗