Pacing-induced increase in QT dispersion predicts sudden cardiac death following cardiac resynchronization therapy.

OBJECTIVES: This study was designed to determine whether cardiac resynchronization therapy (CRT) by means of biventricular pacing (BiVP) alters the QT interval (QT(c)) and QT dispersion (QTD), and whether such changes relate to the risk of developing major arrhythmic events (MAE). BACKGROUND: Prolonged QT(c) is associated with MAE. Left ventricular pacing and BiVP alter QT(c). METHODS: A total of 75 patients with drug-resistant heart failure (New York Heart Association functional class III/IV) and QRS duration > or =120 ms underwent CRT. The QT(c) and QTD were measured before and 48 days after BiVP. RESULTS: Over 807 days (range 93 to 1,543 days), 11 patients had a MAE. Compared to baseline, at 48 days after CRT, QTD increased in 47% of patients and QT(c) decreased in 53%. The QT(c) at follow-up was higher in MAE patients compared with no-MAE patients (35.9 +/- 14.2 ms vs. 0.52 +/- 6.0 ms; p = 0.0323). Similar differential responses for QTD were observed (46.4 +/- 13.5 ms in MAE vs. -5.1 +/- 4.1 ms in no MAE, p < 0.0001). The MAE occurred in 29% of patients exhibiting an increase in QTD and in 3% of those exhibiting a decrease (p = 0.0017). In multiple regression analyses, change in QTD from baseline (DeltaQTD) strongly predicted MAE, independent of DeltaQT(c), QRS duration, and left ventricular ejection fraction and end-diastolic volume (p < 0.001). Differences in survival curves were observed when patients were dichotomized according to whether QTD increased or decreased in relation to baseline values (p < 0.0001). CONCLUSIONS: The MAE in patients with BiVP are related to pacing-induced increases in QTD. Measures of ventricular repolarization at the time of pacemaker implantation may guide selection of patients for combined CRT and defibrillator therapy.

Interleukin-6, tissue factor and von Willebrand factor in acute decompensated heart failure: relationship to treatment and prognosis.

Arterial thrombotic and thromboembolic complications are increased in congestive heart failure (CHF), and are a particular problem in acute decompensated heart failure, which carries a poor prognosis. As interleukin-6 (IL-6) has been shown to induce the potent procoagulant tissue factor (TF) in experimental models, we hypothesized that the pro-inflammatory IL-6 may be one mechanism contributing to thrombosis in heart failure, mediated via endothelial expression of TF on activated/damaged cells [indicated by plasma von Willebrand factor (vWF)]. Seventy-seven patients (67% men, New York Heart Association class III-IV, 87%) with acute CHF were recruited, and were compared with 53 chronic stable CHF patients in sinus rhythm (66% men, New York Heart Association class III-IV, 2%) and 37 healthy controls (68% men). Acute CHF patients in sinus rhythm had elevated baseline levels of IL-6 (P < 0.0001), TF (P = 0.041) and vWF (P < 0.0001) (all measured by enzyme-linked immunosorbent assay) compared with both chronic CHF and healthy control groups. A correlation exists in acute CHF between baseline TF and IL-6 (Spearman r = 0.64, P < 0.0001). After 3 months treatment, with control or alleviation of heart failure symptoms in 40 patients, there was a fall in levels of IL-6 (P < 0.0001) and vWF (P < 0.0001), but levels still remained significantly higher than healthy controls. Patients who died at 6 months follow-up also had higher baseline levels of IL-6 (P = 0.008), TF (P = 0.037) and vWF (P = 0.039) when compared with those who remained alive. Elevated IL-6 may contribute to the thrombotic and thromboembolic complications in acute heart failure, in a process mediated via increased TF and vWF. Improvement of symptoms and plasma markers after treatment of acute CHF and prediction of prognosis by the markers may be useful in the clinical setting.

Neither carvedilol nor bisoprolol in maximally tolerated doses has any specific advantage in lowering chronic heart failure oxidant stress: implications for beta-blocker selection.

We hypothesized that abnormal oxidative stress in chronic heart failure (CHF) could be related to endothelial damage and platelet activation, and that the vasodilating beta-blocker carvedilol would have beneficial effects on these processes compared with a selective non-vasodilating cardioselective beta-blocker, bisoprolol. We therefore assessed the effects of introducing carvedilol and bisoprolol in a prospective manner on indices of oxidative stress [lipid hydroperoxides (LHP)], endothelial damage [von Willebrand factor (vWf)], platelet activation (soluble P-selectin) and coagulation (fibrinogen) and their inter-relationships in stable outpatients with CHF in sinus rhythm. We recruited 46 patients [23 male; age 64 +/- 13 years (mean +/- S.D.); range 38-85 years] with CHF. Baseline levels of serum LHP (P<0.002), plasma vWf (P<0.001) and soluble P-selectin (P=0.02), but not fibrinogen (P=0.16), were higher in CHF patients compared with 22 age- and sex-matched healthy controls. After treatment for 2 months, systolic blood pressure fell in both arms of the study (both P<0.01), but there were no statistically significant (defined as P<0.01) decreases in LHP, vWf, fibrinogen or soluble P-selectin levels with either carvedilol or bisoprolol. In conclusion, patients with CHF have increased levels of plasma LHP and vWf, indicating increased oxidative stress and endothelial damage respectively. Contrary to the proposed antioxidative effects of carvedilol, initiating and titrating such therapy did not result in a reduction in levels of LHP in CHF.

Anti-oxidative properties of beta-blockers and angiotensin-converting enzyme inhibitors in congestive heart failure.

BACKGROUND: Chronic elevation of plasma catecholamines and sympathetic stimulation in chronic heart failure (CHF) leads to increased production of free radicals, and so possibly to endothelial damage/dysfunction and atheroma formation. Abnormal oxidative stress may therefore be related to some of the high mortality and morbidity in CHF. The objective of the present prospective open study was to compare the effects of beta-blockers and ACE inhibitors in relation to oxidative stress and endothelial damage in CHF. METHODS: We studied 66 outpatients with CHF: 46 patients were established on an ACE inhibitor and were then started on a beta-blocker, and 20 patients not previously on ACE-inhibitors were started on lisinopril. Baseline levels of the measured parameters were compared to 22 healthy control subjects. Serum lipid hydroperoxides (LHP) and total antioxidant capacity (TAC) were determined as indices of oxidative damage and antioxidant defence, and plasma von Willebrand factor (vWf) as an index of endothelial damage/dysfunction. RESULTS: Baseline indices for the measures of oxidative damage and endothelial function in the 66 CHF patients were significantly higher than healthy control subjects [median LHP 7.5 (5.9-12.6) vs. 4.8 micromol/l, P=0.0022; TAC 428 (365-567) vs. 336 Trollox Eq. Units, P=0.0005; mean vWf 134+/-27 vs. 89+/-23 IU/dl, P<0.0001]. Following 3 months of maintenance therapy with beta-blockers, there was significant reduction in LHP levels, but not TAC or vWf. ACE inhibitor therapy also significantly reduced vWf levels, but failed to have any statistically significant effects on LHP or TAC. CONCLUSION: This pilot study suggests that oxidative stress in CHF may be due to increased free radical production or inefficient free radical clearance by scavengers. beta-Blockers, but not ACE inhibitors, reduced lipid peroxidation in patients with CHF. No relation was demonstrated between a reduction in oxidative damage and endothelial damage/dysfunction.