Stefania Paolillo

Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials.

OBJECTIVES The objectives of this study were to verify whether improvement in 6-min walk distance (6MWD) is associated with clinical outcome in pulmonary arterial hypertension (PAH). BACKGROUND 6MWD is used as an endpoint to assess the benefit of therapies in PAH. However, whether changes in 6MWD correlate with clinical outcome is unknown. METHODS Randomized trials assessing 6MWD in patients with PAH and reporting clinical endpoints were included in a meta-analysis. The meta-analysis was performed to assess the influence of treatment on outcomes. Meta-regression analysis was performed to test the relationship between 6MWD changes and outcomes. RESULTS Twenty-two trials enrolling 3,112 participants were included. Active treatments led to significant reduction of all-cause death (odds ratio [OR]: 0.429; 95% confidence interval [CI]: 0.277 to 0.664; p < 0.01), hospitalization for PAH, and/or lung or heart-lung transplantation (OR: 0.442; 95% CI: 0.309 to 0.632; p < 0.01), initiation of PAH rescue therapy (OR: 0.555; 95% CI: 0.347 to 0.889; p = 0.01), and composite outcome (OR: 0.400; 95% CI: 0.313 to 0.510; p < 0.01). No relationship between 6MWD changes and outcomes was detected. CONCLUSIONS In patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes.

Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis.

OBJECTIVES The purpose of this paper was to assess whether statins reduce all-cause mortality and cardiovascular (CV) events in elderly people without established CV disease. BACKGROUND Because of population aging, prevention of CV disease in the elderly is relevant. In elderly patients with previous CV events, the use of statins is recommended by guidelines, whereas the benefits of these drugs in elderly subjects without previous CV events are still debated. METHODS Randomized trials comparing statins versus placebo and reporting all-cause and CV mortality, myocardial infarction (MI), stroke, and new cancer onset in elderly subjects (age ≥ 65 years) without established CV disease were included. RESULTS Eight trials enrolling 24,674 subjects (42.7% females; mean age 73.0 ± 2.9 years; mean follow up 3.5 ± 1.5 years) were included in analyses. Statins, compared with placebo, significantly reduced the risk of MI by 39.4% (relative risk [RR]: 0.606 [95% confidence interval (CI): 0.434 to 0.847]; p = 0.003) and the risk of stroke by 23.8% (RR: 0.762 [95% CI: 0.626 to 0.926]; p = 0.006). In contrast, the risk of all-cause death (RR: 0.941 [95% CI: 0.856 to 1.035]; p = 0.210) and of CV death (RR: 0.907 [95% CI: 0.686 to 1.199]; p = 0.493) were not significantly reduced. New cancer onset did not differ between statin- and placebo-treated subjects (RR: 0.989 [95% CI: 0.851 to 1.151]; p = 0.890). CONCLUSIONS In elderly subjects at high CV risk without established CV disease, statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term.

Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: A multiparametric approach to heart failure prognosis

OBJECTIVES We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables. BACKGROUND HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty. METHODS Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041days (range 4-5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant. RESULTS Six variables (hemoglobin, Na(+), kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754-0.852) at 1year, 0.789 (0.750-0.828) at 2years, 0.762 (0.726-0.799) at 3years and 0.760 (0.724-0.796) at 4years. CONCLUSIONS This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC.

Calcium channel blockers and cardiovascular outcomes: a meta-analysis of 175 634 patients

Objective The aim of this study was to assess the effect of calcium channel blocker (CCB) treatment, compared with other drugs or placebo/top of therapy, on all-cause mortality, cardiovascular death, major cardiovascular events, heart failure, myocardial infarction and stroke. Methods We performed a meta-analysis of randomized controlled trials that compared a long-acting calcium channel blocker with another drug or placebo/top of therapy and that assessed all-cause mortality and cardiovascular events. Results We included 27 trials (175 634 patients). The risk of all-cause death was reduced by dihydropyridine CCBs [odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93–0.99; comparison P = 0.026; heterogeneity P = 0.87)] without influence of placebo trials. The risk of heart failure was increased by CCBs compared with active treatment (OR 1.17; 95% CI 1.11–1.24; comparison P = 0.0001; heterogeneity P = 0.0001), and it was decreased when compared with placebo (OR 0.72; 95% CI 0.59–0.87; comparison P = 0.001; heterogeneity P = 0.77), also in the subgroup of coronary artery disease patients (OR 0.76; 95% CI 0.61–0.95; comparison P = 0.01; heterogeneity P = 0.29). CCBs did not increase the risk of myocardial infarction (OR 1; 95% CI 0.95–1.04; comparison P = 0.83, heterogeneity P = 0.004), cardiovascular death (OR 0.97; 95% CI 0.93–1.02; comparison P = 0.24; heterogeneity P = 0.16), major cardiovascular events (OR 0.97; 95% CI 0.90–1.06; comparison P = 0.53; heterogeneity P = 0.0001). CCBs decreased the risk of fatal or nonfatal stroke (OR 0.86; 95% CI 0.82–0.90; comparison P = 0.0001, heterogeneity P = 0.12), also, when compared with angiotensin-converting enzyme inhibitors (OR 0.87; 95% CI 0.78–0.97; comparison P = 0.016; heterogeneity P = 0.48). Conclusion Our study demonstrates that CCBs reduce the risk of all-cause mortality compared with active therapy and prevent heart failure compared with placebo. Furthermore, with the inclusion of recent trials, we confirm that they reduce the risk of stroke, also in comparison to angiotensin-converting enzyme inhibitors and do not increase the risk of cardiovascular death, myocardial infarction and major cardiovascular events.

Impact of Diabetes on Cardiac Sympathetic Innervation in Patients With Heart Failure: A 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study

OBJECTIVE Impaired parasympathetic and sympathetic nervous system activity have been demonstrated in patients with diabetes mellitus (DM) and correlated with worse prognosis. Few data are available on the effect of DM on cardiac neuropathy in heart failure (HF). The aim of the current study was to assess cardiac sympathetic activity in HF patients with and without DM. RESEARCH DESIGN AND METHODS Patients with severe HF (n = 75), with (n = 37) and without DM (n = 38), and 14 diabetic patients with normal cardiac function underwent 123I meta-iodobenzylguanidine scintigraphy from which early and late heart-to-mediastinum (H/M) ratios were calculated. Clinical, echocardiographic, and biochemical data were measured. RESULTS DM compared with non-DM patients showed significantly lower early (1.65 ± 0.21 vs. 1.75 ± 0.21; P < 0.05) and late H/M ratios (1.46 ± 0.22 vs. 1.58 ± 0.24; P < 0.03). Early and late H/M were significantly higher in DM patients without HF (2.22 ± 0.35 and 1.99 ± 0.24, respectively) than HF patients with (P < 0.0001) and without (P < 0.0001) DM. In HF patients, an inverse correlation between early or late H/M ratio and hemoglobin A1c (HbA1c) (Pearson = −0.473, P = 0.001; Pearson = −0.382, P = 0.001, respectively) was observed. In DM, in multivariate analysis, HbA1c and ejection fraction remained significant predictors of early H/M; HbA1c remained the only significant predictor of late H/M. No correlation between early or late H/M and HbA1c was found in non-DM patients. CONCLUSIONS Diabetic patients with HF show lower cardiac sympathetic activity than HF patients not having DM or than DM patients with a similar degree of autonomic dysfunction not having HF. HbA1c correlated with the degree of reduction in cardiac sympathetic activity.

The Prognostic Value of Normal Stress Cardiac Magnetic Resonance in Patients with Known or Suspected Coronary Artery Disease: A Meta-analysis

Background—Ischemia detection with stress cardiac magnetic resonance (CMR) is typically based on induction of either myocardial perfusion defect or wall motion abnormality. Single-center studies have shown the high value of stress CMR for risk stratification. The aim of this study was to define the prognostic value of stress CMR for prediction of adverse cardiac events in patients with known or suspected coronary artery disease. Methods and Results—Studies published between January 1985 and April 2012 were identified by database search. We included studies using stress CMR to evaluate subjects with known or suspected coronary artery disease and providing primary data on clinical outcomes of nonfatal myocardial infarction or cardiac death with a follow-up time ≥3 months. Total of 14 studies were finally included, recruiting 12 178 patients. The negative predictive value for nonfatal myocardial infarction and cardiac death of normal CMR was 98.12% (95% confidence interval, 97.26–98.83) during a weighted mean follow-up of 25.3 months, resulting in estimated event rate after a negative test equal to 1.88% (95% confidence interval, 1.17–2.74). The corresponding annualized event rate after a negative test was 1.03%. Comparable negative predictive values for major coronary events were obtained in studies considering the absence of inducible perfusion defect compared with those evaluating the absence of inducible wall motion abnormality (98.39% versus 97.31%, respectively; P=0.227 by meta-regression analysis). Conclusions—Stress CMR has a high negative predictive value for adverse cardiac events, and the absence of inducible perfusion defect or wall motion abnormality shows a similar ability to identify low-risk patients with known or suspected coronary artery disease.

Exercise testing in the clinical management of patients affected by pulmonary arterial hypertension.

Patients affected by pulmonary arterial hypertension (PAH) show a reduced exercise tolerance with early occurrence of dyspnoea and fatigue. The origin of functional capacity limitation is multifactorial and several mechanisms have been proposed, including right heart failure, which leads to a limited increase in cardiac output during exercise, and hyperventilation with a reduced perfusion of properly ventilated alveoli. In addition, abnormalities in arterial blood gases are observed, with the occurrence of hypoxemia and hypocapnia, related to an abnormal ventilation/perfusion match, gas diffusion abnormalities, low mixed venous oxygen saturation and to the development of intra- and extra-pulmonary right-to-left shunts. At present, the 6-minute walking test is the most used method to assess exercise tolerance in PAH; it is also useful to monitor the response to therapy and provides prognostic information. However, the assessment of functional capacity by cardiopulmonary exercise test (CPET) seems to be more complete, because CPET allows for discrimination between the metabolic, cardiovascular and pulmonary components of exercise limitation. Moreover, CPET estimates the severity of disease and assesses patients’ prognosis and response to therapy. In PAH, a typical CPET-response is observed, characterized by a severe reduction in peak VO2, work rate, O2 pulse and anaerobic threshold and by a marked increase in VE/VCO2 slope and in the dead space to tidal volume ratio. However, the use of CPET should be limited to experienced centres. This review will focus on resting lung function and exercise tolerance tests, showing that CPET can provide the physiological explanation of functional limitation in PAH.

Exercise tolerance can explain the obesity paradox in patients with systolic heart failure: Data from the MECKI Score Research Group

AIMS Obesity has been found to be protective in heart failure (HF), a finding leading to the concept of an obesity paradox. We hypothesized that a preserved cardiorespiratory fitness in obese HF patients may affect the relationship between survival and body mass index (BMI) and explain the obesity paradox in HF. METHODS AND RESULTS A total of 4623 systolic HF patients (LVEF 31.5 ± 9.5%, BMI 26.2 ± 3.6 kg/m(2) ) were recruited and prospectively followed in 24 Italian HF centres belonging to the MECKI Score Research Group. Besides full clinical examination, patients underwent maximal cardiopulmonary exercise test at study enrolment. Median follow-up was 1113 (553-1803) days. The study population was divided according to BMI (<25, 25-30, >30 to ≤35 kg/m(2) ) and predicted peak oxygen consumption (peak VO2 , <50%, 50-80%, >80%). Study endpoints were all-cause and cardiovascular deaths including urgent cardiac transplant. All-cause and cardiovascular deaths occurred in 951 (28.6%, 57.4 per person-years) and 802 cases (17.4%, 48.4 per 1000 person-years), respectively. In the high BMI groups, several prognostic parameters presented better values [LVEF, peak VO2 , ventilation/carbon dioxide slope, renal function, and haemoglobin (P < 0.01)] compared with the lower BMI groups. Both BMI and peak VO2 were significant positive predictors of longer survival: both higher BMI and peak VO2 groups showed lower mortality (P < 0.001). At multivariable analysis and using a matching procedure (age, gender, LVEF, and peak VO2 ), the protective role of BMI disappeared. CONCLUSION Exercise tolerance affects the relationship between BMI and survival. Cardiorespiratory fitness mitigates the obesity paradox observed in HF patients.

Prognostic Value of Indeterminable Anaerobic Threshold in Heart Failure

Background—In patients with heart failure (HF), during maximal cardiopulmonary exercise test, anaerobic threshold (AT) is not always identified. We evaluated whether this finding has a prognostic meaning. Methods and Results—We recruited and prospectively followed up, in 14 dedicated HF units, 3058 patients with systolic (left ventricular ejection fraction <40%) HF in stable clinical conditions, New York Heart Association class I to III, who underwent clinical, laboratory, echocardiographic, and cardiopulmonary exercise test investigations at study enrollment. We excluded 921 patients who did not perform a maximal exercise, based on lack of achievement of anaerobic metabolism (peak respiratory quotient ⩽1.05). Primary study end point was a composite of cardiovascular death and urgent cardiac transplant, and secondary end point was all-cause death. Median follow-up was 3.01 (1.39–4.98) years. AT was identified in 1935 out of 2137 patients (90.54%). At multivariable logistic analysis, failure in detecting AT resulted significantly in reduced peak oxygen uptake and higher metabolic exercise and cardiac and kidney index score value, a powerful prognostic composite HF index (P<0.001). At multivariable analysis, the following variables were significantly associated with primary study end point: peak oxygen uptake (% pred; P<0.001; hazard ratio [HR]=0.977; confidence interval [CI]=0.97–0.98), ventilatory efficiency slope (P=0.01; HR=1.02; CI=1.01–1.03), hemoglobin (P<0.05; HR=0.931; CI=0.87–1.00), left ventricular ejection fraction (P<0.001; HR=0.948; CI=0.94–0.96), renal function (modification of diet in renal disease; P<0.001; HR=0.990; CI=0.98–0.99), sodium (P<0.05; HR=0.967; CI=0.94–0.99), and AT nonidentification (P<0.05; HR=1.41; CI=1.06–1.89). Nonidentification of AT remained associated to prognosis also when compared with metabolic exercise and cardiac and kidney index score (P<0.01; HR=1.459; CI=1.09–1.10). Similar results were obtained for the secondary study end point. Conclusions—The inability to identify AT most often occurs in patients with severe HF, and it has an independent prognostic role in HF.

Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: A digital reactive hyperemia study

BACKGROUND To assess endothelial function (EF) in type 2 diabetic patients with angiographically normal coronaries compared to diabetic patients with obstructive coronary artery disease (CAD) and to non-diabetic patients, with and without CAD. METHODS One hundred eighty-three patients undergoing coronary angiography were divided in: group 1 with diabetes mellitus (DM) and CAD (n = 58); group 2 with DM without CAD (n = 58); group 3 with CAD without DM (n = 31) and group 4 without CAD and DM (n = 36). EF was assessed by reactive hyperemia index (RHI) using a fingertip peripheral arterial tonometry and compared to values obtained in 20 healthy volunteers. RESULTS RHI was significantly lower in patients with DM compared to patients without DM (1.69 ± 0.38 vs 1.84 ± 0.44; p = 0.019). RHI was comparable among groups 1, 2 and 3, each value being significantly lower compared to group 4 (2 ± 0.44; p<0.001 vs group 1; p<0.005 vs group 2; p<0.002 vs group 3). At multivariate analysis DM and CAD were significant predictors of endothelial dysfunction (ED) (OR = 2.29; p = 0.012; OR = 2.76; p = 0.001, respectively), whereas diabetic patients (n = 116) CAD and glycated haemoglobin (HbA1c) were independent significant predictors of ED (OR = 3.05; p = 0.009; OR = 1.96; p = 0.004, respectively). Diabetic patients with ED (n = 67) had higher levels of HbA1c than diabetic patients with normal endothelial function (7.35 ± 0.97 vs 6.87 ± 0.90; p = 0.008) and RHI inversely correlated to HbA1c (p = 0.02; r = -0.210). CONCLUSIONS Diabetic patients with and without CAD show significantly impaired peripheral vascular function compared to non-diabetic patients without CAD. ED in diabetic patients without CAD is comparable to that of patients with CAD but without DM. HbA1c is a weak independent predictor of ED.