Marc Klapholz

Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure The PRECISE Trial

Background Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. Methods and Results We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction ≤0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n=145) or carvedilol (n=133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P=.014) or by a global assessment of progress judged either by the patient (P=.002) or by the physician (P<.001). In addition, treatment with carvedilol...

Natriuretic peptides: biochemistry, physiology, and therapeutic role in heart failure.

Cardiac natriuretic peptides are a family of structurally related peptides that are important in sodium and volume homeostasis. They consist of atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide and are elevated in patients with left ventricular dysfunction. In contrast with vasoconstrictive hormones, such as norepinephrine, angiotensin II, and arginine vasopressin, which worsen the physiological milieu in patients with left ventricular dysfunction and heart failure, the natriuretic peptides ameliorate these effects by promoting natriuresis, diuresis, peripheral vasodilation, and by inhibiting the renin-angiotensin system. The serum levels of the natriuretic peptides correlate with the severity of heart failure and appear to have prognostic value. The present article reviews the biochemistry, molecular biology, and physiology of natriuretic peptides and their pathophysiological link to heart failure. The therapeutic uses of natriuretic peptides are also reviewed. This includes the use of intravenous nesiritide, a synthetic human brain natriuretic peptide, and the recently developed vasopeptidase inhibitors which are designed to inhibit the degradation of natriuretic peptides.

The STAT-MI (ST-Segment Analysis Using Wireless Technology in Acute Myocardial Infarction) Trial Improves Outcomes

OBJECTIVES The goal of this study was to evaluate the impact of the STAT-MI (ST-Segment Analysis Using Wireless Technology in Acute Myocardial Infarction) network on outcomes in the treatment of patients presenting with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Shortening door-to-balloon (D2B) time remains a national priority for the treatment of STEMI. We previously reported a fully automated wireless network (STAT-MI) for transmission of electrocardiograms (ECGs) for suspected STEMI from the field to offsite cardiologists, allowing early triage with shortening of subsequent D2B times. We now report the impact of the STAT-MI wireless network on infarct size, length of hospital stay (LOS), and mortality. METHODS A fully automated wireless network (STAT-MI) was developed to enable automatic 12-lead ECG transmission and direct communication between emergency medical services personnel and offsite cardiologists that facilitated direct triage of patients to the cardiac catheterization laboratory. Demographic, laboratory, and time interval data of STAT-MI network patients were prospectively collected over a 33-month period and compared with concurrent control patients who presented with STEMI through non-STAT-MI pathways. RESULTS From June 2006 through February 2009, 92 patients presented via the STAT-MI network, and 50 patients presented through non-STAT-MI pathways (control group). Baseline clinical and demographic variables were similar in both groups. Overall, compared with control subjects, STAT-MI patients had significantly shorter D2B times (63 [42 to 87] min vs. 119 [96 to 178] min, U = 779.5, p < 0.00004), significantly lower peak troponin I (39.5 [11 to 120.5] ng/ml vs. 87.6 [38.4 to 227] ng/ml, U = 889.5, p = 0.005) and creatine phosphokinase-MB (126.1 [37.2 to 280.5] ng/ml vs. 290.3 [102.4 to 484] ng/ml, U = 883, p = 0.001), higher left ventricular ejection fractions (50% [35 to 55] vs. 35% [25 to 52], U = 1,075, p = 0.004), and shorter LOS (3 [2 to 4] days vs. 5.5 [3.5 to 10.5] days, U = 378, p < 0.001). CONCLUSIONS A fully automated, field-based, wireless network that transmits ECGs automatically to offsite cardiologists for the early evaluation and triage of patients with STEMI shortens D2B times, reduces infarct size, limits ejection fraction reduction, and shortens LOS.

Osteopontin in cardiovascular disease: a potential therapeutic target.

Osteopontin (OPN), also known as 44kDa bone phosphoprotein, sialoprotein I, secreted phosphoprotein I, 2ar, uropontin, and early T-lymphocyte activation-1 (Eta-1), is a multifunctional protein. OPN has been found to be expressed in various cell types and species with many physiologic and pathologic functions. OPN has emerged as a potential biomarker and mediator in cardiovascular disease. In this review, we will discuss the roles of OPN in cardiovascular disease, specifically in vascular and valvular heart disease, myocardial infarction and heart failure.

Factors Contributing to Global Cognitive Impairment in Heart Failure: Results From a Population-Based Cohort

BACKGROUND Heart failure (HF) and cognitive impairment are both common in older adults. However, the association between the two has not been well studied. METHODS AND RESULTS We explored the relationship between very probable HF, determined by self-reported symptoms, and cognitive impairment, defined as four or fewer correct on the Six-item Screener, in 14,089 participants of the Reasons for Geographic and Racial Differences in Stroke cohort. We determined the effect of adding demographic, socioeconomic status (SES), health behavior, and comorbidity covariates. In the univariate model, participants with very probable HF were 1.51 (95% confidence interval: 1.15-1.96) times more likely to have cognitive impairment than those without HF. As covariates were added to the model, the relationship between HF and cognitive impairment was attenuated and lost statistical significance after adjustment for depression. Demographic variables, Stroke Belt location (1.28 [1.11-1.48]), SES factors, prior stroke (1.43 [1.18-1.73]), and depression (1.66 [1.38-2.01]) remained significant in the multivariable model. Higher hemoglobin was associated (0.95 [0.9-1.00]) with modestly reduced odds of cognitive impairment. CONCLUSIONS The relationship between cognitive impairment and HF can be accounted for by multiple demographic and SES factors, and by comorbidities, some of which are modifiable. Persons with HF and cognitive impairment should be screened for anemia and depression.

The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure

To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF).

Vasopressin and vasopressin receptor antagonists in heart failure.

Antidiuretic hormone, also known as arginine vasopressin, is a hormone with a multitude of physiologic activities including the control of urinary free water excretion. Antidiuretic hormone also plays a role in vasoconstriction and has 3 receptors that have been identified. Vasopressin analogs and antagonists have been extensively studied in animal models as well as in humans. Because heart failure is associated with a state of water retention, several vasopressin antagonists have been evaluated for their potential aquaretic effect. Diuretics remain the mainstay of treatment in acute and chronic volume overload but are not shown to improve survival. In fact, they are associated with numerous side effects including hypotension, electrolyte abnormalities, worsening renal function, and activation of renin-angiotensin-aldosternone system. Tolvaptan, conivaptan, and lixivaptan are some of the vasopressin antagonists that have been studied in heart failure. The results were initially encouraging with alleviation of symptoms and effective aquaresis without worsening of hyponatremia or renal function, but yet failed to show any effect on mortality in heart failure. With an increasing number of more selective orally active vasopressin antagonists, further studies are underway to establish the role of “Vaptans” in the treatment of heart failure and other disease states with volume overload and hyponatremia.

Rationale and Design of the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF).

BACKGROUND Daily measurements of left atrial pressure (LAP) may be useful for guiding adjustments in medical therapy that prevent clinical decompensation in patients with severe heart failure (HF). STUDY DESIGN LAPTOP-HF is a prospective, multicenter, randomized, controlled clinical trial in ambulatory patients with advanced heart failure in which the safety and clinical effectiveness of a physician-directed patient self-management therapeutic strategy based on LAP measured twice daily by means of an implantable sensor will be compared with a control group receiving optimal medical therapy. The trial will enroll up to 730 patients with New York Heart Association functional class III symptoms and either a hospitalization for HF during the previous 12 months or an elevated B-type natriuretic peptide level, regardless of ejection fraction, at up to 75 investigational centers. Randomization to the treatment group or control group will be at a 1:1 ratio in 3 strata based on the ejection fraction (EF > or ≤35%) and the presence of a de novo CRT device indication. SUMMARY LAPTOP-HF will provide essential information about the role of implantable LAP monitoring in conjunction with a new HF treatment paradigm across the spectrum of HF patients.

Uremic Cardiomyopathy: An Underdiagnosed Disease

Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD); however, the early implementation of hemodialysis may halt its progression. Nonconventional hemodialysis, such as frequent hemodialysis, appears to have an advantage over conventional hemodialysis. Kidney transplantation has been shown to reverse uremic cardiomyopathy and to confer a significant survival advantage over hemodialysis. Targeting future therapies at the underlying cellular mechanisms of uremic cardiomyopathy may finally start to reduce the burden of uremic cardiomyopathy in the CKD and ESRD population.

Acute eosinophilic myocarditis: Diagnosis and treatment

Abstract Hypereosinophilic syndrome (HES) is a rare disorder of unregulated eosinophilia, which if untreated, may lead to systemic tissue infiltration and inflammation. Cardiac involvement is a common and serious associated complication. We describe a case of HES associated myocarditis mimicking a non-ST elevation MI (NSTEMI). Unlike myocarditis in general, our patient responded well to high dose methylprednisone, the standard of care in HES. We review the clinical presentation, pathophysiology, pathology and treatment of eosinophilic myocarditis related to HES.