Myocardial function in hearts with transgenic overexpression of the G protein-coupled receptor kinase 5

BACKGROUND: Chronic heart failure is associated with impairment of the myocardial beta-adrenergic receptor (beta-AR) system. In this study, the effects of G protein-coupled receptor kinase 5 (GRK5) overexpression on myocardial performance were directly assessed in the hearts of transgenic mice using an isolated work-performing murine heart preparation and computerized analysis of functional data. METHODS: A controlled experimental study was performed to evaluate cardiac function in both transgenic mice with a 30-fold overexpression of GRK5 (n = 9, 23 to 29 g) and littermate controls (n = 10, 22 to 29 g). Preload-dependent cardiac output, contractility, stroke work, stroke volume, and heart rate were compared between the two groups. RESULTS: Significant decreases in preload-dependent cardiac output and contractility were observed in the mice with GRK5 overexpression when compared with control group mice and occurred in association with significant decreases in stroke work and stroke volume. There was no significant difference in the average heart rate between the two groups. CONCLUSIONS: These data suggest that GRK5 upregulation may be partially responsible for alterations in myocardial function in chronic heart failure.     

Does Ventricular Fibrillation Cause Myocardial Stunning During Defibrillator Implantation?

Abstract Induction of ventricular fibrillation (VF) is an important part of the process of inserting implantable cardioverter defibrillators (ICDs), allowing the measurement of defibrillation thresholds. However, animal studies have revealed that repeated cycles of VF and defibrillation result in depressed left ventricular (LV) function and reduced cardiac output. Short intervals of VF do not affect myocardial contractility but longer periods produce heart failure. Induced VF was used in a canine model to study profound myocardial stunning leading to heart failure, as well as the therapeutic potential of the phosphodiesterase inhibitor, amrinone (combined with epinephrine and norepinephrine). Amrinone was found to significantly (p < 0.05) increase contractility when added to a stable preparation supported by epinephrine and norepinephrine infusion; amrinone or catecholamines alone had no effect. In the clinical setting, the following factors may affect LV contractility during ICD surgery: catecholamines released as a result of hypotension; negative VF; ischemia; antiarrhythmic drugs; anesthetics; and bradycardia after device testing. Patients (n = 125) have tolerated ICD insertion well. Early data reveals no significant changes in ejection fraction. Though rare, death due to myocardial stunning and LV power failure can occur during ICD insertion. It may be possible to use arterial pressure monitoring to predict this event in vulnerable patients.     

Myocardial function, energy provision, and carnitine deficiency in experimental uremia

Cardiac complications are the leading cause of mortality in patients with chronic renal failure. Secondary carnitine deficiency, which is frequently observed in hemodialysis patients, has been associated with cardiac hypertrophy and heart failure and may impair myocardial fatty acid oxidation. In chronic kidney disease, impaired carnitine homeostasis also may affect myocardial metabolism. In this study, myocardial function and substrate oxidation in conjunction with carnitine deficiency were investigated in experimental renal failure. Uremia was induced in male Sprague-Dawley rats via a two-stage five-sixths nephrectomy. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C nuclear magnetic resonance at 3 and 6 wk of uremia. Renal impairment as assessed by serum creatinine was more severe initially and was associated with a significant deficiency in serum free carnitine (43%; P < 0.001) and elevated acyl carnitine/free carnitine ratio. Myocardial tissue carnitine concentrations, however, were unaffected. A moderate degree of cardiac hypertrophy (10 to 14%; P < 0.05) was observed in uremia without evidence of dysfunction or changes in myocardial substrate utilization. It is concluded that renal dysfunction is associated with cardiac hypertrophy in the presence of normal myocardial carnitine levels, despite a significant depletion in serum carnitine. This may be a factor in maintaining normal cardiac function and metabolism.     

Abdominal aortic aneurysm repair in a patient with a cardiac transplant

We describe successful elective abdominal aneurysm repair in a patient with a cardiac transplant. In light of the unique physiology and pharmacology of the denervated heart, this presented an unusual combination of complex problems. Whereas the normally innervated heart increases cardiac output via neural stimuli, the denervated heart relies primarily on the Frank Starling mechanism which is dependent on preload and myocardial contractility. Thus, rapidly changing haemodynamic variables associated with aortic cross-clamping require scrupulous attention to the maintenance of adequate preload as well as myocardial function which can only be manipulated by direct-acting agents. We conclude that the denervated heart will readily compensate for the haemodynamic changes brought about by infrarenal aortic crossclamping if a high-normal preload is maintained and if the transplanted donor heart is free of pathology with good inherent myocardial contractility.     

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy

BACKGROUND: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. METHODS: The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). RESULTS: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. CONCLUSIONS: Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.     

The natural history of myocardial disease in dialysis patients.

Among dialysis patients, only 23% have a normal echocardiogram, about 10% have recurrent or chronic congestive heart failure, and 17% have asymptomatic ischemic heart disease. The predisposing factors for congestive heart failure are dilated cardiomyopathy, hypertrophic hyperkinetic disease, and ischemic heart disease. Dilated cardiomyopathy, a disorder of systolic function, includes among its risk factors age, hyperparathyroidism, and smoking. Hypertrophic disease results in diastolic dysfunction, and its predictors include age, hypertension, aluminum accumulation, anemia, and, perhaps, hyperparathyroidism. Ischemic heart disease is due to the presence of coronary artery disease and also to nonatherosclerotic disease caused by the reduction in coronary vasodilator reserve and altered myocardial oxygen delivery and use. The clinical outcome of congestive heart failure is comparable to that of nonrenal patients with medically refractory heart failure. Left ventricular hypertrophy is an important independent determinant of survival. A subset have hyperkinetic disease with severe hypertrophy and have a bad survival, as low as 43% have a 2-yr survival after the first admission to hospital with cardiac failure. The prognosis for those with dilated cardiomyopathy is less severe but is worse than those with normal echocardiogram. The survival of patients with symptomatic ischemic heart disease was little different from that of patients without symptoms, suggesting that the underlying cardiomyopathies had an adverse impact on survival independent of ischemic disease. Much research needs to be undertaken on the risk factors, natural history, and therapy of the various types of cardiac disease prevalent in dialysis patients.     

Morphology of the heart and arteries in renal failure

In patients with renal failure, cardiovascular complications are a major clinical problem; cardiac death is the main cause of death in these patients. Cardiac risk is increased by a factor of 20 in uremic patients, compared with matched segments of the general population. It has been known for a long time that atherosclerosis, particularly plaque in the epicardiac coronary conduit arteries, are more frequent in patients with chronic renal failure. Recently, however, clinical studies showed that myocardial infarction is responsible for only 30% to 50% of all cardiac deaths. In contrast, 30% to 40% of patients with renal failure and ischemic heart disease show patent coronary arteries on coronary angiogram. Thus, it is very likely that in uremic patients myocardial ischemia tolerance is markedly reduced even in the absence of classical atherosclerosis (i.e., relevant stenosis of coronary arteries). This finding in uremic patients can be at least partially explained by structural and metabolic abnormalities of the myocardium, and in part by alterations of the extracardiac vasculature. The present paper focuses on structural changes of the heart and the vasculature, in particular on atherosclerosis of cardiac and extracardiac arteries, and its potential repercussions for cardiovascular function. In 1827 Richard Bright already pointed to the common presence of left ventricular hypertrophy (LVH) and thickening of the aorta in patients with end-stage renal failure (ESRF). At present, cardiovascular complications account for 45% of all deaths in uremic patients [1]. The recent report of Herzog, Ma, and Colins [2] documented a 59.3% 1-year mortality rate in dialyzed patients who survived myocardial infarction (i.e., mortality was significantly higher than in the general population). It is widely acknowledged that several specific structural and nonstructural alterations of the heart and the extracardiac vasculature are present in patients with renal failure, which presumably contribute to the markedly increased cardiovascular risk in these patients [3].     

Peripheral vascular remodelling and changes to the skeletal muscles in heart failure

The syndrome of heart failure causes besides a deterioration in the contractile function of the heart significant alterations of peripheral circulation and skeletal muscles. The distribution of the regional blood flow is influenced by systemic and local neurohumoral factors. The local factors are released by the vascular endothelium or are of nonendothelial origin. The diminution of cardiac output leads to neurohumoral alterations which eventually influence the blood flow distribution: in vital organs, such as the heart and the brain, it is preserved; in the splanchnic, kidney, muscle and skin territories it is diminished. Muscles changes (muscle atrophy, reduction of type I fibres and a relative increase of type IIb fibres) are the main cause restricting the exercise. Techniques of physical rehabilitation associated with proper medication may lead to the improvement of these alterations.     

High-dose intravenous beta 1-blockade in patients early after cardiac operations. Negative inotropism versus myocardial oxygen economy.

A high adrenergic strain during reperfusion after ischemia impedes functional recovery. Conversely, adrenergic blockade may be beneficial during reperfusion. Negative inotropic effects may outweigh the expected benefit, however. Against this background hemodynamic and metabolic effects of early postoperative infusion with the beta 1-selective agent metoprolol were studied in 22 patients after coronary operations. During basal postoperative conditions, intravenous metoprolol reduced cardiac index and stroke volume index compared with control patients, while other variables were unaffected. During the higher adrenergic level of a dopamine infusion (7 micrograms/kg per minute), the heart rate, rate pressure product, and myocardial oxygen uptake were attenuated in proportion to the plasma level of metoprolol. Intravenous beta 1-blockade did not affect the cardiac output or stroke volume responses to dopamine (the cardiac output was still, however, 19% lower than in control patients). A release of myocardial creatinine kinase isoenzyme myocardial band was observed during dopamine infusion, suggesting that myocardial ischemia was induced. The release was not influenced by metoprolol, but it correlated with heart rate (r = 0.60; p < 0.01). It is concluded that infusion of metoprolol early after coronary operations depresses myocardial contractility with some 19%, which was without clinical significance in straightforward patients; the increased myocardial metabolic demand during a period of increased adrenergic stress was attenuated by metoprolol. This may be of importance for myocardial recovery.     

Left ventricular geometry and hypotension in end-stage renal disease: a mechanical perspective

Hemodynamic and nonhemodynamic factors are implicated in the maintenance and aggravation of left ventricular (LV) hypertrophy in ESRD. Functional consequences of LV geometry are of substantial importance in patients who undergo dialysis and may contribute to explain the negative outcome related to LV hypertrophy, also in patients without overt coronary heart disease (CHD). Whereas most patients with eccentric LV hypertrophy have systolic dysfunction and the underlying CHD imposes progression of their disease, when overt CHD does not occur to remodel left ventricle, concentric LV geometry is more prevalent in ESRD and functional consequences are different. Concentric LV geometry is very sensitive to abrupt changes of cardiac loading conditions because of increased LV stiffness. Dialysis-related decrease in LV filling pressure reduces Starling forces recruitment and causes a fall in stroke volume as a result of reduced preload. This fall cannot be compensated by increased contractility, as myocardial mechanics is impaired in concentric LV geometry and no functional reserve can be used. When adequate increase in heart rate is not achieved to compensate reduced stroke volume, cardiac output substantially decreases and hypotension occurs. Occurrence of hypotension in the context of concentric LV geometry might contribute to reduce repeatedly coronary blood flow supply in the stiff and thick myocardium and might accelerate myocardial structural deterioration seen in ESRD.     

Assessment of hemodynamic function and tolerance to ischemia in the absence or presence of calcium antagonists in hearts of Isoproterenol-treated, exercise-trained, and sedentary rats

The effects of cardiac hypertrophy on the structure, function and tolerance to ischemia of rat hearts have been investigated. Multiple injections of low doses of isoproterenol (ISO) resulted in an increase of heart weight/body weight ratio by 60%, and a decrease of myocardial creatine kinase activity by 25%, as compared to normal rats. Compared to age-matched control rats, rats submitted to a swimming program had a higher heart weight by 20%, but similar values of heart weight to body weight ratio. In isolated perfusion, the functional capacities of hearts from ISO-trated rats were severely depressed compared to normal rat hearts whereas exercise-trained rat hearts performed as well or even better than control hearts. The functional recovery of ISO-treated hearts following cardioplegia-induced arrest for 20 min at 37°C was significantly worse than the recovery of normal hearts, but hearts of exercise-trained rats showed a significantly better recovery than control hearts. Exercise training results in improvement of myocardial blood supply resulting in better preservation of the heart during ischemia, compared to normal hearts. Addition of a combination of verapamil and diltiazem to the cardioplegic solution followed by ischemic arrest for 20 min at 37°C resulted for ISO-treated rat hearts in an improved recovery of cardiac output (99%) compared to cardioplegia in the absence of these drugs (72%). In exercise-trained and control rat hearts, calcium antagonists improved the recovery from cardioplegic arrest of cardiac output from 90% to 92% and from 71% to 87%, respectively. Myocardium of ISO-treated rats showed foci of subendocardial infarction and fibrosis, whereas the myocardium of physically stressed animals and of normal rats had no abnormalities. Considering the histological similarities between ISO-treated rat hearts and lesions observed in human hearts with coronary artery disease and cardiac hypertrophy, the present study suggests that the presence of verapamil and diltiazem during cardioplegic arrest favors the functional recovery from cardiac surgery.     

心力衰竭患者的非药物治疗进展

心力衰竭是由各种疾病引起心肌收缩或／和舒张能力减弱，从而使心排血量减少产生的一系列症状和体征；是各种心脏病的终末期表现，也是心脏病患者死亡的主要原因之一。随着人群年龄的增长，心力衰竭的发病率在上升。尽管药物治疗在不断地改进，但其发病率和死亡率仍然很高。近年来，心力衰竭的非药物治疗越来越受到临床医师的重视，外科手术方式日益创新，内科介入也不断推出新的辅助装置，基因学和干细胞技术为其治疗带来了新的希望。现对心力衰竭的外科手术、介入治疗及其相关基因和细胞治疗的研究现状和进展进行综述。     

Urotensin II: a cardiovascular and renal update

PURPOSE OF REVIEW: Urotensin II is a highly conserved undecapeptide which is well represented in the nervous system, heart and kidney. This review summarizes recent studies on cardiovascular and renal pathophysiology of urotensin II and clinical studies exploring the role of this peptide in cardiovascular and renal diseases. RECENT FINDINGS: Urotensin II was initially seen as a vasoconstrictor/cardiodepressant compound and implicated in myocardial and renal dysfunction. Emerging evidence in experimental models and in humans indicates that urotensin II may play a cardioprotective role in coronary heart disease and in chronic renal failure. SUMMARY: Administration of urotensin II produces a cardiodepressant effect in normal rats but exerts beneficial renal hemodynamic effects and preserves myocardial contractility in rats with chronic volume overload. Both urotensin II and urotensin-related peptide exhibit a myocardial protective property in an ischemia-reperfusion injury model in the isolated perfused rat heart. In patients with acute cardiac ischemia, circulating urotensin II is lower than normal and low plasma urotensin II signals a higher risk of adverse clinical events following myocardial infarction. Similarly, low urotensin II appears linked to death, cardiomyopathy and cardiovascular complications in patients with advanced renal insufficiency.     

The Role of Echocardiography in the Differential Diagnosis Between Training Induced Myocardial Hypertrophy Versus Cardiomyopathy

Increased myocardial mass due to regular high-volume intense exercise training (so-called athlete’s heart) is not uncommon. Although directly correlated with the extent of training loads, myocardial hypertrophy is not present exclusively in well-trained or elite athletes. Athlete’s heart is considered a physiological phenomenon with no known harmful consequences. However, extreme forms of myocardial hypertrophy due to endurance training resemble a structural heart disease such as hypertrophic cardiomyopathy, a condition associated with substantially increased risk of cardiac event. Endurance sports such as rowing and road cycling, rather than strength/power training, are most commonly associated with left ventricular (LV) wall thickness compatible with hypertrophic cardiomyopathy. The differentiation between physiological and maladaptive cardiac hypertrophy in athletes is undoubtedly important, since untreated cardiac abnormality often possesses a real threat of premature death due to heart failure during intense physical exertion. Luckily, the distinction from pathological hypertrophy is usually straightforward using transthoracic echocardiography, as endurance athletes, in addition to moderately and proportionally thickened LV walls with normal acoustic density, tend to possess increased LV diameter. In more uncertain cases, a detailed evaluation of myocardial function using (tissue) Doppler and contrast echocardiography is effective. When a doubt still remains, knowledge of an athlete’s working capacity may be useful in evaluating whether the insidious cardiac pathology is absent. In such cases cardiopulmonary exercise testing typically resolves the dilemma: indices of aerobic capacity are markedly higher in healthy endurance athletes compared to patients. Other characteristics such as a decrease of LV mass due to training cessation are also discussed in the article.

Key points

• Transthoracic echocardiography is still the most common relevant differentiation technique applied to distinguish athlete’s heart from the cardiomyopathy.
• Conventional echocardiographic criteria such as left ventricular chamber size and diastolic function parameters are to be regarded first when making differential diagnosis between substantially increased wall thickness in athlete’s heart (i.e. physiological adaptation) versus a disease (usually hypertrophic cardiomyopathy).
• When conventional echocardiographic parameters fail to diagnose the nature of myocardial hypertrophy, other differentiation criteria such as aerobic fitness, cardiac performance in response to physical exertion, and changes in echocardiographic parameters due to detraining, must be taken into consideration.
• Tissue Doppler, contrast and three-dimensional imaging are state-of-the-art echocardiographic techniques which have recently appeared in the differential diagnostics.

Key words: Left ventricle, physical exercises, physiological adaptation     

Cardiomyocyte Ca2+ dynamics: clinical perspectives

In the heart, Ca²⁺ signals regulate a variety of biological functions ranging from contractility to gene expression, cellular hypertrophy and death. In this review, we summarize the role of local Ca²⁺ homeostasis in these processes in healthy cardiac muscle cells, and highlight how mismanaged Ca²⁺ handling contributes to the pathophysiology of conditions such as cardiac arrhythmia, ischemic heart disease, cardiac hypertrophy and heart failure. Aiming to provide an introduction to the field with a clinical perspective, we also indicate how current and future therapies may modulate cardiomyocytes Ca²⁺ handling for the treatment of patients.     

N-acetylcysteine Improves Cardiac Contractility and Ameliorates Myocardial Injury in a Rat Model of Lung Ischemia and Reperfusion Injury

ObjectivesLung ischemia and reperfusion (I/R) injury is the major complication subsequent to cardiopulmonary bypass surgery and lung transplantation. Lung I/R injury frequently induces cardiac dysfunction leading to significant mortality. So far, the literature on therapeutic interventions in cardiac dysfunction and myocardial injury is still scarce. In this study, we examined the efficacy of N-acetylcysteine (NAC) administration against lung I/R injury–induced cardiac dysfunction.MethodsLung ischemia was established by occluding the left lung hilum for 60 minutes, followed by 2 hours of reperfusion. Studies were performed in 3 groups: sham-operated (same surgical procedure except vessel occlusion; N = 8), lung I/R injury (N = 12), and NAC-administered group (N = 12). The cardiac function was assessed using simultaneous left ventricular (LV) pressure and volume measured via a high-fidelity pressure-volume catheter. Myocardial injury was assessed based on serum creatine kinase muscle brain fraction (CK-MB) and troponin I (cTnI) level, and lung injury based on the degree of protein concentration in lung lavage. We also examined the degrees of myocardial lipid peroxidation and hydroxyl radical production with and without NAC.ResultsDuring lung ischemia, LV stiffness increased with relative intact contractility. After 2 hours of reperfusion, LV contractility decreased with dilated and stiffened ventricle, along with apparent myocardial and lung injury. NAC administration effectively attenuated heart and lung injury, and ameliorated impaired LV contractility and stiffening resulting from lung I/R injury.ConclusionsNAC administration reduced lung I/R-induced increases in myocardial hydroxyl radical production and lipid peroxidation, and ameliorated LV contractility and stiffening.     

Management of heart failure

Heart failure is an increasingly common syndrome, which is associated with a high 1-year mortality and significant morbidity. Currently ischaemic heart disease is the most common cause in western societies but the majority of causes produce a similar clinical picture of reduced cardiac output, salt and water retention and peripheral vasoconstriction. Advances in the understanding of the pathophysiology of heart failure have lead to an alteration in the way in which it is managed and the development of different models of heart failure. Salt and water retention is managed with the use of fluid restriction and diuretics. Inotropic therapy remains useful in the short-term management of heart failure when acute decompensation leads to critical hypoperfusion of vital organs. Finally the maladaptive neurohumoral activation found in heart failure can be antagonised by the use of beta-blockers, angiotensin converting enzyme inhibitors and spironolactone, all of which reduce mortality and improve symptoms.     

Neurohumoral activation in heart failure: the role of adrenergic receptors

Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.