Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study.
Measurement of microvolt-level T wave alternans (TWA) during routine exercise stress testing now is possible as a result of sophisticated noise reduction techniques and analytic methods that have become commercially available. Even though this technology is new, the available data suggest that microvolt TWA is a potent predictor of arrhythmia risk in diverse disease states. As this technology becomes more widely available, physicians will be called upon to interpret microvolt TWA tracings. This review seeks to establish uniform standards for the clinical interpretation of microvolt TWA tracings.
Background and purpose: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. Experimental approach: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. Key results: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. Conclusions and implications: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.
Among patients with heart disease and LVEF < or =0.40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit from ICD prophylaxis.
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