Michel Rousseau

Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor☆

Left ventricular function and neurohormonal status in patients with heart failure remaining symptomatic during therapy with angiotensin-converting enzyme inhibitors were assessed, and the effects of dopaminergic receptor stimulation in this setting were determined. Neurohormonal and left ventricular function (radionuclide angiography) data were obtained in 19 patients with symptomatic ischemic heart failure. Measurements were repeated after 4 to 6 weeks of therapy with the dopamine agonist ibopamine (100 mg, 3 times/day) or placebo administered in a double-blind, randomized, parallel group design. At baseline, despite therapy with enalapril, the angiotensin II levels (mean 39.4 pg/ml; p < 0.01 vs controls) were significantly increased, as were plasma norepinephrine (497 +/- 240 pg/ml; p < 0.01 vs controls), endothelin-1, atrial natriuretic peptide and arginine vasopressin. Moreover, in comparison with pretreatment values, left ventricular ejection fraction had decreased substantially (-9.1%) in patients with plasma norepinephrine > or = 600 pg/ml, but not in those with lower values of norepinephrine. With ibopamine, plasma norepinephrine decreased from 516 +/- 241 to 391 +/- 208 pg/ml (n = 8; p < 0.025 vs placebo), whereas it increased with placebo. In conclusion, the neurohormonal control provided by an angiotensin-converting enzyme inhibitor is reduced in a large subset of patients during prolonged therapy; ibopamine appears to be a potentially useful drug to improve neurohormonal control in this setting.

Residual vascular risk in T2DM: the next frontier

In T2DM, macroand microvascular complications represent the major cause for morbi/mortality, decreased quality of life and healthcare costs. Current guidelines for standards of care in T2DM emphasize the significance of multifactorial intervention on standard modifiable variables, in order to achieve recommended levels of blood glucose, LDL-C and blood pressure. T2DM patients achieving such targets represent a minority. Many of those not meeting those targets are exposed to high residual vascular risk (RVR) to develop incident microand macrovascular events and/or to suffer from progression of existing complications. Determining RVR in T2DM patients is of major relevance, as a substantial fraction of it is modifiable, including a lipid-related fraction, associated with both LDL and non-LDL lipids and lipoproteins. Atherogenic dyslipidemia (AD) is characterized by raised fasting triglycerides and low HDL-C. AD contributes to RVR of microand macrovascular disease in T2DM, even when LDL-C and/or hyperglycemia are controlled. The presence of a metabolic syndrome, or its score, is an additional means to capture modifiable components of RVR for microand macroangiopathy. AD is best prevented and addressed by therapeutic lifestyle changes, fibrates, or nicotinic acid. In the ACCORD Lipid trial, RVR of macrovascular events was high despite background simvastatin, and was substantially decreased in patients with AD following bitherapy with fenofibrate plus simvastatin. In FIELD and/or ACCORD trials, fenofibrate also decreased RVR of retinopathy progression, irrespective of baseline lipids, reduced albuminuria incidence and risk of diabetes-related lower-limb amputations. These data suggest a wider role for fenofibrate in the management of multisite microvessel RVR in T2DM. As regards other anti-dyslipidaemic drugs, ongoing trials will establish whether targeting low HDL-C with niacin reduces RVR in high-risk T2DM patients.

Regional Diastolic Dysfunction in Coronary Artery Disease: Clinical and Therapeutic Implications

Alterations in left ventricular diastolic function, such as reduction in the rate of pressure-decrease during isovolumic relaxation, impaired rate of rapid filling, or upward shift of the diastolic pressure-volume relation, are found in most patients with coronary artery disease [1–9]. These abnormalities are particularly severe during angina [2, 8], but they are also frequently evident in the absence of clinical signs of ischemia [3–6, 9, 10]. It has also been shown that these altered diastolic properties may be improved by several therapeutic interventions [6, 9–11].