Efectos electrofisiológicos del aumento de la presión intraventricular en un modelo experimental de insuficiencia cardiaca

Abstract

Sudden cardiac death (SCD) is a major cause of death in patients with heart failure (HF).[1, 2] HF electrophysiological remodeling (HF-ER) has been identified as a key element in the proarrhythmic state of these patients.[3] Accordingly, the persistent stretch to which the ventricles may be subjected to is a factor potentially associated with HF-ER.[4-8] Also, HF-status worsening or de novo acute HF episodes, as in the setting of tachycardiomyopathy, are often associated with acutely increased intraventricular pressures (IVPs), and this factor itself might also promote arrhythmias.[9, 10] Indeed, a recent study in patients with HF have highlighted the important proarrhythmic role of acute increases in IVP. In that study,[11] the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) events for a particular patient was doubled on days when subjectspecific pressures were acutely increased compared with their average pressure values. In addition, HF is associated with numerous ionic distortions, which might be especially prevalent in decompensated status requiring hospitalization. These ionic features include low levels of sodium, potassium, and magnesium that associated with significantly higher levels of circulating catecholamines may predispose to ventricular arrhythmias.[12] Treating HF-ER with conventional antiarrhythmic drugs has been demonstrated not to diminish SCD rates.[2, 13] In fact, only chronic therapies aimed to improve the hemodynamic and humoral conditions have been proven to decrease SCD in HF.[2] The hypothesis of this work is that increased IVPs and/or anionic imbalanced (acidified), catecholamine-rich (adrenergic) milieu (AA milieu) may contribute as much as HF-ER to the substrate for reentry in HF. METHODS: A porcine model of tachycardiomyopathy was used to evaluate the individual/combined contributions of (1) increased IVPs, (2) HF-ER, and (3) an AA milieu. HF-ER was induced in 7 pigs by rapid pacing. Seven pigs were used as controls. Hearts were isolated and Langendorff perfused. Programmed ventricular stimulation was conducted under low or increased IVP and normal/AA milieu (4 combinations). Epicardial optical mapping was used to quantify conduction velocity (CV), action potential duration (APD), and dispersion of repolarization (DoR). RESULTS: HF-ER decreased CV (-34%; P = 0.002) and increased APD (11%; P = 0.024) and DoR (21%; P = 0.007). Increased IVP amplified DoR (36%; P < 0.001) and decreased CV (-17%; P = 0.001) and APD (-8%; P 0.001). The AA milieu consistently modified only APD (-9%; P < 0.001) and led to amplified inter-/intra-subject heterogeneity. Increased IVP similarly raised the odds of inducing sustained VT/VF as the presence of HF-ER (> 6-fold). CONCLUSION: By magnifying DoR, decreasing CV, and shortening APD, increased IVP was as harmful as HF-ER in favouring the substrate for sustained reentry in this model. The AA milieu contributed to a much lesser extent. Thus, a stricter control of IVP might be postulated as a useful add-on antiarrhythmic strategy in HF. Based on the results mentioned above, where the pressure overload and HF-ER are associated with increased DoR and decreased CV, leading to higher risk of ventricular arrhythmia. A second part of this research was developed, with the aim of achieve a wide available clinical parameter, that can help to identify HF patients with deteriorated hemodynamic status, and thus on a higher risk of fatal arrhythmias. The objective was to establish the correlation between QRS complex duration and underlying changes in CV during increased IVP and/or HF-ER ex-vivo, and to determine whether QRS duration could be sensitive to an acute increase in left ventricular (LV) afterload in-vivo. METHODS: HF-ER was induced in 7 pigs by high-rate ventricular pacing. Seven weightmatched animals were used as controls. Isolated Langendorff-perfused hearts underwent programmed ventricular stimulation to study QRS complex duration and CV under low/high IVP, using volume-conducted ECG and epicardial optical mapping, respectively. Four additional pigs underwent open-chest surgery to increase LV afterload by partially clamping the ascending aorta, while measuring QRS complex duration during sinus rhythm (SR). RESULTS: In 13 hearts included for analysis, both HF-ER and increased IVP showed significantly slower epicardial CV (-40% and -15%, p < 0.001 and p = 0.004, respectively), which correlated with similar widening of the QRS complex (+41% and +17%, p = 0.005 and p < 0.001, respectively). HF-ER hearts showed larger prolongation of the QRS complex than controls upon increasing the IVP (+21% vs. +12%, respectively. HF-ER*IVP interaction: p = 0.004). QRS complex widened after increasing LV afterload in-vivo (n=3), with correlation between QRS duration and aortic diastolic pressures (R = 0.58, p < 0.001). CONCLUSION: high IVP and/or HF-ER significantly decrease CV, which correlates with QRS widening on the ECG during ventricular pacing. Increased myocardial wall stress also widens the QRS complex during SR in-vivo.