Bellavia, Diego

Abstract Aims MicroRNAs play a role in pathogenic mechanisms leading to heart failure. We measured a panel of 754 miRNAs in the myocardial tissue and in the serum of patients with heart failure with reduced ejection fraction due to dilatative idiopathic cardiomyopathy (DCM, N = 10) or ischaemic cardiomyopathy (N = 3), referred to left ventricular assist device implant. We aim to identify circulating miRNAs with high tissue co-expression, significantly associated to echocardiographic and haemodynamic measures. Methods and results We have measured a panel of 754 miRNAs in the myocardial tissue [left ventricular (LV) apex] and in the serum obtained at the same time in a well selected study population of end-stage heart failure with reduced ejection fraction due to either DCM or ischaemic cardiomyopathy, referred to continuous flow left ventricular assist device implant. We observed moderate agreement for miR-30d, miR-126-3p, and miR-483-3p. MiR-30d was correlated to LV systolic as well as diastolic volumes (r = 0.78, P = 0.001 and r = 0.80, P = 0.005, respectively), while miR-126-3p was associated to mPAP and PCWP (r = −0.79, P = 0.007 and r = −0.80, P = 0.005, respectively). Finally, serum miR-483-3p had an association with right ventricular end diastolic diameter (r = −0.73, P = 0.02) and central venous pressure (CVP) (r − 0.68 p 0.03). Conclusions In patients with DCM, few miRNAs are co-expressed in serum and tissue: They are related to LV remodelling (miR-30d), post-capillary pulmonary artery pressure (miR-126-3p), and right ventricular remodelling/filling pressures (miR-483-3p). Further studies are needed to confirm their role in diagnosis, prognosis or as therapeutic targets in heart failure with reduced ejection fraction.

Background: Very few long-term data are available on patients undergoing mitral valve surgery for chronic ischemic mitral regurgitation (CIMR). Objective:to identify determinants of survival and adverse cardiovascular events, at very long-term outcome. Methods and Results: We reviewed complete left and right ventricular echocardiographic data, six-minute walking test (6-MWT) and BNP levels at pre, peri and follow-up, on 137 consecutive patients who underwent restrictive mitral annuloplasty (RMA) or mitral valve replacement (MVR) and CABG, for CIMR. Combined adverse cardiovascular events were defined as composite of death, heart failure, angina, myocardial infarction and re-hospitalization. Mean age was 67±0.7. Preoperative EF was 35±06%. Among 137 patients, 46% underwent RMA and 54% had MVR. Median follow- up was 7 years (range: 0.3-15.4). Early mortality was 7% (p=NS). In the RMA 42% of patients experienced MR recurrence. Overall survival at 5, 10 and 15 years were 84, 76 and 62% in RMA, and 87, 62 and 54% in MVR (p=0.65). At univariate analysis, preop B-blocker, 6-MWT, mean transmitral gradients and RV size were predictors of adverse events.The Cox Hazard multivariate analysis identified preoperative atrial fibrillation (p=0.005), preop BNP (p=0.025) as independent predictors of long-term mortality.Freedom from cardiovascular events at 5, 10 and 15 years were 90, 75 and 48% in RMA, and 90, 62 and 45% in MVR (p=0.57). . The Cox Hazard multivariate analysis identified preop B-blocker therapy (p=0.001), atrial fibrillation (p=0.01), postoperative mean transmitral gradients (p=0.047 ) and indexed effective orifice area (p=0.02) as independent predictors of adverse cardiovascular events. Conclusions: Our study confirms an high rate of true MR recurrence, at very long-term follow-up. Among collected variables, preoperative BNP and atrial fibrillation were independent predictors of survival, whereas B-blocker therapy, atrial fibrillation, postoperative mean transmitral gradients and indexed effective orifice area were independent predictors of adverse cardiovascular events. Type of surgery did not affect the very long-term outcome.

Background: Assessment of coexisting pericardial and myocardial disease in constrictive pericarditis (CP) remains a diagnostic challenge and decision for pericardiectomy depends on the degree of pericardial versus myocardial restraint limiting left ventricular (LV) filling. Early diastolic longitudinal mitral annulus velocity (Ea) can help to differentiate CP from restrictive cardiomyopathy. Recently, acceleration rate of Ea has been shown to be an index of LV myocardial relaxation. We therefore assessed acceleration (Ea-AR) and deceleration (Ea-DR) rate of Ea in patients with CP before and after pericardiectomy. Methods: We retrospectively studied patients (n=42) with surgically confirmed CP who underwent radical pericardiectomy between 2003–2006 at Mayo Clinic Rochester. Ea-AR and Ea-DR slopes were measured before (pre-Echo) and after (post-Echo) pericardiectomy. Patients were divided into primary CP (idiopathic & acute pericarditis with presumed normal myocardial function) and secondary CP (cardiac surgery & chest irradiation with presumed abnormal myocardial function). Results: Ea-AR and Ea-DR changed significantly after pericardiectomy in primary CP patients, however remained similar in secondary CP patients. Diagnostic accuracy of Ea-AR, Ea-DR and Ea to discriminate primary versus secondary CP by ROC analysis was 0.88, 0.80 and 0.81 respectively. Conclusion: Assessment of Ea-AR and Ea-DR in patients with CP is useful to discriminate primary from secondary CP and may help to predict coexistence of myocardial disease: Prepericardiectomy Ea-AR and Ea-DR appear to reflect the interaction of intrinsic myocardial relaxation with enhanced early LV filling. The lack of decrease of Ea-AR and Ea-DR in patients with secondary CP seems to indicate a primarily restrictive component. The significant decrease of Ea-DR in patients with primary CP after pericardiectomy could reflect abolition of a predominant pericardial limitation to LV filling. Early Diastolic Longitudinal Mitral Annulus Motion before and after Pericardiectomy

Backgrounds: Left ventricular torsion (LVtor) is an integral part of systole and untwisting plays an important role in diastole. The aim of this study was to characterize LVtor and untwisting in different grades of diastolic dysfunction. Methods: We studied 135 patients with normal LV EF with various grades of diastolic dysfunction (40 group1:mild,42 group 2:moderate,and 22 group 3:severe dysfunction) and 31 controls with normal diastolic function. Apical and basal short axis rotations were measured by 2D STE. LVtor was defined as net difference between apical and basal rotation. Results: Age, gender, and EF were similar in 3 groups and control. Mitral annulus early diastolic velocity was reduced in all 3 groups (see table ). Peak LVtor was significantly greater in group 1 compared with control, group 2 and group 3. The time from peak LVtor to Mitral valve opening, and to peak early diastolic velocity were significantly delayed in group 1 compared to control (p=0.0030 and 0.0409, respectively). The twisting rate and untwisting rate were found to be highest in group 1. Conclusions: Systolic torsion and diastolic untwisting are significantly increased in patients with mild diastolic dysfunction. In patients with advanced diastolic dysfunction with increased filling pressure, torsion and untwisting are normalized. Hence, vigorous LV torsion appears to be a compensatory mechanism during an early stage of diastolic dysfunction to maintain normal filling in the setting of reduced longitudinal myocardial motion.

Background: Identifying candidates for left ventricular assist device surgery at risk of right ventricular failure remains difficult. The aim was to identify the most accurate predictors of right ventricular failure among clinical, biological, and imaging markers, assessed by agreement of different supervised machine learning algorithms. Methods: Seventy-four patients, referred to HeartWare left ventricular assist device since 2010 in two Italian centers, were recruited. Biomarkers, right ventricular standard, and strain echocardiography, as well as cath-lab measures, were compared among patients who did not develop right ventricular failure (N = 56), those with acute–right ventricular failure (N = 8, 11%) or chronic–right ventricular failure (N = 10, 14%). Logistic regression, penalized logistic regression, linear support vector machines, and naïve Bayes algorithms with leave-one-out validation were used to evaluate the efficiency of any combination of three collected variables in an “all-subsets” approach. Results: Michigan risk score combined with central venous pressure assessed invasively and apical longitudinal systolic strain of the right ventricular–free wall were the most significant predictors of acute–right ventricular failure (maximum receiver operating characteristic–area under the curve = 0.95, 95% confidence interval = 0.91–1.00, by the naïve Bayes), while the right ventricular–free wall systolic strain of the middle segment, right atrial strain (QRS-synced), and tricuspid annular plane systolic excursion were the most significant predictors of Chronic-RVF (receiver operating characteristic–area under the curve = 0.97, 95% confidence interval = 0.91–1.00, according to naïve Bayes). Conclusion: Apical right ventricular strain as well as right atrial strain provides complementary information, both critical to predict acute–right ventricular failure and chronic–right ventricular failure, respectively.

Abstract Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality, but the identification of LVAD candidates at risk for RVF remains challenging. We undertook a systematic review and meta-analysis of observational studies of risk factors associated with RVF after LVAD implant. Thirty-six studies published between 1 January 1995 and 30 April 2015, comprising 995 RVF patients out of a pooled final population of 4428 patients, were identified. Meta-analysed prevalence of post-LVAD RVF was 35%. A need for mechanical ventilation [odds ratio (OR) 2.99], or continuous renal replacement therapy (CRRT; OR 4.61, area under the curve 0.78, specificity 0.91) were the clinical variables with the highest effect size (ES) in predicting RVF. International normalized ratio [INR; standardized mean difference (SMD) 0.49] and N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD 0.52) were the biochemical markers that best discriminated between RVF and No-RVF populations, though NT-proBNP was highly heterogeneous. Right ventricular stroke work index (RVSWI) and central venous pressure (CVP) (SMD −0.58 and 0.47, respectively) were the haemodynamic measures with the highest ES in identifying patients at risk of post-LVAD RVF; CVP was particularly useful in risk stratifying patients undergoing continuous-flow LVAD implant (SMD 0.59, P < 0.001, I2 = 20.9%). Finally, pre-implant moderate to severe right ventricular (RV) dysfunction, as assessed qualitatively (OR 2.82), or a greater RV/LV diameter ratio (SMD 0.51) were the standard echocardiographic measurements with the highest ES in comparing RVF with No-RVF patients. Longitudinal systolic strain of the RV free wall had the highest ES (SMD 0.73) but also the greatest heterogeneity (I2 = 74%) and was thus only marginally significant (P = 0.05). Patients on ventilatory support or CRRT are at high risk for post-LVAD RVF, similarly to patients with slightly increased INR, high NT-proBNP or leukocytosis. High CVP, low RVSWI, an enlarged right ventricle with concomitant low RV strain also identify patients at higher risk.

Background— Alterations at the level of the coronary circulation with aging may play an important role in the evolution of age-associated changes in left ventricular (LV) fibrosis and function. However these age-associated changes in the coronary vasculature remain poorly defined primarily due to the lack of high resolution imaging technologies. The current study was designed to utilize cardiac micro–computed tomography (micro-CT) technology as a novel imaging strategy, to define the 3-dimensional coronary circulation in the young and aged heart and its relationship to LV fibrosis and function. Methods and Results— Young (2 months old; n=10) and aged (20 months old; n=10) Fischer rats underwent cardiac micro-CT imaging as well as echocardiography, blood pressure, and fibrosis analysis. Importantly, when indexed to LV mass, which increased with age, the total and intramyocardial vessel volumes were lower, whereas the epicardial vessel volume, with and without indexing to LV mass, was significantly higher in the aged hearts compared with the young hearts. Moreover, the aged hearts had a significantly lower percentage of intramyocardial vessel volume and a significantly higher percentage of epicardial vessel volume, when normalized to the total vessel volume, compared with the young hearts. Further, the aged hearts had significant LV fibrosis and mild LV dysfunction compared with the young hearts. Conclusions— This micro-CT imaging study reports the reduction in normalized intramyocardial vessel volume within the aged heart, in association with increased epicardial vessel volume, in the setting of increased LV fibrosis, and mild LV dysfunction.

Background— Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR). Methods and Results— We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction. Conclusions— AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.

Myocardial aging is characterized by left ventricular (LV) fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent antifibrotic and antiproliferative properties of C-type natriuretic peptide (CNP); however, the relationship between circulating CNP, LV fibrosis, and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2-, 11-, and 20-month–old male Fischer rats. Further in vitro, we established the antiproliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis that precedes impairment of diastolic and systolic function. Additionally, we demonstrate in cultured adult human cardiac fibroblasts that the direct antiproliferative actions of high-dose CNP may involve a non-cGMP pathway via the clearance receptor. Together, these studies provide new insights into myocardial aging and the relationship to the antifibrotic and antiproliferative peptide CNP.