Maria Anastasiou-Nana

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.

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.

Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure

Background Heart rate recovery (HRR1) immediately after exercise reflects parasympathetic activity, which is markedly attenuated in chronic heart failure (CHF) patients. The aim of our study was to examine both continuous and interval exercise training effects on HRR1 in these patients. Design The population study consisted of 29 stable CHF patients that participated at a rehabilitation program of 36 sessions, three times per week. Of the 29 patients, 24 completed the program. Patients were randomly assigned to interval {n = 10 [100% peak work rate (WRp) for 30 s, alternating with rest for 30 s]} and to continuous training [n = 14 (50%WRp)]. Methods All patients performed a symptom-limited cardiopulmonary exercise test on a cycle ergometer before and after the completion of the program. Measurements included peak oxygen uptake (VO2p), anaerobic threshold (AT), WRp, first degree slope of VO2 during the first minute of recovery (VO2/t-slope), chronotropic response [% chronotropic reserve (CR) = (peak HR - resting HR) × 100/(220 - age - resting HR)], HRR1 (HR difference from peak exercise to one minute after). Results After the completion of the rehabilitation program there was a significant increase of WRp, VO2p, AT and VO2/t-slope (by 30%, P=0.01; 6%, P=0.01; 10%, P=0.02; and 27%, P=0.03 respectively for continuous training and by 21%, P≤0.05; 8%, P=0.01; 6%, P=NS; and 48%, P=0.02 respectively for interval training). However, only patients exercised under the continuous training regime had a significant increase in HRR1 (15.0±9.0 to 24.0±12bpm; P=0.02) and CR (57±19 to 72±21%, P=0.02), in contrast with those assigned to interval training (HRR1: 21 ± 11 to 21 ± 8 bpm; P=NS and CR: 57 ± 18 to 59 ± 21%, P=NS). Conclusions Both continuous and interval exercise training program improves exercise capacity in CHF patients. However, continuous rather than interval exercise training improves early HRR1, a marker of parasympathetic activity, suggesting a greater contribution to the autonomic nervous system.

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.

Managing the underestimated risk of statin-associated myopathy

In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.

Relation of Dispersion of QRS and QT in Patients With Advanced Congestive Heart Failure to Cardiac and Sudden Death Mortality

This study examined the usefulness of 01 and QRS dispersion in the prognosis of patients with advanced congestive heart failure (CHF). One hundred four patients in New York Heart Association functional classes II to IV, with a left ventricular ejection fraction of <35%, and untreated with antiarrhythmic drugs, were followed prospectively. QRS and QT dispersion were defined as the maximum difference in QRS and QT interval duration, respectively, measured on all leads of standard 12-lead electrocardiograms. The end points of the study were non-sudden and sudden cardiac mortality. During an average follow-up of 20 months, there were 13 non-sudden and 10 sudden deaths. The average QRS duration was significantly longer in nonsurvivors than in survivors (125 ¿ 34 vs 113 ¿ 34 ms, respectively, p <0.04). Similar results were obtained with 01 dispersion (95 ¿ 48 ms vs 78 ¿ 31 ms, respectively, p <0.03) and QRS dispersion (54 ¿ 17 ms vs 46 16 ms, respectively, p <0.02). Furthermore, patients who died suddenly had significantly greater QRS dispersion than patients who survived (56 ¿ 13 vs 46 ¿ 16 ms, respectively, p <0.02). In a multivariate analysis, QT and QRS dispersion were both independent predictors of non-sudden cardiac death (p = 0.01 and p = 0.001, respectively), and QRS dispersion was also an independent predictor of sudden cardiac death (p = 0.04). Death rate in patients with 01 dispersion >90 ms was 2.8-fold higher than those with 01 dispersion 90 ms (95% confidence intervals [CI] 1.2 to 6.4). Similarly, the death rate in patients with QRS dispersion >46 ms was 3.9-fold higher than in those with QRS dispersion 46 ms (95% Cl 1.6 to 9.5). These findings suggest that QT and QRS dispersion are useful predictors of mortality in patients with advanced CHF. ¿2000 by Excerpta Medica, Inc.

The effects of exercise training on the kinetics of oxygen uptake in patients with chronic heart failure.

Background Prolonged oxygen uptake kinetics (O2 kinetics), following the onset of a constant workload of exercise has been associated with a poor prognosis in patients with chronic heart failure. This study aimed to determine both continuous and interval training effects on the different O2-kinetics phases in these patients. Design Twenty-one patients (60 ± 8 years) with stable chronic heart failure participated in a 36-session exercise rehabilitation program (three times weekly). Patients were randomly assigned to interval training (n = 11; 100% of peak work rate for 30 s, alternating with 30s-rest) and to continuous training (n = 10; 50% of peak work rate). Methods Before and after the completion of the program, all patients performed both incremental symptom-limited and constant workload submaximal cardiopulmonary exercise tests. Phase I O2-kinetics was evaluated by time (t), from the start of exercise until the onset of decreased respiratory exchange ratio and phase II by the time constant (τ) of the response from the end of phase I until steady state. Results After training, there was a significant increase in peak oxygen uptake and peak work rate in both continuous (15.3 ± 4.4 vs. 16.6 ± 4.5 ml/kg per min; P=0.03 and 81.8 ± 40.1 vs. 94.7 ± 46.1 W; P=0.03) and interval training groups (14.2 ± 3.1 vs. 15.4 ± 4.2 ml/kg per min; P=0.03 and 82.5 ± 24.1 vs. 93.7 ± 30.1 W; P=0.04). Patients who underwent interval training had a significant decrease in t (39.7 ± 3.7 to 36.1 ± 6.9s; P=0.05), but not τ (59.6 ± 9.4 to 58.9 ± 8.5 s; P=ns), whereas those assigned to continuous training had a significant decrease in both t (40.6 ± 6.1 to 36.4 ± 5.4 s; P=0.01) and τ (63.3 ± 23.6 to 42.5 ± 16.7 s; P=0.03). Conclusions Exercise training improves O2 kinetics in chronic heart failure patients. Both continuous and interval training improve phase I O2-kinetics, but continuous training results in superior improvement of the phase II O2-kinetics, an indirect index of muscle oxidative capacity.

Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis.

Background—We investigated the effects of anakinra, an interleukin-1 receptor antagonist, on coronary and left ventricular function in coronary artery disease (CAD) patients with rheumatoid arthritis. Methods and Results—In a double-blind crossover trial, 80 patients with rheumatoid arthritis (60 with CAD and 20 without) were randomized to a single injection of anakinra or placebo and after 48 hours to the alternative treatment. At baseline and 3 hours after treatment, we assessed (1) flow-mediated dilation of brachial artery; (2) coronary flow reserve, ejection fraction, systemic arterial compliance, and resistance by echocardiography; (3) left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity by speckle tracking; and (4) interleukin-1&bgr;, nitrotyrosine, malondialdehyde, protein carbonyl, and Fas/Fas ligand levels. At baseline, patients with CAD had 3-fold higher interleukin-1&bgr;, protein carbonyl, higher nitrotyrosine, malondialdehyde, and Fas/Fas ligand than non-CAD (P<0.05). After anakinra, there was a greater improvement of flow-mediated dilation (57±4% versus 47±5%), coronary flow reserve (37±4% versus 29±2%), arterial compliance (20±18% versus 2±17%), resistance (−11±19% versus 9±21%), longitudinal strain (33±5% versus 18±2%), circumferential strain (22±5% versus 13±5%), peak twisting (30±5% versus 12±5%), untwisting velocity (23±5% versus 13±5%), ejection fraction (12±5% versus 0.5±5%), apoptotic and oxidative markers, and, in particular, of protein carbonyl (35±20% versus 14±9%) in CAD than in non-CAD patients (P<0.01). No changes in the examined markers were observed after placebo. Conclusions—Interleukin-1 inhibition causes a greater improvement in endothelial, coronary aortic function in addition to left ventricular myocardial deformation and twisting in rheumatoid arthritis patients with CAD than in those without. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01566201.

Short-term statin administration in hypercholesterolaemic rabbits resistant to postconditioning: effects on infarct size, endothelial nitric oxide synthase, and nitro-oxidative stress

AIMS The effectiveness of postconditioning (POC) in hypercholesterolaemia is in dispute. We investigated the effects of 3-day lipophilc (simvastatin) or hydrophilic (pravastatin) statin treatment, without or with POC in normocholesterolaemic (Norm) and hypercholesterolaemic (Chol) rabbits. METHODS AND RESULTS Norm or Chol rabbits were subjected to 30 min ischaemia and randomized in two series of 12 groups each: control, simvastatin (Sim), pravastatin (Prav), POC, Sim-POC, Prav-POC, Chol, Sim-Chol, Prav-Chol, POC-Chol, Sim-POC-Chol, Prav-POC-Chol. After ischaemia, rabbits of the first series underwent 3 h reperfusion, followed by infarct size, total cholesterol, and low density lipoprotein plasma level evaluation; animals of the second series underwent 10 min reperfusion followed by tissue sampling for nitrotyrosine (NT), malondialdehyde, endothelial nitric oxide synthase (eNOS), and Akt analyses. N-nitro-l-arginine methylester (L-NAME) was given in two additional groups (POC-L-NAME and Prav-Chol-L-NAME) for infarct size assessment. All interventions reduced infarction in Norm (24.3 ± 1.3, 25.9 ± 2.8, 27.9 ± 3.1, 23.3 ± 2.3, and 33.4 ± 2.5%, in POC, Sim, Prav, Sim-POC, and Prav-POC groups, respectively, vs. 49.3 ± 1.9% in control, P < 0.05), but only Prav did so in Chol animals (25.7 ± 3.3 and 25.3 ± 3.9% in Prav-Chol and Prav-POC-Chol vs. 50.9 ± 1.7, 44.8 ± 4.3, 41.5 ± 3.5, and 49.3 ± 5.5% in Chol, Sim-Chol, POC-Chol, and Sim-POC-Chol, respectively, P < 0.05). L-NAME abolished the infarct size-limiting effect of POC and Prav-Chol. Prav induced the greatest reduction in NT, while it was the only intervention that increased myocardial eNOS and Akt in Chol rabbits (P < 0.05 vs. all others). CONCLUSION Prav, in contrast to same-dose Sim or POC, reduces infarction in Chol rabbits independently of lipid lowering, potentially through eNOS activation and nitro-oxidative stress attenuation.

VE/VCO2 slope is associated with abnormal resting haemodynamics and is a predictor of long-term survival in chronic heart failure.

Patients with chronic heart failure (CHF) present with exercise‐induced hyperpnea, but its pathophysiological mechanism has not been thoroughly investigated. We aimed to determine the relationship between exercise‐induced hyperpnea, resting haemodynamic measurements and the validity of ventilatory response (VE/VCO2 slope) as a mortality predictor in CHF patients.