Arrhythmia mechanisms in the failing heart

Background: Heart failure (HF) claims over 200,000 lives annually in the United States alone. Approximately 50% of these deaths are sudden and unexpected, and presumably the consequence of lethal ventricular tachyarrhythmias. Electrical remodeling that occurs at the cellular and tissue network levels predisposes patients with HF to malignant arrhythmias. Our limited understanding of fundamental arrhythmia mechanisms has hampered the development of effective treatment strategies for these patients.
Methods and Conclusions: In this review, we outline recent advances in our understanding of arrhythmia mechanisms in the failing heart, highlighting various aspects of remodeling of ion channels, calcium handling proteins, and gap junction-related molecules. As will be discussed, these changes promote the prolongation of the action potential, the enhancement of spatio-temporal gradients of repolarization, the formation of calcium-mediated triggers and conduction abnormalities, all of which combine to form an electrophysiological substrate that is ripe for the genesis of lethal arrhythmias and sudden cardiac death.     

Aortic stenosis and the failing heart

The combination of aortic stenosis and left-ventricular dysfunction is a challenging situation for the physician. Diagnosis of this condition requires a detailed evaluation to understand the etiology and reversibility of the ventricular dysfunction and to accurately determine the real severity of the stenosis. Whether the aortic stenosis the cause of the left ventricular failure or is an independent disease has significant diagnostic, prognostic and therapeutic implications. Dobutamine echocardiography provides critical information to determine the real severity and the left ventricle's potential to recover (contractile reserve). Attempts to delay the progression of the aortic stenosis with medical treatment have been limited, and valve replacement remains the hallmark of ultimate treatment. If surgery is inadvertently delayed, left ventricular systolic dysfunction will result in clinically evident congestive heart failure and this situation carries a very high short-term mortality. Aortic valve replacement in this setting improves the outcome, but perioperative mortality is high, and particularly when coronary revascularization is also needed, there is no ventricular contractile reserve and transvalvular gradients are low. Adequate timing of surgery is extremely important and increasingly more difficult. Management decisions should be tailored by the results of dobutamine echocardiography and made on a case-by-case basis.     

Limits of ventricular function: from athlete's heart to a failing heart

The interest in the study of ventricular function has grown considerably in the last decades. In this review, we analyse the extreme values of ventricular function as obtained with Doppler echocardiography. We mainly focus on the parameters that have been used throughout the history of Doppler echocardiography to assess left ventricular (LV) systolic and diastolic function. The ‘athlete's heart’ would be the highest expression of ventricular function whereas its lowest expression is represented by the failing heart, independently from the original aetiology leading to this condition. There are, however, morphological similarities (dilation and hypertrophy) between the athlete's and the failing heart, which emerge as physiological and pathophysiological adaptations, respectively. The introduction of new assessment techniques, specifically speckle tracking, may provide new insight into the properties that determine ventricular filling, specifically left ventricular twisting. The concept of ventricular function must be always considered, although it may not be always possible to distinguish the normal heart of sedentary individuals from that of highly trained hearts based solely on echocardiographic or basic studies.     

Use of the rabbit with a failing heart to test for torsadogenicity

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades de pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades de pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades de pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts.     

Defective lipid metabolism in the failing heart

The metabolism of long chain fatty acids was investigated in the failing heart of guinea pigs with chronic constriction of the ascending aorta. Homogenates prepared form failing hearts exhibited (a) a decreased capacity to oxidize palmitic acid (failure = 0.50 +/- 0.06 mumole/g of protein per 20 min; control = 1.09 +/- 0.10); (b) a reduced level of carnitine, a myocardial constituent which serves to control the oxidation rate of long chain fatty acids in the heart (failure = 0.91 +/- 0.10 mumole/g wet weight; control = 1.69 +/- 0.10); and (c) an increased rate of palmitate incorporation into triglycerides and lecithin. Exogenous carnitine effected a restoration of the defective palmitate metabolism of the homogenates towards normal. In contrast to long chain fatty acid oxidation, glucose oxidation by the failing heart was not impaired. As a consequence of this selective lesion in energy substrate utilization, the failing heart might be forced to rely on substrates other than long chain fatty acids for its major energy supply.     

NO/redox disequilibrium in the failing heart and cardiovascular system

There is growing evidence that the altered production and/or spatiotemporal distribution of reactive oxygen and nitrogen species creates oxidative and/or nitrosative stresses in the failing heart and vascular tree, which contribute to the abnormal cardiac and vascular phenotypes that characterize the failing cardiovascular system. These derangements at the integrated system level can be interpreted at the cellular and molecular levels in terms of adverse effects on signaling elements in the heart, vasculature, and blood that subserve cardiac and vascular homeostasis.     

Alpha-1 adrenergic receptors in the nonfailing and failing human heart

We examined alpha-1 adrenergic receptor density in ventricular myocardium from nonfailing and failing human hearts, utilizing the alpha-1 radioligand [125I]IBE2254. The alpha-1 receptor population comprised a relatively small portion of the total adrenergic receptors, 14.6 +/- 1.9%. However, in failing human ventricular myocardium the alpha-1 adrenergic receptor population constituted a much greater portion, 27.3 +/- 2.1% (P less than .01). The reason for the increased proportion of alpha-1 adrenergic receptors was not that the total concentration of alpha-1 receptors was increased, but instead was due to selective down-regulation of the beta-1 adrenergic receptor population. Beta-2 adrenergic receptors behaved similarly to alpha-1 adrenergic receptors in the failing human heart, and were increased in proportion and unchanged in total number. Additionally, the ability of alpha-1 stimulation to increase the incorporation of label from [3H]inositol into inositol phosphates was examined in tissue homogenates. Maximal doses of norepinephrine produced only marginal stimulation of phosphatidylinositol hydrolysis, in contrast to a more substantial response produced by muscarinic stimulation. We conclude that human ventricular myocardium contains alpha-1 adrenergic receptors that 1) are of relatively low density, 2) are unchanged in density by heart failure and 3) mediate relatively low-level stimulation of phosphatidylinositol hydrolysis.     

ABO-incompatible heart transplantation: a perfusion strategy

Infants with fatal cardiac disease often die awaiting transplantation because of the shortage of donor hearts. The Hospital for Sick Children (HSC), Toronto, Canada, has researched and applied the concept of crossing the blood group compatibility barrier. Heart transplantation at HSC unrestricted by ABO compatibility greatly contributed to decreasing the mortality rate among infants on the waiting list from 58% to 10%. From January 1996 to January 2002, 16 infants less than 14 months of age received ABO-incompatible heart transplants at our institution. The cardiopulmonary bypass (CPB) circuit is primed with additional volume to replace the patient's blood volume. Packed red blood cells (PRBC) used in priming must be ABO-compatible with the recipient. All plasma components and platelets must contain no anti-A or anti-B antibodies to donor or recipient. CPB is initiated and the patient's venous blood is collected into a transfusion bag and sent to the blood bank. The total amount collected should be one and a half to two times the patient's blood volume. The plasma is separated and discarded, returning only the PRBC, thus reducing the concentration of circulating antibodies to blood group antigens. Our team has experienced an 87% survival rate with this technique. The success is believed to be associated with the recipients' immunologic immaturity. Newborns do not produce isohemagglutinins, and serum anti-A and anti-B antibody titers usually remain low until 12-14 months of age. The complement system is not fully developed, therefore, the mediators of hyperacute rejection are absent during early infancy. Heart transplantation unrestricted by the need for ABO compatibility would effectively expand the available donor pool and decrease waiting times.     

Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.     

Adenylylcyclase gene transfer increases function of the failing heart

A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.ACVI) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of Galphaq.Galphaq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5x1010 viral particles of Ad.ACVI or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.ACVI increased LV ejection fraction (p<0.01) and velocity of circumferential fiber shortening (p<0.03). Detailed measurements in isolated hearts showed that ACVI gene transfer increased LV positive dP/dt (p=0.02) and LV negative dP/dt (p=0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.