Plasma levels of oxidized-low-density lipoproteins are higher in patients with unstable angina and correlated with angiographic coronary complex plaques.

OBJECTIVES: To measure circulating levels of oxidized-low-density lipoproteins (ox-LDL) in patients with stable and unstable angina and controls, and to investigate their correlation with the extent of coronary artery disease (CAD) and the presence of complex plaques at coronary angiography. METHODS AND RESULTS: Circulating ox-LDL were assessed, using ELISA, in patients with unstable angina (UA, n=26), stable angina (SA, n=29) and in controls (C, n=27). All patients underwent coronary angiography. The extent of CAD was evaluated using a quantitative score, while the presence of complex, vulnerable plaques was angiographically assessed. Ox-LDL were higher in UA patients than in SA patients and in C subjects, and in SA patients than in C subjects (C, 45.6+/-12.8 U/L; SA, 58.8+/-11.0 U/L; UA, 73.7+/-13.6 U/L; p<0.001). No correlation was found with the extent of atherosclerotic disease in the coronary tree. Patients with angiographic complex lesions showed significantly higher levels of ox-LDL (68.4+/-13.9 U/L versus 55.2+/-16.4 U/L, p<0.001). Multiple regression analysis showed that ox-LDL were independent predictors of the presence of complex plaques (p<0.023). CONCLUSIONS: Ox-LDL levels are higher in unstable patients and correlate with the presence of angiographically documented complex plaques. Ox-LDL might be markers of destabilization of CAD.

Aortic stiffness correlates with an increased extracellular matrix turnover in patients with dilated cardiomyopathy.

BACKGROUND: An increased extracellular matrix (ECM) turnover has been associated with poor survival in patients with chronic heart failure (CHF) due to dilated cardiomyopathy (DCM). However, the influence of the accelerated collagen turnover on the progressive large artery stiffening process characterizing CHF has not been clarified. This is relevant because aortic stiffening imposes an additional systolic load and impairs exercise tolerance in CHF patients. Therefore, we investigated whether the serum aminoterminal propeptide of type III collagen (PIIINP), an established marker of ECM turnover and tissue fibrosis in DCM, was associated with aortic stiffness in DCM patients. METHODS AND RESULTS: A total of 89 patients with clinical diagnosis of DCM (age 62 +/- 9 years, 80% men, mean ejection fraction 34% +/- 8%) were selected. Aortic pulse-wave velocity (PWV), a well-established marker of aortic stiffness, was measured by Doppler ultrasonography. Serum concentration of PIIINP was determined by radioimmunoassay. Mean aortic PWV was 5.7 +/- 2.3 m/s, and PIIINP was 5.0 +/- 1.3 microg/L. The variables correlated with aortic PWV were age (r = 0.33, P = .002), PIIINP (r = 0.30, P = .005), heart rate (r = 0.27, P = .02), stroke volume (r = -0.24, P = .03) and New York Heart Association class (r = 0.25, P = .02). In a multivariate analysis, age (P = .02) and PIIINP (P = .01) were independently related with aortic PWV, accounting for 27% of its variance. CONCLUSIONS: Higher serum PIIINP levels are independently associated with a stiffer aorta in DCM patients. This suggests that abnormalities in the ECM turnover might involve the proximal elastic vasculature and could partially explain the progressive large artery stiffening process characterizing CHF.

Carotid atherosclerotic plaque instability in patients with acute myocardial infarction.

UNLABELLED: The instability of atherosclerotic plaque is partly determined by local factors, but systemic factors such as infection, inflammation, autoimmunity or genes might also be important. We aimed to analyze whether patients with acute myocardial infarction (AMI) might have a higher proportion of unstable plaques in the carotid arteries compared with patients who had had no acute coronary events. METHODS: Sixty-nine consecutive patients with AMI (Group 1) and 95 patients without acute coronary events (Group 2) had carotid artery duplex ultrasounds. Carotid atherosclerosis was quantified by number of plaques in the two carotid arteries, intimal media thickening and degree of maximal stenosis. According to their morphology, plaques were divided into stable (fibrocalcific) and unstable (soft and/or not homogeneous). RESULTS: The two groups did not differ as regards age (66+/-8 vs. 68+/-19; p=0.3), female sex (13% vs. 21%; p=0.3), mean number of carotid plaques (2.8+/-1 vs. 2.5+/-2; p=0.2), degree of stenosis (59+/-2% vs. 36+/-1%; p=0.2) or intimal media thickening (1.04+/-0.2 vs. 1.06+/-0.2; p=0.8). However, Group 1 pts more frequently had unstable carotid plaques compared with Group 2 (43% vs. 15%; p=0.004), and had a greater number of unstable carotid plaques (0.51+/-0.6 vs. 0.16+/-0.4: p<0.0001) and a higher ratio of unstable to stable plaque (19% vs. 8%; p=0.005). In the overall population, logistic regression analysis showed that after adjustment for degree of maximal stenosis, the presence of coronary artery event (AMI pts) predicted the presence of unstable carotid plaque (OR: 4.3 95% CI: 2.0-9.2; p=0.0002). CONCLUSION: Patients with unstable coronary artery disease expressed clinically as AMI, frequently had unstable atherosclerotic plaques in other arterial sites such as carotid arteries. This finding supports the hypothesis that plaque instability might reflect a systemic process.

Impact of body mass index on short-term outcome after acute myocardial infarction: does excess body weight have a paradoxical protective role?

BACKGROUND: Obesity is a risk factor for acute myocardial infarction (AMI), due in part to obesity-related conditions. However, the relation between BMI (body mass index) and outcome in patients with AMI has not been completely clarified. The aim of our study was to assess the impact of BMI on short-term outcome after AMI. METHODS: We retrospectively studied 717 consecutive patients admitted to our Intensive Coronary Care Unit for AMI. The end-point of the study was all-cause mortality. RESULTS: The mean age was 64+/-12 years. Mean BMI was 26+/-3.5 kg/m2. During follow-up 15 patients died. Non-survivors were significantly older than survivors (p<0.0001); BMI (p = 0.0027) and weight (p = 0.0002) were significantly lower in non-survivors than survivors; left ventricular dimensions (end-diastolic diameter: p = 0.0023; end-systolic diameter: p = 0.0019), the number of akinetic segments (p<0.0001) and contractile efficiency (p<0.0001) were also significantly lower in non-survivors. At Cox proportional univariate analysis low BMI (p = 0.0019), female sex (p = 0.0041), age (p<0.0001), left ventricular dimensions (end-diastolic diameter = 0.0040, end-systolic diameter = 0.0053), number of akinetic segments (p = 0.0001) and degree of left ventricular dysfunction (p = 0.0002) were significant predictors of prognosis. The prognostic power of BMI remained after adjustment for age (p<0.05), left ventricular dimensions (end-diastolic diameter: p<0.0042; end-systolic diameter p = 0.04), contractile efficiency (p = 0.0045) or number of akinetic segments (p = 0.0070). CONCLUSION: Low BMI is an independent predictor of poor prognosis in the short-term outcome after AMI. The underlying mechanisms remain to be investigated.

Chronic heart failure with preserved left ventricular ejection fraction: diagnostic and prognostic value of left atrial size.

BACKGROUND: Almost 40% of patients with heart failure (HF) have preserved left ventricular (LV) ejection fraction (EF) and prognosis similar to those with reduced EF. Data on prognostic markers in such patients are limited. We analyzed the prevalence and prognostic value of left atrial (LA) size in this condition. METHODS: 89 normal subjects (Group I), 38 asymptomatic hypertensive patients (Group II) and 183 HF patients with preserved EF (EF >45%) (Group III) were studied. LA diameter (LAD), LV diastolic (LVD) and systolic (LVS) dimensions and mass (LVmass) and EF were measured. E and A wave velocities and E/A were measured. The primary end point was all cause mortality in group III patients. RESULTS: Groups did not differ in age, gender or EF. Group III patients had larger LAD (4.6+-1.0 cm) compared with both Group I (3.7+/-0.6) and Group II (3.7+/-0.5 cm) (p<0.0001). A markedly enlarged (arbitrarily defined as LAD higher or equal 5 cm) had an odds ratio of 34 (95% CI 8-144) in distinguishing HF patients from normals. After a mean follow-up period of 29+/-27 months, 40 patients (21.9%) died. In Cox univariate analysis, NYHA class (HR 2.8 95% C.I. 1.8-4.3; p<0.0001), diastolic blood pressure (DBP) (HR 0.92 95% C.I. 0.88-0.96; p<0.0001), age (HR 1.059 95% C.I. 1.01-1.11; p=0.02) and LAD (HR 1.72 95% C.I. 1.27-2.3; p=0.0005) were predictors of mortality. LAD predicted survival independently of other variables. CONCLUSION: The left atrium is frequently dilated in HF patients compared with controls despite similar EF. LAD showed powerful prognostic value independent of clinical variables.

Aortic distensibility independently affects exercise tolerance in patients with dilated cardiomyopathy.

BACKGROUND: Peak exercise oxygen consumption (VO2) is crucial for the prognostic stratification of patients with congestive heart failure, but its hemodynamic determinants are still not completely understood. Aortic wall elasticity modulates left ventricular function and coronary blood flow. Whether an increased aortic pulse-wave velocity (PWV), a known marker of arterial stiffness, may predict peak VO2 in patients with dilated cardiomyopathy (DCM) has to be clarified. METHODS AND RESULTS: A total of 78 patients with clinical diagnosis of DCM (aged 62+/-11 years; female 29%; mean ejection fraction 34+/-9%) were selected. All patients underwent a complete echocardiographic-Doppler evaluation. Aortic PWV was measured by Doppler ultrasonography immediately before the exercise. A bicycle exercise test with expiratory gas exchange monitoring was performed to determine VO2 . Plasma concentration of the amino-terminal propeptide of type III procollagen (PIIINP), a marker of extracellular matrix turnover, was determined. Mean PWV was 5.7+/-2.2 m/s, and VO2 was 16.5+/-4.5 mL x kg(-1) x min(-1). The hemodynamic variables correlated with VO2 were PWV (r=-0.39, P=0.0007) and stroke volume (r=0.38, P=0.002). In a multivariate analysis, PWV (P=0.04) and stroke volume (P=0.05) were independently correlated with VO2 , accounting for 34% of its variance. PIIINP levels correlated with PWV (r=0.35, P=0.002) and a more restrictive diastolic filling pattern (r=0.40, P=0.02). CONCLUSIONS: Increased aortic stiffness measured by PWV is an independent predictor of peak VO2 and could partially explain exercise intolerance in patients with DCM.

Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy.

OBJECTIVES: We aimed to investigate the determinants of left atrial (LA) volume and its prognostic value in patients with dilated cardiomyopathy (DCM). BACKGROUND: Enlargement of the LA is a marker of mortality in the general population. Patients with DCM are characterized by a wide range of LA sizes, but the clinical role of this observation has been played down. METHODS: A complete echocardiographic Doppler examination was performed in 337 patients (age 60 +/- 13 years; 84% male) with the diagnosis of DCM. Left atrial maximal volume (LA(max)) was measured at left ventricular (LV) end systole (four-chamber view; area-length method). Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) and ejection fraction (EF) were also measured. Mitral regurgitation (MR) was graded using a 5-point scale. Mitral E-wave (E) and A-wave (A) velocities, as well as their ratio (E/A), were measured off-line. RESULTS: Determinants of LA(max) were: atrial fibrillation (r = 0.34, p < 0.0001), LVEDV (r = 0.46, p < 0.0001), EF (r = 0.40, p < 0.0001), MR (r = 0.39, p < 0.0001), and E/A ratio (r = 0.36, p < 0.0001). During follow-up (41 +/- 29 months), 77 patients died and 12 underwent heart transplantation. Univariate Cox analysis showed that LA(max) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.007-1.013, p < 0.0001), LVESV (HR 1.003, CI 1.001-1.005, p = 0.0003), E/A ratio (HR 1.6, CI 1.3-2.005, p < 0.0001), and MR (HR 1.21, CI 1.03-1.44, p = 0.02) were related to the outcome. On bivariate Cox analysis, LA(max) predicted the prognosis independently of each determinant. Patients with a larger LA volume (LA(max)/m(2) >68.5 ml/m(2)) had a risk ratio of 3.8 compared with those with a smaller LA volume. CONCLUSIONS: In patients with DCM, LA volume is associated with LV remodeling, diastolic dysfunction, and the degree of MR. The maximal volume of the LA has an independent and incremental prognostic value, compared with all its determinants.

Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure.

OBJECTIVES: This study was designed to assess the effects of spironolactone (SP) on left ventricular (LV) function and exercise tolerance in patients with chronic heart failure (CHF). BACKGROUND: In severe heart failure (HF), SP improves survival, but the underlying mechanisms are not clear. METHODS: We randomized 106 outpatients with HF to SP (12.5 to 50 mg/day) (group 1) or control (group 2). Complete echocardiography and cardiopulmonary exercise testing were performed at baseline and 12 months after randomization. RESULTS: Left ventricular end-systolic volume at baseline and at follow-up was 188 +/- 94 ml and 171 +/- 97 ml in group 1 and 173 +/- 71 ml and 168 +/- 79 ml in group 2 (treatment group-by-time interaction, p = 0.03). Left ventricular ejection fraction at baseline and at follow-up was 33 +/- 7% and 36 +/- 9% in group 1 and 34 +/- 7% and 34 +/- 9% in group 2 (treatment group-by-time interaction, p = 0.02). At baseline, 9 patients in group 1 and 3 patients in group 2 had a restrictive mitral filling pattern, a marker of severe diastolic dysfunction; at follow-up, 3 patients in group 1 and no patient in group 2 improved their pattern. No patient in group 1 and 4 patients in group 2 worsened their pattern (chi-square, p = 0.02). Peak oxygen consumption increased significantly in patients treated with 50 mg of SP and decreased in group 2 (17.7 +/- 5.2 vs. 18.5 +/- 5.9 and 19.1 +/- 5.6 vs. 17.9 +/- 5.3, respectively; analysis of variance, p = 0.01). CONCLUSIONS: Spironolactone improves LV volumes and function; furthermore, it improves exercise tolerance at the highest administered dose. Our data might explain the mortality reduction during aldosterone antagonism in patients with HF.

Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials.

OBJECTIVES: We sought to compare, through a meta-analytic process, the transradial and transfemoral approaches for coronary procedures in terms of clinical and procedural outcomes. BACKGROUND: The radial approach has been increasingly used as an alternative to femoral access. Several trials have compared these two approaches, with inconclusive results. METHODS: The MEDLINE, CENTRAL, and conference proceedings from major cardiologic associations were searched. Random-effect odds ratios (ORs) for failure of the procedure (crossover to different entry site or impossibility to perform the planned procedure), entry site complications (major hematoma, vascular surgery, or arteriovenous fistula), and major adverse cardiovascular events (MACE), defined as death, myocardial infarction, emergency revascularization, or stroke, were computed. RESULTS: Twelve randomized trials (n = 3,224) were included in the analysis. The risk of MACE was similar for the radial versus femoral approach (OR 0.92, 95% confidence interval [CI] 0.57 to 1.48; p = 0.7). Instead, radial access was associated with a significantly lower rate of entry site complications (OR 0.20, 95% CI 0.09 to 0.42; p < 0.0001), even if at the price of a higher rate of procedural failure (OR 3.30, 95% CI 1.63 to 6.71; p < 0.001). CONCLUSIONS: The radial approach for coronary procedures appears as a safe alternative to femoral access. Moreover, radial access virtually eliminates local vascular complications, thanks to a time-sparing hemostasis technique. However, gaining radial access requires higher technical skills, thus yielding an overall lower success rate. Nonetheless, a clear ongoing trend toward equalization of the two procedures, in terms of procedural success, is evident through the years, probably due to technologic progress of materials and increased operator experience.

Ischemic etiology of heart failure identifies patients with more severely impaired exercise capacity.

BACKGROUND: Peak oxygen uptake (peak VO2) and the regression slope of ventilation against CO2 production during exercise (VE/VCO2 slope) are powerful prognostic indicators in patients with chronic heart failure (CHF). Our purpose was to evaluate the influence of CHF etiology on peak VO2 and VE/VCO2 slope, independently of demographic, clinical, Doppler-echocardiographic and neurohormonal factors. METHODS: Data were collected from 239 CHF patients referred for a cardiopulmonary exercise test as part of their clinical evaluation. Patients were stratified according to their CHF etiology (ischemic versus non-ischemic). RESULTS: The etiology of heart failure was ischemic in 143 patients (60%) and non-ischemic in 96 (40%). Patients with ischemic etiology, compared with those with non-ischemic etiology, showed a lower peak VO2 (15.4+/-4.2 versus 17.8+/-4.8 ml/kg/min, p<0.0001) and a steeper VE/VCO2 slope (38.1+/-6.8 versus 34+/-5.3, p<0.0001). In the univariate model, age (r=-0.36, p<0.0001), female sex (r=-0.21, p=0.001), ischemic CHF etiology (r=-0.26, p<0.0001) and NYHA class (r=-0.52, p<0.0001) correlated with peak VO2. At multivariate analysis, ischemic CHF etiology (beta=-0.23, p=0.001) was a predictor of peak VO2 (R(2)=0.49) independently of age (beta=-0.23, p=0.001), female sex (beta=-0.25, p=0.0006) and NYHA class (beta=-0.31, p<0.0001). Similarly, ischemic etiology (beta=0.29, p=0.001) predicted the VE/VCO2 slope (R(2)=0.38) independently of E/A ratio (beta=0.27, p=0.01) and resting heart rate (beta=0.22, p=0.01). CONCLUSIONS: Etiology of heart failure may influence the functional capacity and the ventilatory response to exercise.

Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure.

BACKGROUND: Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype. METHODS: We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months. Genotype for the insertion/deletion polymorphism of the ACE gene was determined by polymerase chain reaction. An echocardiographic examination was performed at baseline and at the end of the 12 months. RESULTS: The mean (+/- SD) age of the 93 patients was 62 +/- 9 years, and the mean New York Heart Association class was 2 +/- 1. The genotype was DD in 26 patients (28%). Forty-seven patients were assigned to spironolactone treatment (mean dose, 32 +/- 16 mg). In the treated group, only patients with a non-DD genotype showed significant improvement in left ventricular ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to 4.8%; P = 0.002), end-systolic volume (-23 mL; 95% CI: -36 to -11; P = 0.0005), and end-diastolic volume (-27 mL; 95% CI: -43 to -12; P = 0.001). In the multivariate analysis, the estimated net effect of treatment was 29 mL better (95% CI: -20 to 78 mL) for end-diastolic volume, 20 mL better (95% CI: -18 to 58 mL) for end-systolic volume, but 1.4% worse (95% CI: -3.4% to 6.2%) for left ventricular ejection fraction in patients with non-DD versus DD genotypes. CONCLUSION: The effects of spironolactone treatment on left ventricular systolic function and remodeling may in part depend on ACE genotype.

Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy.

OBJECTIVE: To assess whether serum uric acid, which is a marker of impaired oxidative metabolism, might correlate with left ventricular systolic and diastolic dysfunction in patients with chronic heart failure (CHF). BACKGROUND: Uric acid levels, which are frequently elevated in patients with CHF, correlate with leg vascular resistance. The effects of elevated levels of uric acid on cardiac function in patients with CHF have never been evaluated. METHODS: We studied 150 outpatients with CHF who came to our heart failure clinic. Patients underwent a complete echo-Doppler examination, with measurement of mitral E wave and mitral A wave velocities, E/A ratio, E wave deceleration time (DtE), left ventricular volumes, ejection fraction, and stroke volume. A restrictive mitral filling pattern (RMFP) was defined as either E/A ratio >2 or E/A >1 and DtE <140 milliseconds. RESULTS: Mean age was 62.2 +/- 7.8 years (86% male); 24 patients (16%) had an RMFP. Patients with an RMFP had significantly higher uric acid levels compared with patients without RMFP (0.48 +/- 0.14 mmol/L vs 0.38 +/- 0.08 mmol/L, respectively, P <.001). Uric acid levels correlated significantly with mitral E wave velocity (r =.22, P <.01), E/A ratio (r =.21, P <.05), DtE (r =.26, P <.01), and RMFP (P =.0001). There was no correlation between uric acid and left ventricular volumes, ejection fraction, or stroke volume. In a multivariate model, uric acid predicted DtE independently of renal function, diuretic dose, and left ventricular volumes. CONCLUSION: Elevated uric acid levels are associated with diastolic dysfunction in CHF. Xanthine oxydase inhibition in patients with CHF might theoretically result in an improvement of diastolic function.

Feasibility and safety of transeophageal atrial pacing stress echocardiography in patients with known or suspected coronary artery disease.

To investigate the feasibility and safety of the transesophageal atrial pacing stress test combined with echocardiography (TAPSE) 1,727 TAPSE tests were performed on 1,641 patients consecutively referred to our echocardiographic laboratory for nonexercise stress testing (1,319 men; mean age 60 +/- 9 years; 34% of whom were outpatients). Wall motion abnormalities were present at baseline echocardiography in 975 cases (56%). TAPSE was feasible in 1,648 cases (95.4%). It was not feasible in 79 patients due to failure of positioning the transnasal catheter (n=11), the patient's intolerance of esophageal stimulation (n=24), failure to obtain any or stable atrial capture (n=36), or because the echocardiogram could not be evaluated at the peak of the test (n=8). TAPSE was diagnostic in 1,584 cases (96% of the feasible tests, 92% of all attempts). TAPSE was nondiagnostic in 64 cases (4% of the feasible tests) due to second-degree atrioventricular type I block resistance to atropine administration with failure to achieve 85% of the age-predicted maximum heart rate (n=59) or due to side effects, such as arrhythmias (n=3) or hypertension (n=2), which required premature interruption of the test. There were no major complications (death, myocardial infarction, or life-threatening arrhythmias). There were 28 instances of minor complications that comprised transient arrhythmias, including atrial fibrillation (n=8), paroxysmal supraventricular tachycardia (n=6), automatic atrial tachycardia (n=1), sinus arrest (n=1), atrioventricular junctional rhythm (n=2), ectopic atrial rhythm (n=2), nonsustained ventricular tachycardia (maximum 6 beats, n=3), hypotension (n=1), and hypertension (n=4) leading to interruption of the test. Only 5 complications hampered a diagnostic result, whereas 18 occurred during or after a positive test and 5 during a negative, but diagnostic, test. Thus, TAPSE is a highly feasible and very safe stress test. It gives high percentage of diagnostic tests and may represent a valid alternative to pharmacologic stressors.

Relation of aldosterone "escape" despite angiotensin-converting enzyme inhibitor administration to impaired exercise capacity in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

In patients with chronic congestive heart failure (CHF), aldosterone production may occur despite the administration of angiotensin-converting enzyme (ACE) inhibitors. This phenomenon has been termed aldosterone "escape"; its relation to the severity of the disease is unknown. We sought to assess whether aldosterone escape might be related to disease severity or functional impairment in patients with CHF. One hundred forty-one consecutive patients with CHF who received ACE inhibitors (> 6 months) underwent an evaluation of neurohormonal activation and body composition, an echo-Doppler examination, and a cardiopulmonary exercise test. Aldosterone escape was defined as plasma levels of aldosterone above the normal range in our laboratory (> 0.42 nmol/L). Fourteen patients (10%) had aldosterone escape. There were no differences between patients with and without aldosterone escape with regard to age, New York Heart Association class, neurohormonal activation, ACE inhibitor dose, hemodynamics, or skeletal muscle bulk. In contrast, mean peak oxygen consumption (14.2 +/- 3.5 vs 17.3 +/- 4.9 ml/min/kg, p < 0.05) and the slope of the relation between ventilation and carbon dioxide production (41 +/- 7 vs 36 +/- 6, p <0.05) were significantly worse in patients with aldosterone escape compared with those without it. Thus, aldosterone escape is associated with reduced exercise capacity in patients with CHF. This factor does not seem to be linked with hemodynamic mechanisms or with a reduced skeletal muscle bulk.

Selection of endpoints for heart failure clinical trials.

In assessing the efficacy and the safety of a new drug, randomized clinical trials represent the standard scientific method. The selection of the best response variables in a clinical trial of a treatment in congestive heart failure patients is often not straightforward; the primary end point of a trial should be clinically relevant, directly related to the primary goal of the trial, and with favorable distributional properties. All-cause mortality is undoubtedly the most unbiased endpoint, but there is interest both in assessing cause-specific mortality and hospitalization rate and in evaluating 'soft' endpoints (functional status, exercise tolerance); the latter, in fact, are clinically relevant and potentially more useful in mild heart failure patients. Physiopathologic variables (e.g. left ventricular function) could provide information on drug action mechanism. In this paper, several recent large clinical trials are reviewed and the advantages and drawbacks of the response variables used, are analyzed.

Can left ventricular diastolic stiffness be measured noninvasively?

BACKGROUND: A noninvasive estimation of left ventricular (LV) diastolic chamber stiffness (K(LV)) is still a challenge. Experimental data suggests that K(lv) can be obtained by using Doppler mitral flow deceleration time (DT) as the only variable: K(lv) = (70/[DT-20])(2) mm Hg/mL. We assessed the accuracy of this noninvasive estimate of K(lv) by comparing it with invasive measurement of K(lv) in intact patients with a wide range of LV size and function under varying loading conditions. METHODS: Twenty-five patients (age 54 +/- 12 years) with ischemic heart disease (n = 19) or primary LV dysfunction (n = 6), with a wide range of DT (79-324 ms) and ejection fraction (8%-57%), underwent simultaneous assessment of LV pressure by micromanometer and volume by 2-dimensional (2D) echocardiography-guided Doppler mitral flow velocity (where volume = mitral flow velocity integral x annular area) calibrated to 2D echocardiography stroke volume. Invasive K(lv) [delta pressure (from minimum to end-diastolic)/delta volume (during the same time interval)] was obtained at baseline and in 23 patients after LV unloading by prostaglandin E(1) (30-60 ng/kg/min) (n = 12), nitroglycerin (0.2 mg) (n = 9) or magnesium (1 g) (n = 2). Noninvasive K(lv) was estimated according to the above formula. RESULTS: In this set of patients with normal mitral annular area (3.9 +/- 1.1 cm(2)/m(2)), multivariate analysis showed that DT is inversely related to K(lv) (P <.001) but not to left atrial chamber stiffness, LV volume, relaxation time constant, mitral valve opening pressure, or area. The relation between noninvasively calculated and directly measured K(lv) was close to the line of identity under all conditions, (y = 0.93x + 0.05, r = 0.67, n = 48, P <.001), although with a wide standard error of the estimate (0.26 mm Hg/mL). CONCLUSION: We conclude that K(lv) can be calculated +/- 0.5 mm Hg/mL from noninvasively measured DT in patients.

Myocardial viability independently influences left ventricular diastolic function in the early phase after acute myocardial infarction.

BACKGROUND: After acute myocardial infarction, a broad range of left ventricular (LV) end-diastolic pressure (LVEDP) is expected because of chamber remodeling. However, intrinsic characteristics of the infarcted tissue (necrosis or viability) may also play a role. We aimed to evaluate whether myocardial viability (Mviab) has an influence on LVEDP. METHODS: One hundred twenty-three consecutive patients with acute myocardial infarction underwent low-dose dobutamine echocardiography (5-10 microg/kg/min) to assess Mviab. Mviab was quantitatively evaluated by the variation of Delta wall motion score index. Patients underwent left heart catheterization with recording of LVEDP and a complete echocardiographic examination with measurement of LV volumes, ejection fraction, and mass. RESULTS: The overall population (81% male; mean age 58 +/- 10 years) was divided into 2 groups according to the presence (group 1; 66 patients) or absence (group 2; 57 patients) of Mviab. LVEDP was higher in patients without Mviab (16 +/- 8 vs 20 +/- 7 mm Hg; P =.02). The multivariate analysis showed that Delta wall motion score index correlated with LVEDP (P =.01) independent of wall motion score index and LV end-systolic volume. CONCLUSIONS: After acute myocardial infarction, LVEDP shows wide variability and is independently associated with Mviab.

Is vasopressin superior to adrenaline or placebo in the management of cardiac arrest? A meta-analysis.

Vasopressin is currently recommended in the management of patients with cardiac arrest, but its efficacy is still incompletely established. We systematically reviewed randomized trials comparing vasopressin to control treatment in the management of cardiac arrest in humans and animals. Two human and 33 animal studies were retrieved. At pooled analysis vasopressin appeared equivalent to adrenaline (epinephrine) in the management of human cardiac arrest (N=240), with, respectively 63 (78/124) vs 59% (68/116) ROSC (P=0.43), and 16 (20/124) vs 14% (16/116) survival to hospital discharge (P=0.52). In animal trials (N=669) vasopressin appeared instead significantly superior to both placebo (ROSC, respectively 93 [98/105] vs 19% [14/72], P<0.001) or adrenaline (ROSC, respectively 84 [225/268] vs 52% [117/224], P<0.001). In conclusion, vasopressin is superior to both placebo or adrenaline in animal models of cardiopulmonary resuscitation. Evidence in humans is still limited and confidence intervals estimates too wide to reliably confirm or disprove results obtained in experimental animal settings.

The role of angiotensin-converting enzyme polymorphism in congestive heart failure.

Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase, with primary known functions of converting angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II and inactivating bradykinin. There is high variability among individuals in ACE concentrations, mainly due to the presence of a genetic polymorphism. The ACE gene has, in fact, insertion/deletion polymorphism in intron 16, consisting of a 287-base pair Alu repeat sequence, with three genotypes: insertion polymorphism, insertion/deletion polymorphism, and deletion polymorphism. The genetic effect accounts for 47% of the total variance of serum ACE. The determination of this polymorphism has allowed researchers to study the implications of the ACE gene in many case-control studies of cardiovascular disease, including myocardial infarction and hypertrophic and dilated cardiomyopathy. We review the current knowledge about the ACE gene polymorphism and its implications in heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Interpretation of the results of studies about the role of this polymorphism are controversial. The repetition of epidemio-genetic studies and the creation of adequate experimental studies will help to definitively establish the pathogenetic role of the permanent increase in ACE expression associated with the deletion polymorphism genotype.

Skeletal muscle abnormalities in chronic heart failure patients: relation to exercise capacity and therapeutic implications.

Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles.