Abstract
E. Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension.Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventri-cle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca 2ϩ handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca 2ϩ transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(en-do)plasmic reticular Ca 2ϩ-ATPase activity, increased sarcoplasmic reticular Ca 2ϩ-release fraction, and increased Ca 2ϩ spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca 2ϩ handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs. electrocardiography; monocrotaline; calcium signaling; voltage-sensitive dye imaging; alternans ALTHOUGH RIGHT VENTRICULAR (RV) failure most often develops as a consequence of left ventricular (LV) failure, RV failure occurs in many, increasingly common, diseases associated with dysfunction of the pulmonary circulation (6, 18, 58). This includes pulmonary hypertension, where RV failure is the major cause of death in patients (6). Pulmonary hypertension is associated with RV electrical remodeling (23, 26, 27) and a higher risk of arrhythmias (17). Sudden death occurs in 30-40% of sufferers (10, 63), and lethal arrhythmias are thought to be one cause, in addition to other mechanisms, such as pulmonary embolism and pulmonary artery dissection. Interestingly, the RV is not currently a target for therapeutic intervention in this disease (19). There are several established mechanisms by which arrhyth-mias can arise. Increased electrical heterogeneity and steeper electrical restitution (1, 32, 53) increase the probability of alternans and arrhythmias. This is because heterogeneity increases the dispersion of refractoriness and steeper restitution decreases the stability of action potential (AP) duration (APD) and diastolic interval adaptation to a change in heart rate, also increasing the dispersion of refractoriness. This makes conduction block and reentry more likely (9, 35, 49, 60). Alternans describe the events where parameters such as APD or intracel-lular Ca 2ϩ concentration ([Ca 2ϩ ] i) transient amplitude alternate in size on a beat-to-beat basis. They are established predictors of sudden cardiac death, and discordant alternans, where the parameter in question is out of phase in different regions of the ventricles, are most likely to generate reentrant arrhythmias (9, 35, 49, 60). Defective Ca 2ϩ handling also leads to the generation of arrhythmias. Increased sarcoplasmic reticulum (SR) Ca 2ϩ leak, SR release fraction, SR Ca 2ϩ content, and slowed SR Ca 2ϩ reuptake are thought to contribute to the generation of Ca 2ϩ transient alternans and thus to APD and T-wave alternans (via modulation of Ca 2ϩ-dependent currents) by facilitating beat-to-beat fluctuations in SR Ca 2ϩ release (38, 49). This is because increased SR Ca 2ϩ content favors SR Ca 2ϩ leak and places activated ryanodine receptors in a refractory state for the next beat, leading to fluctuations in SR Ca 2ϩ release (48). Additionally, elevated SR Ca 2ϩ content and release fraction in the presence of a slowed SR Ca 2ϩ reuptake lead to intra-SR fluctuations in Ca 2ϩ content (13). Structural changes, such as an alteration in connexin expression or increased fibrosis, which disrupts the normal myofiber organization, can slow conduction, create electrical heteroge-neity (31), and contribute to dysfunctional electrical activity (16). Given the number of potential arrhythmic mechanisms, the specific occurrence and relative importance of these mechanisms need to be characterized for any given pathology, if that pathology is to be fully understood and treated.