Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

AIMS: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC. METHODS AND RESULTS: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction. CONCLUSION: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.

Systematic Review of Clozapine Cardiotoxicity.

Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

Relationship between prosthesis-patient mismatch and pro-brain natriuretic peptides after aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: It has been shown previously that elevated plasma levels of B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-pro-BNP) are related to the degree and progression of native aortic valve disease. In addition, NT-pro-BNP levels have been shown to decrease after successful aortic valve replacement (AVR). The presence of a valve prosthesis-patient mismatch (PPM) may affect the beneficial effects of AVR, however. The study aim was to investigate the relationship between PPM and NT-pro-BNP plasma levels late after AVR. METHODS: A series of consecutive patients (42 males, 31 females; mean age 66 +/- 13 years) who had undergone isolated AVR between May 2004 and July 2007 was enrolled into the study. Patients with preoperative moderate to severe mitral regurgitation, coronary artery disease, left ventricular (LV) dysfunction (ejection fraction <45%) and serum creatinine >150 mmol/l were excluded. PPM was defined severe as an indexed effective orifice area (EOAi) < or = 0.65 cm2/m2, or moderate when the EOAi was 0.66-0.85 cm2/m2. Plasma NT-pro-BNP levels and echocardiographic assessments were performed in all patients during routine follow up after surgery. RESULTS: The patients received either a biological (n = 42) or mechanical (n = 31) prosthesis. Among the patients, 21 had no PPM, 27 moderate PPM, and 25 severe PPM. At a median follow up of 18 months, the mean NT-pro-BNP plasma level was 532 pg/ml (95% CI: 393.1-671.6), and the mean LV mass index (LVMI) 120 +/- 4 g/m2, the LVEF 60 +/- 1%, the peak aortic prosthesis gradient 28 +/- 2 mmHg, and the EOAi 0.74 +/- 0.02 cm2/m2. Multivariate statistical analysis showed that NT-pro-BNP level correlated with age (beta = 0.57, p<0.0001), LVMI (beta = 0.32, p = 0.02), NYHA class (beta = 0.50, p = 0.003) and EOAi (beta = -0.38, p = 0.02). CONCLUSION: The study results showed that NT-pro-BNP levels were independently related to PPM late after isolated AVR in patients with preserved LV function. However, further investigations are required to confirm these findings and to identify their clinical implications.

Impairment of left ventricular function early in treatment with clozapine: a preliminary study.

This preliminary prospective study evaluated cardiac status in 15 treatment-resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C-reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine.

Relation between right and left ventricular function in patients undergoing chronic dialysis.

AIMS: Occurrence of heart failure during dialysis treatment is associated with high mortality. However, mechanisms underlying left ventricular dysfunction (LVD) in these patients are still elusive. In patients undergoing haemodialysis, arteriovenous fistula (AVF) is associated with right ventricular dysfunction (RVD) and a further impairment is observed when AVF is brachial rather than radial. However, it is not known whether AVF-induced RVD is associated with an impaired left ventricular function. We studied the relation between right and left ventricular function in 120 patients undergoing either haemodialysis or peritoneal dialysis and 100 healthy age-matched controls. METHODS: Echocardiography including tissue Doppler imaging (TDI) was performed for both ventricles. Average myocardial performance index (MPI) of the right ventricle (RV MPI) was obtained with a multisegmental approach by using TDI. RESULTS: RVD was higher in haemodialysis than peritoneal dialysis patients and a further increase was observed in haemodialysis patients with brachial access. Interestingly, RV MPI inversely correlated with indices of both left ventricular contraction and relaxation and the association was even stronger in haemodialysis patients, particularly in those with brachial AVF. Of note, dialysis patients in the upper tertile of RV MPI showed the larger impairment of left ventricular function. Regression analyses showed that RV MPI was independently associated with reduced left ventricular function. By contrast, LVD did not significantly affect right ventricular performance in this setting. CONCLUSION: AVF-induced RVD may contribute to LVD in dialysis patients. AVF plays a pivotal role in triggering LVD via right-to-left ventricular interdependence.

Impact of prosthesis-patient mismatch on the regression of secondary mitral regurgitation after isolated aortic valve replacement with a bioprosthetic valve in patients with severe aortic stenosis.

BACKGROUND: Secondary mitral regurgitation (SMR) is generally reduced after isolated aortic valve replacement (AVR), but there is important interindividual variability in the magnitude of this reduction. Prosthesis-patient mismatch (PPM) may hinder normalization of left ventricular geometry and pressure overload following AVR, therefore we aimed to investigate the relationship between PPM and regression of SMR following AVR for aortic valve stenosis. METHODS AND RESULTS: A total of 419 patients with AS who underwent isolated AVR at 2 institutions and presenting moderate SMR (mitral regurgitant volume 30 to 45 mL/beat) not considered for surgical correction were included in this study. Clinical and echocardiographic follow-up were completed at a median follow-up time of 37 months. PPM was defined as an indexed effective orifice area ≤0.85 cm(2)/m(2) and was found in 170/419 patients (40.6%). There were no significant differences in baseline and operative characteristics between patients with or without PPM. Patients with PPM had less regression of SMR following AVR compared with those with no PPM (change in mitral regurgitant volume: -11±4 versus -17±5 mL, respectively; P<0.0001). Variables significantly associated with postoperative change in mitral regurgitant volume on univariable analysis were entered in a multivariable linear regression model, which showed indexed effective orifice area (P<0.0001) and left atrial diameter (P=0.006) to be independently associated with mitral regurgitant volume improvement. Patients with PPM also had less postoperative improvement in 6-minute walking test distance (80±78 versus 42±41 m, P<0.0001). CONCLUSIONS: PPM is associated with lesser regression of SMR following AVR. This unfavorable effect was associated with worse functional capacity. These findings emphasize the importance of operative strategies aiming to prevent PPM in patients with aortic valve stenosis and concomitant SMR.

Evaluation of systolic properties in hypertensive patients with different degrees of diastolic dysfunction and normal ejection fraction.

BACKGROUND: Left ventricular (LV) diastolic dysfunction (DD) associated with a preserved ejection fraction (EF) is a frequent alteration in hypertensive patients, usually considered an impairment of the diastolic phase alone. However, because systole and diastole are strictly correlated to one another, it is possible that hypertensive patients with isolated DD may also present with initial abnormalities of LV systolic properties, particularly those presenting with a more severe degree of DD. We performed a multiparametric echocardiographic assessment of LV systolic properties in patients without cardiovascular diseases, with preserved EF and different degrees of DD. METHODS: We evaluated 1,073 hypertensive subjects showing EF >55% and no overt heart disease. RESULTS: A total of 362 patients had normal diastolic function (N), 609 displayed delayed relaxation pattern (DR), and 102 presented a pseudonormal filling pattern (PN). Albeit most of the subjects with DD (DR, PN) had systolic indexes within normal range, they presented a significant reduction of index stroke volume (SV) (P < 0.0001) and stroke work (SW) (P < 0.0001), EF (P < 0.01), midwall shortening (MFS) (P < 0.0001), circumferential end-systolic stress-corrected MFS (cESS-MFS) (P < 0.001), and tissue Doppler (TD) systolic velocity (P < 0.0001) as compared to the N group, particularly the PN group.After adjustments, the reductions of LV systolic indexes were still significantly related to DD, particularly to PN. CONCLUSIONS: Our results suggest a relation between LV systolic and diastolic properties in patients with normal EF. They also highlight the early onset of a preclinical reduction of systolic properties in patients with "isolated" DD, which is related to the degree of dysfunction.