John N. Nanas

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaborati

Authors/Task Force Members: John J.V. McMurray (Chairperson) (UK)*, Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Auricchio (Switzerland), Michael Bohm (Germany), Kenneth Dickstein (Norway), Volkmar Falk (Switzerland), Gerasimos Filippatos (Greece), Cândida Fonseca (Portugal), Miguel Angel Gomez-Sanchez (Spain), Tiny Jaarsma (Sweden), Lars Kober (Denmark), Gregory Y.H. Lip (UK), Aldo Pietro Maggioni (Italy), Alexander Parkhomenko (Ukraine), Burkert M. Pieske (Austria), Bogdan A. Popescu (Romania), Per K. Ronnevik (Norway), Frans H. Rutten (The Netherlands), Juerg Schwitter (Switzerland), Petar Seferovic (Serbia), Janina Stepinska (Poland), Pedro T. Trindade (Switzerland), Adriaan A. Voors (The Netherlands), Faiez Zannad (France), Andreas Zeiher (Germany).

The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study

Background— During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Methods and Results— Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE–eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69–1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04–1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80–1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. Conclusions— During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808067.

Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone

Background and Objectives High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. Design and Methods Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. Results Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. Interpretation and Conclusions The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.

Hormonal profile in patients with congestive heart failure

BACKGROUND Recent progress has been made in the understanding of the cellular and molecular mechanisms of growth hormone action and of its effects on cardiac tissue. The aim of this study was to measure growth hormone concentrations, along with various other hormones, in patients with stable chronic congestive heart failure due to idiopathic dilated cardiomyopathy. METHODS The study included 23 ambulatory men, 51.2+/-9.3 years of age, on standard medical therapy for heart failure due to idiopathic dilated cardiomyopathy. All patients underwent clinical and laboratory evaluations, including echocardiogram, radionuclide ventriculography, right heart catheterization, coronary angiography, and right ventricular endomyocardial biopsy. Serum or plasma concentrations of growth, thyroid, sex and adrenal hormones were measured in all patients and compared with those found in 20 age-matched healthy men. RESULTS Growth hormone, insulin-like growth factor I, and free testosterone values in patients with idiopathic dilated cardiomyopathy and heart failure were 0.37+/-0.2 ng/ml, 123.7+/-50 ng/ml and 48.6+/-23.8 pmol/l, respectively, versus 0.5+/-0.4 ng/ml (P<0.01), 236.3+/-66.4 ng/ml (P<0.001) and 105+/-17 pmol/l (P<0.01), respectively, in the healthy age-matched individuals. All other hormone concentrations were comparable in both groups. CONCLUSIONS Chronic heart failure due to idiopathic dilated cardiomyopathy is associated with a significant decrease in growth hormone, insulin-like growth factor I, and testosterone concentrations, probably due to chronic disease.

Counterpulsation: Historical Background, Technical Improvements, Hemodynamic and Metabolic Effects

The intraaortic balloon counterpulsation is performed today on the same principles that were described in its first experimental use in 1962. Experimental studies have shown significant increase of the mean aortic diastolic pressure, the diastolic pressure-time index, endocardial viability ratio, cardiac output, ejection fraction, coronary cerebral and renal blood flow, lactate utilization and myocardial oxygen supply and significant decrease of the systolic aortic pressure, left-ventricular end-diastolic pressure, left-ventricular work, tension time index, myocardial oxygen consumption and lactate production. In similar studies, intraaortic balloon pump (IABP) decreases the size of myocardial infarction. New IABP driving systems, small size sheaths and balloon catheters for percutaneous insertion made the use of the IABP easier and safer. The paraaortic counterpulsation device is suitable for chronic mechanical assistance. It is more effective than the IABP and shows excellent biocompatibility in chronic experiments. Its clinical application in 3 patients showed excellent biocompatibility and promising hemodynamic effects. In conclusion, the salutary hemodynamic effects of the IABP have been shown in several experimental studies. The technical improvements and the development and use of new devices suggest that we still need to learn more about the usefulness of the counterpulsation technique.

Effect of Acute Cigarette Smoking on Endothelium-Dependent Brachial Artery Dilatation in Healthy Individuals

The effect of short-term smoking on endothelium-dependent and endothelium-independent dilatation of the brachial artery was tested in 27 healthy volunteers using high-resolution ultrasound imaging. Short-term smoking led to a significant decrease in endothelium-dependent dilatation.

Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy.

OBJECTIVES We sought to examine the relationship between coronary flow reserve (CFR) and myocardial capillary density (MCD) in patients with idiopathic dilated cardiomyopathy, heart failure, and normal coronary arteries. BACKGROUND Coronary flow reserve is depressed in patients with idiopathic dilated cardiomyopathy, particularly in those with end-stage congestive heart failure. METHODS We studied 18 patients, 48 +/- 10 years of age, who had a mean New York Heart Association functional class of 2.9 +/- 1.3, mean left ventricular ejection fraction of 22 +/- 8%, and mean pulmonary capillary wedge pressure of 23 +/- 10 mm Hg. CFR measurements were made with a 0.014-inch pressure-temperature sensor-tipped guide wire placed in the distal left anterior descending coronary artery. Thermodilution curves were constructed in triplicate at baseline and during maximum hyperemia induced by intravenous adenosine. CFR was calculated from the ratio of mean transit times. Right heart endomyocardial biopsies were performed during the same procedure. Autopsied specimens from nonfailing hearts were used as controls. The tissue was histochemically stained with CD-34 for morphometric measurements of MCD. RESULTS We observed a close linear relationship between CFR and MCD (r = 0.756, p = 0.0001). The MCD in 7 patients with a CFR >or=2.5 (73.2 +/- 16) was similar to that measured in normal control patients, (85 +/- 11, p = NS). In contrast, the MCD in 11 patients with a CFR <2.5 was 33.2 +/- 14, which was significantly lower than in patients with heart failure and normal CFR (73.2 +/- 16, p = 0.001) or in controls (85 +/- 11, p < 0.0001). CONCLUSIONS A marked decrease in MCD was found in patients presenting with congestive heart failure as the result of idiopathic dilated cardiomyopathy and a depressed CFR.

Bridge to Recovery Understanding the Disconnect Between Clinical and Biological Outcomes

Left ventricular (LV) assist devices (LVADs) are increasingly used in everyday clinical practice either as a bridge for end-stage heart failure (HF) patients to heart transplantation or as a permanent (destination) therapy.1,2 Yet, there is still significant uncertainty about the consequences of this intervention both at the level of the detailed myocardial biology (ie, biological outcomes) and at the functional cardiovascular response of the patient at the organ level (ie, clinical outcomes). The LVAD patient population presents a series of significant advantages as far as research is concerned. First, LVAD therapy offers the ability to acquire paired human myocardial tissue at LVAD implantation and again on LVAD removal. The ability to obtain human tissue and the possibility for its serial examination before and after any therapeutic investigational therapy combined with LVADs provide an important opportunity for in-depth study of the changes in the structure and function of the diseased human heart caused by the specific investigational therapy. Second, this population represents a relatively safe investigational platform because the hemodynamic support provided by VADs makes these patients significantly less vulnerable to any arrhythmic3 or hemodynamic adverse events potentially associated with new aggressive investigational therapies. Third, the volumes of potential study subjects for these investigations (ie, patients who receive LVADs) are rapidly increasing; because of a lack of donor organs and incremental progress in device design and durability, the number of advanced HF patients with LVADs has been continuously increasing.1,2 These 3 research advantages create an ideal setting for various new HF therapies to test their potential efficacy in LVAD patients. Fourth, this population offers an opportunity to investigate the effects of the LVAD-induced removal of excess mechanical load, which drives the vicious cycle of myocardial remodeling and eventually leads to the clinical HF syndrome. …

Respiratory Muscles Performance Is Related to Oxygen Kinetics During Maximal Exercise and Early Recovery in Patients With Congestive Heart Failure

BACKGROUND Dyspnea and fatigue are the main causes of exercise limitation in chronic heart failure (CHF) patients, whose peak inspiratory (Pi(max)) and expiratory pressures (Pe(max)) are often reduced. The aim of this study was to examine the relationship between respiratory muscle performance and oxygen kinetics. METHODS AND RESULTS A total of 55 patients (NYHA class I to III) and 11 healthy subjects underwent cardiopulmonary exercise tests (CPET) on a treadmill. In 45 of the 55 patients (group I) and in healthy subjects (group II), pulmonary function tests, Pi(max), and Pe(max) were measured before and 10 minutes after exercise, and oxygen kinetics were monitored throughout and during early recovery from CPET. The first degree slope of oxygen consumption (VO(2)) decline during early recovery (VO(2)/t-slope) and VO(2) half-time (T(1/2)) were calculated. In 10 of the 55 CHF patients (group III), the measurements of Pi(max) were repeated 2, 5, and 10 minutes after CPET. A >10% reduction in Pi(max) after CPET (subgroup IA) was measured in 11 of 45 patients. In contrast, 34 of 45 CHF patients (subgroup IB) and all control subjects (group II) had Pi(max)>90% of baseline value after CPET. Subgroup IA patients had significantly lower peak VO(2) (13.5+/-2.1 versus 17.8+/-5.6 mL. kg(-1). min(-1); P<0.001), lower anaerobic thresholds (10.1+/-2.4 versus 13.6+/-4.6 mL. kg(-1). min(-1); P=0.003) and lower VO(2)/t-slopes (0.365+/-0.126 versus 0.519+/-0.227 L. min(-1). min(-1); P=0.008) than subgroup IB patients. CONCLUSIONS The reduction of Pi(max) after exercise is associated with prolonged early recovery of oxygen kinetics, which may explain, in part, the role played by respiratory muscles in exercise intolerance in CHF patients.

Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study

OBJECTIVES We sought to prospectively and randomly compare survival with clinical and hemodynamic variables in patients with congestive heart failure (CHF) treated with standard versus high doses of enalapril. BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors produce hemodynamic and symptomatic benefits in patients with CHF, but there is still controversy about the optimal dose in this clinical setting. METHODS Two hundred and forty-eight patients with advanced CHF (age 56.3+/-12 years) were randomized to receive a maximal tolerated dose of enalapril, up to 20 mg/day in group 1 (mean dose achieved 17.9+/-4.3 mg/day, n = 122) and 60 mg/day in group 2 (mean dose achieved 42+/-19.3 mg/day, n = 126). RESULTS At enrollment, patients in group 1 were in New York Heart Association (NYHA) functional class 2.6+/-0.7 and had a mean systolic blood pressure (SBP) of 117+/-18 mm Hg, a mean heart rate (HR) of 85+/-16 beats/min and a left ventricular ejection fraction (LVEF) of 20.0+/-9.8%. In group 2, patients were in NYHA class 2.6+/-0.7; their SBP was 118+/-17 mm Hg, HR 83+/-15 beats/min and LVEF 18.8+/-8.1%. There were no significant differences in these characteristics between the two groups of patients at enrollment. After 12 months of follow-up, 22 (18%) of 122 patients in group 1 and 23 (18%) of 126 patients in group 2 had died (p = 0.995, with 80% power of the study to detect a delta difference of 13%). The NYHA class was the same (1.9+/-0.7) in both groups; SBP was 111+/-16 and 111+/-17 mm Hg, HR 77+/-12 and 79+/-13 beats/min and LVEF 31+/-19% and 30+/-12% in groups 1 and 2, respectively. These differences were not statistically significant. The study had a power of 80% to detect (p = 0.05) the following changes: 13% in death rate, 0.25 units in NYHA class, 6 mm Hg in SBP, 5 beats/min in HR and 6% in LVEF. CONCLUSIONS No significant differences were found in survival and clinical and hemodynamic variables between patients receiving standard and those receiving high doses of enalapril.