Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure.

BACKGROUND: A reduction in the relative lymphocyte count is a marker of the stress response; however, its prognostic value remains undetermined. The objective of this study was to investigate the predictive value of the relative lymphocyte count for survival in elderly patients with congestive heart failure (CHF). METHODS AND RESULTS: One thousand two hundred seventy-four consecutive patients above the age of 65 years hospitalized with heart disease were enrolled in the CHF Italian Study and followed up for 3 years. Of these, 413 patients were excluded because of factors that could affect the lymphocyte count. Of the remaining 861 patients, 423 (49%) met the criteria for the diagnosis of CHF (mean age 76 +/- 7 years, 51% men), of whom 162 patients (38%) had a relative lymphocyte count < or = 20%. The 3-year all-cause mortality in patients with CHF and a relative lymphocyte count < or = 20% was 64% compared with 40% in patients with a relative lymphocyte count > 20% (P < .0001). The age- and sex-adjusted hazard ratio for death in patients with CHF and low relative lymphocyte count was 1.76 (95% confidence interval 1.34-2.32, P = .0001). After adjustment for baseline differences and variables associated with or known to affect lymphocyte count, the hazard ratio remained significantly different from 1.0 (hazard ratio 1.73, 95% confidence interval 1.21-2.48, P = .0026). CONCLUSION: A low relative lymphocyte count is an independent marker of poor prognosis in elderly patients with CHF. The relative lymphocyte count is a simple, accurate, widely available, and inexpensive marker that can help to identify elderly patients with CHF who are at increased risk for mortality. The pathophysiologic mechanism of this observation remains to be determined.

Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity.

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.

"Warm-up" phenomenon in adult and elderly patients with coronary artery disease: further evidence of the loss of "ischemic preconditioning" in the aging heart.

BACKGROUND: A reduction of exercise-induced ischemia in patients with coronary artery disease by means of brief period of exercise followed by resting is called the "warm-up" phenomenon. This phenomenon may represent a clinical counterpart of "ischemic preconditioning." We studied the warm-up phenomenon in both adult and elderly patients with similar angiographic evidence of coronary artery disease, using three exercise tests after excluding the "training effect." METHODS: In order to verify the presence of "training effect," three exercise tests were performed in days 1, 2, and 3 ("training" tests). The third test was used as baseline for a successive test, performed after a recovery period of 10 minutes to reestablish baseline electrocardiographic conditions. A third exercise test was performed 30 minutes later ("warm-up" tests). RESULTS: "Training" tests did not differ in all parameters in both adult and elderly patients. "Warm-up" tests showed that time to onset 1-mm ST depression was significantly higher (p < .001). whereas ST depression and time to recovery was significantly lower in the second and third test in adult but not in elderly patients (p < .001 ). Difference (in seconds) in the time at which 1-mm ST depression occurred on first warm-up exercise compared with the second was inversely correlated with age (p < .001 ). CONCLUSIONS: Previous exercise followed by resting is able to reduce the successive exercise-induced ischemia ("warm-up" phenomenon) in adult but not in elderly patients with coronary artery disease. This is independent of a greater age-related severity of coronary disease and of "training effect." These results confirm the hypothetical age-related reduction of "ischemic preconditioning" in aging heart.

Effect of beta-blockade on the premature ventricular beats/heart rate relation and heart rate variability in patients with coronary heart disease and severe ventricular arrhythmias.

We examined the effects of beta-blockers on the associations between heart rate and number of premature ventricular beats (PVBs) and on heart rate variability and myocardial ischemia in patients with coronary heart disease. After 2 weeks of run-in placebo treatment, 18 patients with coronary artery disease were randomized to a 7-day treatment with either propranolol (40 mg) three times a day or placebo. During run-in and after 7 days of treatment, patients underwent 24-hour Holter monitoring and exercise tests. We analyzed the 24-hour Holter recordings with customized software that computes the correlation between heart rate and occurrence of PVBs. We also computed spectral measures of heart rate variability on the same recordings. Propranolol caused a significant decrease in the log-transformed total number of PVBs recorded over 24 hours and during the day. The number of PVBs was much lower during the night than during the day both after placebo and after propranolol. There were no differences between the two treatments. During the day, there was a positive correlation between heart rate and the number of PVBs in all 18 patients. The mean correlation coefficients between heart rate and number of PVBs increased significantly after propranolol treatment both during the 24-hour monitoring (p < 0.05) and during the day (p < 0.05). The night-recorded correlation coefficients between heart rate and number of PVBs were not significantly different in the placebo versus propranolol group. Propranolol significantly increased the total power during the day. Placebo caused a significant decrease in the low-frequency band (LF) and a significant increase in the high-frequency band (HF) during the night compared with the day. During the day, propranolol significantly reduced LF power and increased HF power, with respect to placebo. After propranolol treatment, the values of LF and HF power during the day were comparable to those recorded at night. The LF/HF ratio decreased significantly after propranolol treatment with respect to placebo in the day and became similar to that recorded during sleep. Propranolol significantly reduced heart rate and systolic blood pressure at rest and at peak exercise and reduced signs of myocardial ischemia. Propranolol administration reduces PVBs in patients with coronary artery disease and severe ventricular arrhythmias possibly through an improvement of cardiac autonomic regulation and through anti-ischemic effects, antiarrhythmic effects, or both.

Verapamil reduces dipyridamole-induced myocardial ischemia in patients with coronary artery disease.

The aim of this study was to evaluate the effects of verapamil administration on dipyridamole-induced transient wall-motion abnormalities as detected by two-dimensional echocardiographic monitoring in patients with coronary artery disease. Twenty-eight patients (16 men and 12 women; mean age, 60+/-7 years) with angiographic evidence of significant coronary artery disease, positive dipyridamole echocardiography test results at basal condition on two consecutive days, were prospectively studied. Patients were randomized to verapamil (360 mg/day) or placebo treatments, given in three divided doses daily for 7 days; at the end of this time, each patient crossed over to the alternate regimen. Dipyridamole echocardiographic testing was repeated at the end of each treatment period. Our data demonstrate that verapamil significantly reduces the dipyridamole-induced wall-motion score index, a quantitative marker of acute myocardial ischemia (1.7+/-0.4 vs. 1.3+/-0.2; p<0.001). Hemodynamic data show that the drug reduces heart rate and rate-pressure product at basal condition (heart rate from 75+/-8 to 67+/-9 beats/min; p<0.001; rate-pressure product from 99+/-13 to 86+/-13 U x 10(-2); p<0.001) and at peak dipyridamole infusion (heart rate from 96+/-8 to 89+/-6 beats/min; p<0.001; rate pressure product from 127+/-21 to 118+/-13 U x 10(-2); p<0.05) with respect to placebo treatment. We conclude that verapamil is able to reduce dipyridamole-induced ischemia, as detected by two-dimensional echocardiographic monitoring, in patients with coronary artery disease by reducing, at least partially, myocardial oxygen consumption. Moreover, its beneficial action could be related to the effects of the drug on coronary collateral circulation and on sympathetic modulation.

Development and validation of a clinical history form for the diagnosis of congestive heart failure.

Our aim was to develop and validate a new diagnostic tool for congestive heart failure (CHF) based only on clinical examination, medical history and current drug use. In the developmental phase, we enrolled 520 consecutive patients with heart disease of different etiology; the diagnosis of CHF was made by means of Smith's clinical and radiological criteria, and the Boston criteria, with a substantial interscale agreement (kappa = 0.89). The initial version of our Form included 37 items on clinical examination, medical history and drug use information. After an item reduction process, the final version of the Clinical History Form (CH Form) included 15 items, each with a score 1 to 4. The CH Form score showed a progressive, significant increase as NYHA Class increased. With a cut-off of 4 points, sensitivity was 88.6% and specificity 86.8% against Smith's criteria for diagnosis of CHF. Substantial interrater agreement was observed for all the 15 items (kappa > 0.6) on a subsample of 250 patients. In the validation phase, we studied an independent sample of 72 patients with heart disease. The CH Form was significantly correlated with left ventricular ejection fraction (r = 0.42; p < 0.0005) and peak oxygen consumption (r = 0.69; p < 0.0001). In the 64 (89%) patients who underwent non-emergent right-heart catheterization, the CH Form score was significantly correlated with pulmonary capillary wedge pressure (r = 0.84; p < 0.0001). The CH Form may represent a useful instrument for the diagnosis of CHF.

Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients.

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/- 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.

Glucose ingestion affects cardiac ANS in healthy subjects with different amounts of body fat.

Low-to-high frequency ratio (LF/HF) is an indirect index of sympathovagal balance derived by heart rate spectral analysis. We investigated the effect of glucose ingestion on LF/HF in 17 healthy, normotensive young subjects (9 male, 8 female) with a wide body fat content range (body fat = 29 +/- 5.9%; range = 19-42%) and a normal thyroid hormone status. Before and after an oral glucose tolerance test (OGTT), the Holter technique and indirect calorimetry allowed us to determine heart rate and substrate oxidation in all subjects. At baseline, LF/HF correlated with body fat (r = 0.60, P < 0.005), waist-to-hip ratio (r = 0.57, P < 0.01), fasting plasma insulin (r = 0.55, P < 0.04), leptin (r = 0.56, P < 0.01), and norepinephrine (r = 0.58, P < 0.009) concentrations. Age-, body fat-, content-, and fat-free mass-adjusted respiratory quotient (r = 0.59, P < 0.007) and basal metabolic rate (r = 0.61, P < 0.001) were also correlated with basal LF/HF. Along with OGTT plasma glucose, insulin and norepinephrine concentrations and basal LF/HF significantly rose at 60 min and then declined throughout the test. Area under the curve (AUC) for LF/HF correlated with body fat (r = -0.66, P < 0.004), fasting plasma leptin concentration (r = -0.57, P < 0.01), glucose induced thermogenesis (r = 0.62, P < 0.001), glucose uptake (r = 0.59, P < 0.007), and AUC for plasma norepinephrine concentration (r = 0.63, P < 0.001). Water instead of glucose ingestion does not significantly affect LF/HF (n = 8). In conclusion, our study supports the hypothesis that glucose ingestion affects LF/HF and that such change is related to the amount of body fat.

Effect of gallopamil on myocardial microperfusion in patients with stable effort angina: a randomized, cross-over, double-blind, placebo-controlled trial.

We evaluated the efficacy and safety of daily administration of gallopamil 150 mg/day and its effects on myocardial perfusion in a medium-term, randomized, double-blind, cross-over, placebo-controlled trial. We studied 19 patients (17 males and 2 females; mean age 57 +/- 6.8 years) with stable effort angina, angiographically documented coronary artery disease and reversible perfusion defects during exercise thallium-201 myocardial scintigraphy of at least one segment of the left ventricle. After 2 weeks of a single-blind placebo run-in period, during which each patient underwent at least 2 exercise tests and a 48-hour Holter ECG recording, all patients were treated with either placebo or gallopamil 50 mg t.i.d. for 28 days. At the end of this period, patients crossed over to the alternate regimen. This phase was double blind. After treatment with placebo or gallopamil, patients underwent exercise tests, 24-hour Holter ECG recording and thallium-201 myocardial scintigraphy. Weekly angina frequency and trinitroglycerin (TNT) consumption and safety were also evaluated. No patients dropped out of the study because of major side effects. The number of total ischemic and symptomatic events recorded at 24-hour ECG monitoring, weekly angina frequency and TNT consumption were significantly reduced during gallopamil treatment. After gallopamil administration, exercise duration significantly increased (run-in: 419 +/- 116 s, placebo: 420 +/- 118 s, gallopamil: 511 +/- 144 s; p < 0.05), and ST segment depression was significantly reduced (run-in: -1.3 +/- 0.3 mm, placebo: -1.3 +/- 0.3 mm, gallopamil: -0.94 +/- 0.68 mm; p < 0.01), while heart rate, systolic blood pressure and rate-pressure product were unchanged at rest, at submaximal and at peak exercise. Qualitative and quantitative evaluation of myocardial perfusion and the myocardial uptake percentage of thallium-201 in ischemic zones were significantly improved by gallopamil treatment. These findings demonstrate that gallopamil can improve myocardial perfusion and reduce myocardial oxygen consumption.

Quinapril in patients with congestive heart failure: controlled trial versus captopril.

After two weeks of a wash-out run-in period with placebo, 131 patients with congestive heart failure (New York Heart Association [NYHA] class II to III) and left ventricular ejection fraction

The effects of delapril in combination with indapamide on glomerular filtration rate in elderly hypertensive patients.

We performed a placebo-controlled trial on the effects of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1 years) who took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. In the present study (performed simultaneously with our trial on the effects of delapril/indapamide on left ventricular mass in elderly patients with hypertension and on the same patients), we report the effects of this drug combination on glomerular filtration rate. Sitting arterial pressure (mean +/- SE) decreased from 156 +/- 1. 5/101 +/- 1 mm Hg at baseline to 133 +/- 1/73 +/- 1 mm Hg at the end of the 24-week treatment period (p < 0.0001). No significant changes in heart rate or episodes of orthostatic hypotension were observed. Glomerular filtration rate increased from 91.8 +/- 4.42 mL/min at baseline to 106.3 +/- 4.5 mL/min (p < 0.001) at the end of treatment. Our results show that the combination of delapril and indapamide is effective in the elderly hypertensive patient, with a favorable effect on the prevention of deterioration of kidney function.

Congestive heart failure in the elderly.

Several aspects of congestive heart failure are discussed in the light of international literature and of recent findings of our group. The annual incidence of heart failure in elderly subjects, aged >or=75y, is 13 to 50/1000, while it is 1.6/1000 in people aged 45-54 y. The prevalence of heart failure is about 3% in subjects aged 45-64% in subjects aged more than 65 y and 10% in subjects aged more than 75 y. These data are confirmed by our population based study in elderly subjects. The etiology of congestive heart failure is similar in elderly and middle-aged patients. However, several anatomo-functional, hormonal and autonomic nervous system changes, typical of congestive heart failure, occur during physiologic ageing processes also. These findings may explain the dramatic evolution of congestive heart failure in elderly patients. Moreover, some features of the elderly - e.g. comorbidity, atypical clinical presentations, loss of autonomy, increased iatrogen risk should be considered. No specific drugs exist for the pharmacologic treatment of heart failure in the elderly, so that the geriatric specificity in the treatment of heart failure can be recognized in the art of drug choice and dosage, to obtain the best results with the least side effects. The multiple etiology of congestive heart failure, the comorbidity, the loss of autonomy and the deterioration of cognitive functions suggest the need for multidimensional approach and continuative intervention in elderly patients with heart disease, and in particular with congestive heart failure. Further studies on disease- and age-related changes are necessary to develop new and more potent strategies to secure 'successful ageing'.

The brain in congestive heart failure.

In the present paper we discuss two issues about relationships between congestive heart failure and the brain. First, major acute cerebrovascular events are very frequent among elderly people, but stroke does not appear to be frequently associated with congestive heart failure. Second, some cardiovascular conditions may determine progressive damage of cerebral tissue, with consequent impairment of cognitive functions. The association of cognitive impairment and cardiovascular diseases may dramatically increase morbility and mortality risks in the elderly. Recent studies seem to show that hypotension and congestive heart failure are risk factors for dementia in elderly people. In view of this data, an Italian multicentric study on congestive heart failure in hospitalized elderly patients (CHF Italian Study I) included a brief screening of cognitive abilities (MMSE). The presence of congestive heart failure induced a significant decrease of MMSE scores: mean MMSE score after statistical adjustment for the other variables was about one point lower in patients with congestive heart failure respect to elderly patients affected by heart disease but without congestive heart failure. A novel multicentric study (CHF Italian Study II) has been performed to identify cognitive functions more specifically impaired during congestive heart failure in the elderly. Preliminary data relative to 385 patients, confirmed that congestive heart failure may induce a generalized impairment of cognitive functions. These data have relevant clinical implications because they demonstrate that a multidisciplinary approach is necessary in these patients, both for prevention and rehabilitation therapy.

Efficacy and pharmacokinetics of gallopamil in patients with coronary artery disease.

We prospectively studied 10 patients with stable exertional ischaemia, selected from a larger group of patients referred for suspected coronary artery disease or to detect residual ischaemia after myocardial infarction, to evaluate pharmacokinetic changes during chronic treatment with gallopamil and its correlation with clinical efficacy in patients with coronary artery disease. Our study consisted of a 1-week run-in single-blind placebo treatment and a 4-week single-blind gallopamil treatment. At the end of the run-in period patients underwent two different exercise tests, the first 2 hours and the second 7 hours after placebo administration. During active treatment all patients underwent two different exercise tests, the first 2 hours and the second 7 hours after gallopamil (50 mg) administration on the 1st and 28th days of gallopamil therapy. On the same days in eight of the patients we evaluated gallopamil pharmacokinetic changes. Our data revealed a rapid increase of unchanged gallopamil and its metabolite (norgallopamil) in the plasma, and a peak concentration of these substances about 2 hour after oral administration on both the 1st and 28th day of observation. Moreover, our results demonstrated an increase between the first and 28th day of treatment in peak concentration of unchanged gallopamil in the plasma, and of AUC 0-infinity and AUC o-c values during chronic treatment with gallopamil. Our clinical data showed an improvement in exercise results during gallopamil therapy related to increased concentration of the drug.

Clinical determinants of long-term mortality in elderly patients with heart disease.

To determine which of the many clinical parameters routinely collected influence mortality in patients with low left ventricular ejection fraction (LVEF) (< 45% at radionuclide ventriculography), 128 elderly patients (mean age 79 +/- 3 years) with various heart diseases were prospectively followed for 3 years. Twenty-eight-percent had coronary heart disease, 16% hypertensive heart disease, 7% valvular heart disease. The remaining 62 patients (48%) made up a group comprising patients with primitive cardiomyopathy, cor pulmonary with no evidence of coronary heart disease, valvular disease or hypertensive heart disease. Thirty-four-percent of all patients were classified as having congestive heart failure (CHF). Age, sex and 37 clinical variables were analyzed using a Cox proportional model. Forty-four patients died, 36 (82%) of sudden cardiac death. Ten characteristics at study entry predicted an increased mortality risk: S3 gallop, number of clinical signs >or= 3, LVEF or= III, dyspnea, digoxin treatment, rales, number of symptoms >or= 4, asthenia, associated pulmonary disease. Long-term survival of very elderly patients with low ejection fraction is related to the functional capacity, the severity of symptoms and the number of clinical signs. Moreover a LVEF