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Biomedical subjects

Mihai Gheorghiade

Publications and source records attributed to Mihai Gheorghiade.

At least 19 recordsLinked to original sources
PubMed2006

Evidence-based use of levosimendan in different clinical settings.

Levosimendan is a new calcium sensitizer and K-ATP channel opener. Compared with other inodilators, it improves myocardial contractility without increasing oxygen requirements and induces peripheral and coronary vasodilation with a potential anti-stunning, anti-ischaemic effect. The documentation regarding levosimendan is one of the largest ever on the safety and efficacy of a new pharmacological agent in acute heart failure syndromes. Recent experiences in small-scale studies and randomized clinical trials have led to greater interest in the use of this drug for the support of impaired cardiac function also in patients with ischaemic heart disease and cardiogenic or septic shock. It is also demonstrated that this drug could be used as bridge therapy for the peri-operative phase of cardiac surgery in both adult and paediatric populations. This review summarizes the evidence from published scientific literature regarding the use of levosimendan in various clinical settings.

Administration, Oral↗
PubMed2006

Improving outcomes in post-acute myocardial infarction heart failure: incorporation of aldosterone blockade into combination therapy to optimize neurohormonal blockade.

Although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and beta-blockers have been proved to reduce mortality in patients with heart failure post-acute myocardial infarction (AMI), studies show that these agents are consistently underused in this population. Further, morbidity and mortality remain high even when standard-of-care therapies are applied. Thus, new strategies have been sought to better counteract the maladaptive effects of neurohormonal stimulation in post-AMI heart failure. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone, when used in addition to standard therapy, results in significant incremental improvements in survival and morbidity and is safe and well tolerated in this setting. Based on this, major therapeutic guidelines in the United States and Europe now strongly recommend that all eligible patients with concomitant heart failure post-AMI be treated with an aldosterone blocker in addition to an ACE inhibitor (or an ARB) and a beta-blocker. To achieve needed improvements in outcomes in this population, early and consistent initiation of these evidence-based, guideline-recommended therapies in all eligible patients is crucial.

Adrenergic beta-Antagonists↗
PubMed2006

Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <or=30%.

AIMS: Because of the prognostic importance of LV dysfunction following an AMI and the increasing use of electrical and/or mechanical interventions in patients with LV systolic dysfunction, this retrospective analysis of EPHESUS patients with LVEF <or=30% at baseline was conducted to determine the value of eplerenone in this setting. METHODS AND RESULTS: In EPHESUS, 6,632 patients with LVEF <or=40% and clinical heart failure (HF) post-AMI who were receiving standard therapy were randomized to eplerenone 25 mg/day titrated to 50 mg/day or placebo for a mean follow-up of 16 months. Treatment with eplerenone in the subgroup of patients with LVEF <or=30% (N=2106) resulted in relative risk reductions of 21% versus placebo in both all-cause mortality (P=0.012) and cardiovascular (CV) mortality/CV hospitalization (P=0.001), and 23% for CV mortality (P=0.008). The relative risk of sudden cardiac death (SCD) was reduced 33% (P=0.01) and HF mortality/HF hospitalization was reduced 25% (P=0.005) with eplerenone compared with placebo. Within 30 days of randomization, eplerenone resulted in relative risk reductions of 43% for all-cause mortality (P=0.002), 29% for CV mortality/CV hospitalization (P=0.006), and 58% for SCD (P=0.008). CONCLUSIONS: Treatment with eplerenone plus standard therapy in patients with post-AMI HF and LVEF <or=30% provided significant incremental benefits in reducing both early and late mortality and morbidity.

Adult↗
PubMed2006

Vasopressin v(2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia.

Hyponatremia is common and is associated with a poor prognosis. Traditional management with fluid restriction is difficult to maintain, and it is often ineffective. The objective of this study was to determine the effect of tolvaptan versus fluid restriction on serum sodium concentration. The study was a prospective, multicenter, randomized, active-controlled, open-label trial. Twenty-eight hospitalized subjects with serum sodium <135 mmol/L were enrolled in the study. After a 2-day run-in period, subjects were randomized 2:1 to tolvaptan alone (n = 17) or fluid restriction (1,200 ml/day) plus placebo (n = 11). Oral tolvaptan was started at 10 mg/day and increased to 60 mg/day as needed. Treatment was continued for up to 27 days, and follow-up continued for up to 65 days. The primary end point was the normalization of serum sodium, defined as >135 mmol/L or a > or =10% increase from baseline. At the last inpatient visit, serum sodium had increased by 5.7 +/- 3.2 mmol/L in the tolvaptan group and 1.0 +/- 4.7 mmol/L in the fluid restriction group (p = 0.0065). No differences in adverse events were observed between the groups. In conclusion, tolvaptan appears to be more effective than fluid restriction at correcting hyponatremia in hospitalized subjects, without an increase in adverse events.

Aged↗
PubMed2006

The Valsalva maneuver: a bedside "biomarker" for heart failure.

Accurate assessment of volume status remains an important clinical goal in the management of patients with heart failure. Although physical examination can provide clues to volume status, its sensitivity and reproducibility are limited. Other noninvasive methods, such as measurement of natriuretic peptides or the use of impedance cardiography, are not well validated. The cardiovascular response to the Valsalva maneuver had been proposed as a simple, inexpensive bedside test for estimating filling pressures in patients with heart failure. Our objective was to summarize and critically evaluate the evidence for the use of the Valsalva maneuver in evaluating volume status in patients with heart failure. Studies have demonstrated a significant correlation between the cardiovascular response to the Valsalva maneuver and invasively measured ventricular filling pressures in patients with clinical heart failure. Although often overlooked in clinical training and practice, the cardiovascular response to the Valsalva maneuver is a potentially useful, noninvasive means of evaluating filling pressures in patients with heart failure.

Blood Pressure↗
PubMed2006

Tolvaptan: a selective vasopressin type 2 receptor antagonist in congestive heart failure.

The neurohormone arginine vasopressin plays a significant role in the regulation of volume homeostasis, which is mediated via vasopressin type 2 (V2) receptors in the collecting tubules of the kidney. Diseases that are accompanied by abnormal volume homeostasis, including congestive heart failure and cirrhosis, are a frequent cause of hospital admissions and increasing healthcare costs. Recently, several nonpeptide V2 receptor antagonists have emerged as promising agents in the management of these conditions with the advantage of having no electrolyte abnormalities, neurohormonal activation or worsening renal insufficiency. Tolvaptan, a highly selective nonpeptide V2 receptor antagonist, has demonstrated an improvement in the volume status, osmotic balance and haemodynamic profile in preclinical and Phase II trials in patients with congestive heart failure and is currently undergoing testing in Phase III trials. This review discusses the evidence for the potential uses of tolvaptan, and its pharmacology and pharmacokinetics, particularly in congestive heart failure.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2005

Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial.

AIMS: To determine the effects of digoxin on all-cause mortality and heart failure (HF) hospitalizations, regardless of ejection fraction, accounting for serum digoxin concentration (SDC). METHODS AND RESULTS: This comprehensive post-hoc analysis of the randomized controlled Digitalis Investigation Group trial (n=7788) focuses on 5548 patients: 1687 with SDC, drawn randomly at 1 month, and 3861 placebo patients, alive at 1 month. Overall, 33% died and 31% had HF hospitalizations during a 40-month median follow-up. Compared with placebo, SDC 0.5-0.9 ng/mL was associated with lower mortality [29 vs. 33% placebo; adjusted hazard ratio (AHR), 0.77; 95% confidence interval (CI), 0.67-0.89], all-cause hospitalizations (64 vs. 67% placebo; AHR, 0.85; 95% CI, 0.78-0.92) and HF hospitalizations (23 vs. 33% placebo; AHR, 0.62; 95% CI, 0.54-0.72). SDC> or =1.0 ng/mL was associated with lower HF hospitalizations (29 vs. 33% placebo; AHR, 0.68; 95% CI, 0.59-0.79), without any effect on mortality. SDC 0.5-0.9 reduced mortality in a wide spectrum of HF patients and had no interaction with ejection fraction >45% (P=0.834) or sex (P=0.917). CONCLUSIONS: Digoxin at SDC 0.5-0.9 ng/mL reduces mortality and hospitalizations in all HF patients, including those with preserved systolic function. At higher SDC, digoxin reduces HF hospitalization but has no effect on mortality or all-cause hospitalizations.

Adrenergic beta-Antagonists↗
PubMed2005

Overview of vasopressin receptor antagonists in heart failure resulting in hospitalization.

Patients with worsening heart failure (HF) requiring hospitalization commonly have a history of progressive fluid retention, decreased renal function, and hyponatremia. For these patients, diuretics have traditionally been the mainstay of treatment, but they are associated with electrolyte abnormalities and impaired renal function. Previous studies have shown that levels of the endogenous arginine vasopressin (AVP) hormone are elevated in patients with HF and may be the contributing factor to fluid retention and hyponatremia, and probably progression of HF. Vasopressin antagonists represent a unique class of therapeutic agents because of their potential role in both the short- and long-term treatment of patients hospitalized with worsening HF. As "aquaretics," AVP antagonists offer the possibility of added efficacy in relieving congestion and improving symptoms with minimal adverse effects in combination with standard medical therapy. Some AVP receptor antagonists have shown promising results in animal studies and small-scale clinical trials. The purpose of this review was to update the current status of studies with the available AVP antagonists.

Animals↗
PubMed2005

Vasopressin antagonism in heart failure.

Treatment of chronic heart failure (HF) is based on interference with the renin-angiotensin-aldosterone system and the adrenergic nervous system. Diuretics are used in volume-expanded patients. Insights from clinical trials and registries establish the need to consider correcting both cardiac loading conditions and nonload-related biological factors if HF therapy is to be optimized. Arginine vasopressin (AVP) represents a potentially attractive target for therapy in both acute and chronic HF. Excessive AVP secretion could contribute to both systolic and diastolic wall stress via V1a- and V2-mediated effects on the peripheral vasculature and on water retention. Arginine vasopressin also may directly and adversely affect myocardial function due to the effect of V1a activation on myocardial contractility and cell growth. Last, AVP may contribute to hyponatremia, a powerful predictor of poor outcome in HF. The development of effective nonpeptide antagonists to both the V1a and V2 receptors for AVP now allows for testing the hypotheses that interfering with AVP-mediated signaling could be beneficial in HF. This review summarizes the theoretical rationale for further development of such therapy, reviews the status of current compounds under development, and suggests key issues that need to be addressed as these agents undergo further clinical testing.

Animals↗
PubMed2005

Neurohormonal inhibition in heart failure: insights from recent clinical trials.

Heart failure (HF) is a clinical syndrome characterized by chronic, persistent activation of the neuroendocrine system, which has been assumed to be linked to disease progression and adverse outcomes. Clinical trials have shown that adrenergic modulators, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and beta-blockers, improve long-term outcomes in patients with HF. These findings have led to the hypothesis that inhibition of a single neurohormonal or cytokine pathway may continue to provide incremental benefits. However, the results of recent clinical trials, using centrally acting agents--endopeptidase inhibitors or endothelin and cytokine antagonists--suggest that selective inhibition of neurohormonal systems may not be advantageous and actually may have serious adverse effects. The reasons for this lack of benefit may be ascribed to the fact that long-term mortality benefits in patients with chronic HF are primarily the result of treatment of the diseases that have caused HF in the first place rather than treatment of neurohormonal abnormalities.

Clinical Trials as Topic↗
PubMed2005

Hyponatremia in patients with heart failure.

Mild hyponatremia is encountered frequently in patients hospitalized for worsening heart failure. Admission plasma sodium concentration appears to be an independent predictor of increased mortality after discharge and rehospitalization. Recent studies have suggested that correction of hyponatremia may be associated with improved survival. This hypothesis is currently being studied in large prospective randomized clinical trials.

Heart Failure↗
PubMed2005

Pathophysiologic targets in the early phase of acute heart failure syndromes.

An episode of acute heart failure syndromes (AHFS) can be defined as a rapid or gradual onset of signs and symptoms of heart failure (HF) in hospital admission and can arise from a variety of pathophysiologic mechanisms. This article reviews our current understanding of the pathophysiology of AHFS in order to identify potential therapeutic targets. Most patients with AHFS present with either normal systolic blood pressure or elevated blood pressure. Patients who present with elevated systolic blood pressure usually have pulmonary congestion and a relatively preserved left ventricular ejection fraction (LVEF), and have symptoms that typically develop abruptly, these patients often are elderly women. Patients with normal systolic blood pressure presenting with systemic congestion and reduced LVEF are usually younger, with a history of chronic HF, and have symptoms that develop gradually over days or weeks. Accordingly, most episodes of AHFS can be classified as either "vascular" failure or "cardiac" failure. In addition to the abnormal hemodynamics (increase in pulmonary capillary wedge pressure and/or decrease in cardiac output) that characterize patients with AHFS, myocardial injury--which may be related to a decrease in coronary perfusion and/or further activation of neurohormones and renal dysfunction (ie, the cardiorenal syndrome)--probably contributes to short-term and post-discharge cardiac events. Patients with AHFS also have significant cardiac and non-cardiac underlying conditions that contribute to the pathogenesis of AHFS, including coronary artery disease (ischemia, hibernating myocardium, and endothelial dysfunction), hypertension, atrial fibrillation, and type 2 diabetes mellitus. The goals of therapy for AHFS should be not only to improve symptoms and hemodynamics, but also to preserve or improve renal function and prevent myocardial damage.

Acute Disease↗
PubMed2005

The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF).

Acute heart failure syndromes (AHFS) are related to several diseases affecting not only the heart but also the kidneys and blood vessels. Emerging evidence indicates that myocardial injury may also play a role in the pathophysiology of AHFS, as suggested by increased levels of markers of injury, such as cardiac troponin (cTn). Although cTn is a known prognostic marker, the release of cTn during hospitalization has not been evaluated prospectively with serial measures. We prospectively evaluated patterns of cTn release by conducting serial measures of cTnI and cTnT in patients hospitalized for AHFS. This study enrolled 51 patients with AHFS who were admitted with worsening heart failure (HF) and a history of coronary artery disease (CAD) in whom an acute coronary event was not suspected. Levels of cTnI and cTnT were measured at 8, 32, 56, and 80 hours after study entry. At baseline, 73.9% of patients had detectable cTnI, and 43.5% had detectable cTnT levels. The median concentrations of cTnI and cTnT were unchanged from 0 to 32 hours, increased from 32 to 56 hours, then either plateaued (cTnT) or decreased to baseline (cTnI). Of the 26 patients who had no detectable cTn levels at baseline, 2 (7.7%) developed detectable cTnT and 5 (41.7%) developed detectable cTnI release during hospitalization. Detectable levels of cTn at baseline were related to short-term clinical events. In this study of patients with CAD in whom an acute coronary event was not suspected, most had detectable levels of cTn present at admission, and some patients developed cTn release during hospitalization. Because cTn release may be a marker for myocardial injury, this study raises the possibility that injury occurred in most patients admitted with AHFS. Therefore, the goal of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to salvage myocardium. Accordingly, therapies for AHFS that are aimed at improving hemodynamics may affect long-term prognosis by either injuring or salvaging myocardium.

Adrenergic beta-Agonists↗
PubMed2005

Overview of current noninodilator therapies for acute heart failure syndromes.

Several treatment strategies exist for patients hospitalized with acute heart failure syndromes (AHFS). These therapies traditionally focus on improving hemodynamics and relieving congestion. This review focuses on noninodilator therapies, including diuretics, nitrovasodilators (nitroprusside and nitroglycerin), vasodilators (nesiritide), digoxin, and intravenous angiotensin-converting enzyme inhibitors. These agents are used based on their associated symptomatic improvements alone. In the hospitalized setting, none of these agents have demonstrated benefits on long-term outcomes. Future work in AHFS should strive to understand the influence of conventional and new pharmacologic therapies on the underlying pathophysiology of AHFS, the processes that lead to myocardial injury and progressive heart failure, and measurable clinical outcomes.

Acute Disease↗
PubMed2005

Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes.

The appropriate role of intravenous inodilator therapy (inotropic agents with vasodilator properties) in the management of acute heart failure syndromes (AHFS) has long been a subject of controversy, mainly because of the lack of prospective, placebo-controlled trials and a lack of alternative therapies. The use of intravenous inodilator infusions, however, remains common, but highly variable. As new options emerge for the treatment of AHFS, the available information should be reviewed to determine which approaches are supported by evidence, which are used empirically without evidence, and which should be considered inappropriate. For these purposes, we reviewed data available from randomized controlled trials on short-term, intermittent, and long-term use of intravenous inodilator agents (dobutamine, dopamine, and milrinone) in AHFS. Randomized controlled trials failed to show benefits with current medications and suggested that acute, intermittent, or continuous use of inodilator infusions may increase morbidity and mortality in patients with AHFS. Their use should be restricted to patients who are hypotensive as a result of low cardiac output despite a high left ventricular filling pressure.

Acute Disease↗
PubMed2005

Pharmacology of new agents for acute heart failure syndromes.

Current therapies for acute heart failure syndromes (AHFS) target hemodynamics by decreasing congestion or increasing myocardial contraction. Several new agents for AHFS use novel mechanisms of action that focus on new treatment targets, such as those providing anti-ischemic and anti-stunning effects, blocking vasopressin receptors, or blocking endothelin-1 receptors. For example, levosimendan acts as a calcium sensitizer and adenosine triphosphate-dependent potassium (K(ATP)) channel opener that increases contraction, causes vasodilation, and provides cardioprotective effects. This is accomplished by its dual mechanism of action. Levosimendan binds to cardiac troponin C, thereby enhancing calcium myofilament responsiveness and increasing myocardial contraction without increasing intracellular calcium levels. Thus, contraction is increased with no significant increase in myocardial oxygen consumption. The opening of K(ATP) channels by levosimendan causes vasodilation and exerts anti-ischemic and anti-stunning effects on the myocardium. Other new agents target neurohormonal pathways. Tezosentan is an antagonist of endothelin-1 receptors A and B. By inhibiting endothelin-1 receptors, tezosentan may counteract the activities of endothelin-1, which include vasoconstriction, proarrhythmic activities, potentiation of other neurohormones, and mediation of increased vascular permeability. Tolvaptan is a vasopressin V2-receptor antagonist that functions as an aquaretic (ie, it increases urine volume and serum sodium with little or no sodium loss). Therefore, by using novel mechanisms of action, these agents may provide new opportunities for helping patients with AHFS.

Acute Disease↗