Stefano Bonapace

Nonalcoholic Fatty Liver Disease Is Associated With Left Ventricular Diastolic Dysfunction in Patients With Type 2 Diabetes

OBJECTIVE Data on cardiac function in patients with nonalcoholic fatty liver disease (NAFLD) are limited and conflicting. We assessed whether NAFLD is associated with abnormalities in cardiac function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We studied 50 consecutive type 2 diabetic individuals without a history of ischemic heart disease, hepatic diseases, or excessive alcohol consumption, in whom NAFLD was diagnosed by ultrasonography. A tissue Doppler echocardiography with myocardial strain measurement was performed in all patients. RESULTS Thirty-two patients (64%) had NAFLD, and when compared with the other 18 patients, age, sex, BMI, waist circumference, hypertension, smoking, diabetes duration, microvascular complication status, and medication use were not significantly different. In addition, the left ventricular (LV) mass and volumes, ejection fraction, systemic vascular resistance, arterial elasticity, and compliance were also not different. NAFLD patients had lower e′ (8.2 ± 1.5 vs. 9.9 ± 1.9 cm/s, P < 0.005) tissue velocity, higher E-to-e′ ratio (7.90 ± 1.3 vs. 5.59 ± 1.1, P < 0.0001), a higher time constant of isovolumic relaxation (43.1 ± 10.1 vs. 33.2 ± 12.9 ms, P < 0.01), higher LV–end diastolic pressure (EDP) (16.5 ± 1.1 vs. 15.1 ± 1.0 mmHg, P < 0.0001), and higher LV EDP/end diastolic volume (0.20 ± 0.03 vs. 0.18 ± 0.02 mmHg, P < 0.05) than those without steatosis. Among the measurements of LV global longitudinal strain and strain rate, those with NAFLD also had higher E/global longitudinal diastolic strain rate during the early phase of diastole (E/SRE). All of these differences remained significant after adjustment for hypertension and other cardiometabolic risk factors. CONCLUSIONS Our data show that in patients with type 2 diabetes and NAFLD, even if the LV morphology and systolic function are preserved, early features of LV diastolic dysfunction may be detected.

Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health problem of epidemic proportions worldwide. Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease (CHD), abnormalities of cardiac function and structure (e.g., left ventricular dysfunction and hypertrophy, and heart failure), valvular heart disease (e.g., aortic valve sclerosis) and arrhythmias (e.g., atrial fibrillation). Experimental evidence suggests that NAFLD itself, especially in its more severe forms, exacerbates systemic/hepatic insulin resistance, causes atherogenic dyslipidemia, and releases a variety of pro-inflammatory, pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications. Collectively, these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications. The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular, cardiac and arrhythmic complications, to briefly examine the putative biological mechanisms underlying this association, and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.

Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes

Background The relationship between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) in type 2 diabetes is currently unknown. We examined the relationship between NAFLD and risk of incident AF in people with type 2 diabetes. Methods and Results We prospectively followed for 10 years a random sample of 400 patients with type 2 diabetes, who were free from AF at baseline. A standard 12-lead electrocardiogram was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. At baseline, NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases. During the 10 years of follow-up, there were 42 (10.5%) incident AF cases. NAFLD was associated with an increased risk of incident AF (odds ratio [OR] 4.49, 95% CI 1.6–12.9, p<0.005). Adjustments for age, sex, hypertension and electrocardiographic features (left ventricular hypertrophy and PR interval) did not attenuate the association between NAFLD and incident AF (adjusted-OR 6.38, 95% CI 1.7–24.2, p = 0.005). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Other independent predictors of AF were older age, longer PR interval and left ventricular hypertrophy. Conclusions Our results indicate that ultrasound-diagnosed NAFLD is strongly associated with an increased incidence of AF in patients with type 2 diabetes even after adjustment for important clinical risk factors for AF.

Prognostic Relevance of Pulmonary Arterial Compliance in Patients With Chronic Heart Failure

BACKGROUND Reduced pulmonary arterial compliance (Ca) is a marker of poor prognosis in idiopathic pulmonary arterial hypertension. We tested the hypothesis that pulmonary arterial Ca could be a predictor of outcome in patients with chronic heart failure (CHF). METHODS We enrolled 306 patients with CHF due to systolic left ventricular dysfunction (sLVD) who underwent a clinically driven right-sided heart catheterization. Pulmonary arterial Ca was measured by the ratio between stroke volume and pulse pressure (SV/PP). The primary end point was cardiovascular death; secondary end point was the composite of cardiovascular death, urgent heart transplantation, and appropriately detected and treated episode of ventricular fibrillation. RESULTS An inverse relationship was observed between SV/PP and pulmonary vascular resistance, the mean resistance-compliance product (RC-time) being 0.30 ± 0.2 s. In patients with pulmonary capillary wedge pressure (PCWP) < 15 mm Hg, the mean RC-time was 0.34 ± 0.14 s, and in patients with PCWP ≥ 15 mm Hg it was 0.28 ± 0.22 s. Eighty-seven patients died in a follow-up period of 50 ± 32 months. At receiver operating characteristic curve analysis, the optimal prognostic cutoff point of SV/PP was 2.15 mL/mm Hg. An elevated (> 2.15) SV/PP was more strongly associated with survival than any other hemodynamic variable; it was associated with poor prognosis both in patients with high (P = .003) and in patients with normal pulmonary vascular resistance (P = .005). CONCLUSIONS Pulmonary arterial Ca is a strong prognostic indicator in patients with CHF with sLVD. Most importantly, its prognostic role is retained in patients with normal pulmonary vascular resistance.

Aortic Distensibility Independently Affects Exercise Tolerance in Patients With Dilated Cardiomyopathy

Background—Peak exercise oxygen consumption (&OV0312;o2) 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 &OV0312;o2 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 &OV0312;o2. 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 &OV0312;o2 was 16.5±4.5 mL · kg−1 · min−1. The hemodynamic variables correlated with &OV0312;o2 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 &OV0312;o2, 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 &OV0312;o2 and could partially explain exercise intolerance in patients with DCM.

Aortic and Mitral Annular Calcifications Are Predictive of All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes

OBJECTIVE To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals. RESEARCH DESIGN AND METHODS We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992–2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality. RESULTS At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1–4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9–17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality. CONCLUSIONS Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.

Relation of Elevated Serum Uric Acid Levels to Incidence of Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus

The association between serum uric acid (SUA) levels and atrial fibrillation (AF) is currently poorly known. We examined the association between SUA levels and risk of incident AF in patients with type 2 diabetes mellitus. We followed for 10 years a random sample of 400 type 2 diabetic outpatients, who were free from AF at baseline. A standard 12-lead electrocardiography was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. Over 10 years, there were 42 incident AF cases (cumulative incidence of 10.5%). Elevated SUA level was associated with an increased risk of incident AF (odds ratio 2.43, 95% confidence interval 1.8 to 3.4, p <0.0001 for each 1-SD increase in SUA level). Adjustments for age, gender, body mass index, hypertension, chronic kidney disease, electrocardiographic features (left ventricular hypertrophy and PR interval), and use of diuretics and allopurinol did not attenuate the association between SUA and incident AF (adjusted odds ratio 2.44, 95% confidence interval 1.6 to 3.9, p <0.0001). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Results remained unchanged even when SUA was modeled as a categorical variable (stratifying by either SUA median or hyperuricemia), and when patients with previous coronary heart disease or heart failure were excluded from analysis. In conclusion, our findings suggest that elevated SUA levels are strongly associated with an increased incidence of AF in patients with type 2 diabetes mellitus even after adjustment for multiple clinical risk factors for AF.

Left Atrial Volume Provides Independent and Incremental Information Compared With Exercise Tolerance Parameters in Patients With Heart Failure and Left Ventricular Systolic Dysfunction

Objective: Left atrial volume (LAV) is a powerful predictor of outcome in patients with chronic heart failure (CHF) independently of symptomatic status, age and left ventricular (LV) function. It is unknown whether LAV provides independent and incremental information compared with exercise tolerance parameters. Methods: 273 patients with CHF (mean (SD) 62 (9) years; 13% female) prospectively underwent echocardiography and exercise testing with maximal oxygen consumption (Vo2). The primary end point was composite and included cardiac death, hospitalisation for worsening heart failure or cardiac transplantation. Results: At Cox proportional hazard analysis, LAV normalised for body surface area (LAV/BSA) was strongly associated with mortality (hazard ratio (HR) = 1.027 (95% CI 1.018 to 1.04), p<0.001). The predictive value of LAV/BSA was independent of Vo2 and LV ejection fraction (EF) (HR = 1.014 (1.002 to 1.025), p = 0.02; HR = 0.95 (0.91 to 0.99), p = 0.02; HR = 0.89 (0.82 to 0.98), p = 0.02 for LAV/BSA, EF and Vo2, respectively). Receiver operator characteristic (ROC) curve analysis identified the best cut-off values for prediction of the end point. LAV/BSA >63 ml, EF <30% and Vo2 <16 ml/kg/min were considered to be risk factors. Patients with three risk factors had an HR of 38 (95% CI 11 to 129) compared with patients with no risk factors. Conclusion: LAV provides powerful prognostic information incrementally and independently of Vo2. LAV, EF and Vo2 can be used to build a risk prediction model, which can be used clinically.

Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease

PURPOSE Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are two powerful predictors of adverse cardiovascular outcomes in patients with type 2 diabetes, but the etiology of valvular calcification is uncertain. Nonalcoholic fatty liver disease (NAFLD) is an emerging cardiovascular risk factor and is very common in type 2 diabetes, but whether NAFLD is associated with valvular calcification in this group of patients is presently unknown. METHODS We undertook a cross-sectional study of 247 consecutive type 2 diabetic outpatients with no previous history of heart failure, valvular heart diseases (aortic stenosis, mitral stenosis, moderate or severe aortic and mitral regurgitation) or hepatic diseases. Presence of MAC and AVS was detected by echocardiography. NAFLD was diagnosed by ultrasonography. RESULTS Overall, 139 (56.3%) patients had no heart valve calcification (HVC-0), 65 (26.3%) patients had one valve affected (HVC-1) and 43 (17.4%) patients had both valves affected (HVC-2). 175 (70.8%) patients had NAFLD and the prevalence of this disease markedly increased in patients with HVC-2 compared with either HVC-1 or HVC-0 (86.1% vs. 83.1% vs. 60.4%, respectively; p < 0.001). NAFLD was significantly associated with AVS and/or MAC (unadjusted-odds ratio 3.51, 95% CI 1.89-6.51, p < 0.001). Adjustments for age, sex, waist circumference, smoking, blood pressure, hemoglobin A1c, LDL-cholesterol, kidney function parameters, medication use and echocardiographic variables did not appreciably weaken this association (adjusted-odds ratio 2.70, 95% CI 1.23-7.38, p < 0.01). CONCLUSIONS Our results show that NAFLD is an independent predictor of cardiac calcification in both the aortic and mitral valves in patients with type 2 diabetes.

Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes.

Accumulating evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with left ventricular diastolic dysfunction (LVDD) in nondiabetic individuals. To date, there are very limited data on this topic in patients with type 2 diabetes and it remains uncertain whether NAFLD is independently associated with the presence of LVDD in this patient population. We performed a liver ultrasonography and trans-thoracic echocardiography (with speckle-tracking strain analysis) in 222 (156 men and 66 women) consecutive type 2 diabetic outpatients with no previous history of ischemic heart disease, chronic heart failure, valvular diseases and known hepatic diseases. Binary logistic regression analysis was used to examine the association between NAFLD and the presence/severity of LVDD graded according to the current criteria of the American Society of Echocardiography, and to identify the variables that were independently associated with LVDD, which was included as the dependent variable. Patients with ultrasound-diagnosed NAFLD (n = 158; 71.2% of total) were more likely to be female, overweight/obese, and had longer diabetes duration, higher hemoglobin A1c and lower estimated glomerular filtration rate (eGFR) than those without NAFLD. Notably, they also had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without NAFLD (71% vs. 33%; P<0.001). Age, hypertension, smoking, medication use, E/A ratio, LV volumes and mass were comparable between the two groups of patients. NAFLD was associated with a three-fold increased odds of mild and/or moderate LVDD after adjusting for age, sex, body mass index, hypertension, diabetes duration, hemoglobin A1c, eGFR, LV mass index and ejection fraction (adjusted-odds ratio 3.08, 95%CI 1.5–6.4, P = 0.003). In conclusion, NAFLD is independently associated with early LVDD in type 2 diabetic patients with preserved systolic function.