Comprehensive echocardiographic assessment of right ventricular function, pulmonary arterial elastic properties and ventricular-vascular coupling in adult patients with repaired tetralogy of fallot: clinical significance of 3D derived indices.

We aimed to comprehensively analyze by three-dimensional speckle-tracking echocardiography (3DSTE) and Doppler echocardiography right ventricular (RV) performance, pulmonary arterial (PA) elastic properties and right ventricular-pulmonary artery coupling (RVPAC) in patients with repaired tetralogy of Fallot (rTOF) and assess the feasibility and clinical utility of related echocardiographic indices. Twenty-four adult patients with rTOF and twenty-four controls were studied. RV end-diastolic volume(3D-RVEDV), RV end-systolic volume(3D-RVESV), RV ejection fraction(3D-RVEF), RV longitudinal strain(3D-RVLS) and RV area strain(3D-RVAS) were calculated by 3DSTE. RV end-systolic area (RVESA) was obtained by planimetry. Pulmonary regurgitation (PR) was assessed as trivial/mild or significant by cardiac magnetic resonance (CMR) and color-Doppler. Pulmonary artery (PA) elastic properties were determined using two-dimensional/Doppler echocardiography. RV systolic pressure (RVSP) was measured using standard Doppler methods. RVPAC was assessed using various 3DSTE-derived parameters (3DRVAS/RVSP, 3DRVLS/RVESA, 3DRVAS/RVESV). Overall, 3DRVEF and 3DRVAS were impaired in rTOF patients compared with controls. PA pulsatility and capacitance were reduced (p = 0.003) and PA elastance was higher (p = 0.0007) compared to controls. PA elastance had a positive correlation with 3DRVEDV (r = 0.64, p = 0.002) and 3DRVAS (r = 0.51, p = 0.02). By ROC (receiver operating characteristics) analysis, 3DRVAS/RVESV, 3DRVAS/RVSP and 3DRVLS/RVESA cutoff values of 0.31%/mmHg, 0.57%/mmHg and 0.86%/mmHg, respectively, had 91%, 88% and 88% sensitivity and 81%, 81% and 79% specificity in identifying exercise capacity impairment. In rTOF patients increased 3DSTE-derived RV volumes and impaired RV ejection fraction and strain are associated with reduced PA pulsatility and capacitance and increased PA elastance. 3DSTE-derived RVPAC parameters using different afterload-markers are accurate indices of exercise capacity.

Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies.

AIMS: In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate. METHODS AND RESULTS: EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4±0.4kbp and telomerase activity was present in all preparations (1.7×105 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance. CONCLUSIONS: The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures.

Effective percutaneous "edge-to-edge" mitral valve repair with mitraclip in a patient with acute post-MI regurgitation not related to papillary muscle rupture.

A 65-year-old woman was admitted to our institution for rest dyspnea and hypotension. EKG showed sinus tachycardia with signs of infero-posterior STEMI. 2D-echocardiogram showed severe left ventricular systolic dysfunction with a- diskynesia of the inferior and posterior walls and severe functional mitral regurgitation (MR). The patient underwent urgent coronary angiography that showed 3-vessels disease with total occlusion of both first obtuse marginal (OM) branch of the left circumflex artery and right coronary artery (RCA) and critical stenosis of left anterior descending (LAD). Because of extremely high surgical risk, we performed a staged totally percoutaneous approach. First, we reopened the presumed culprit vessels (RCA and OM) and then, after 48 hr, we performed angioplasty of the LAD. Since revascularization provided no significant improvement in respiratory and hemodynamic parameters we performed a percutaneous mitral repair with Mitraclip. MR grade was reduced from severe to trivial with rapid improvement of the respiratory and hemodynamic parameters. The post-procedural course was uneventful and the patient was discharged 7 days later. At the 30-day and 6-month follow-up the patient remained asymptomatic in NYHA I functional class with no recurrence of MR. Acute MR due to post-AMI mechanical complications is generally considered a contraindication to MitraClip implantation for several reasons. However, the present report shows that, in selected cases, the Mitraclip system may be successfully used to reduce the severity of acute MR secondary to AMI and may allow to reverse cardiogenic shock and/or refractory pulmonary congestion related to the acute regurgitation. © 2016 Wiley Periodicals, Inc.

Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: potential utility of immunosuppressive therapy in cardiac damage progression.

OBJECTIVES: Scleroderma heart disease is a major risk of death in systemic sclerosis (SSc). Mechanisms underlying myocardial damage are still unclear. We performed an extensive study of SSc patients with recent-onset symptoms for heart disease and examined the efficacy of immunosuppressive therapy. METHODS: A cohort of 181 SSc patients was enrolled. Of these, 7 patients newly developed clinical symptoms of heart disease (heart failure, chest pain, and palpitation); all of them showed mild but persistent increase in cardiac enzymes. These patients underwent Holter ECG, 2D-echocardiography, perfusional scintigraphy, delayed-enhancement-cardiac magnetic resonance (DE-CMR), coronary angiography, and endomyocardial biopsy. Patients were treated for at least 12 months and followed-up for 5 years. RESULTS: Ventricular ectopic beats (VEBs) were found in 4 patients, wall motion abnormalities in 3, pericardial effusion in 6, and DE in CMR in 6 with T2-hyperintensity in 2. In all patients, histology showed upregulation of endothelium adhesion molecules and infiltration of activated T lymphocytes, with (acute/active myocarditis in 6) or without (chronic/borderline myocarditis in 1) myocyte necrosis. Parvovirus B19 genome was detected in 3. None showed occlusion of coronary arteries or microvessels. Compared with SSc controls, these patients more often had early disease, skeletal myositis, c-ANCA/anti-PR3 positivity, VEBs, pericardial effusion, and systolic and/or diastolic dysfunction. Immunosuppressive therapy improved symptoms and led to cardiac enzyme negativization; however, 2 patients died of sudden death during follow-up. CONCLUSIONS: Myocarditis is a common finding in SSc patients with recent-onset cardiac involvement. Its early detection allowed to timely start an immunosuppressive treatment, preventing cardiac damage progression in most cases.

Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery.

BACKGROUND: The efficacy of bypass surgery in patients with ischemic cardiomyopathy is not easily predictable; preoperative clinical conditions may be similar, but the outcome may differ significantly. We hypothesized that the growth reserve of cardiac stem cells (CSCs) and circulating cytokines promoting CSC activation are critical determinants of ventricular remodeling in this patient population. METHODS AND RESULTS: To document the growth kinetics of CSCs, population-doubling time, telomere length, telomerase activity, and insulin-like growth factor-1 receptor expression were measured in CSCs isolated from 38 patients undergoing bypass surgery. Additionally, the blood levels of insulin-like growth factor-1, hepatocyte growth factor, and vascular endothelial growth factor were evaluated. The variables of CSC growth were expressed as a function of the changes in wall thickness, chamber diameter and volume, ventricular mass-to-chamber volume ratio, and ejection fraction, before and 12 months after surgery. A high correlation was found between indices of CSC function and cardiac anatomy. Negative ventricular remodeling was not observed if CSCs retained a significant growth reserve. The high concentration of insulin-like growth factor-1 systemically pointed to the insulin-like growth factor-1-insulin-like growth factor-1 receptor system as a major player in the adaptive response of the myocardium. hepatocyte growth factor, a mediator of CSC migration, was also high in these patients preoperatively, as was vascular endothelial growth factor, possibly reflecting the vascular growth needed before bypass surgery. Conversely, a decline in CSC growth was coupled with wall thinning, chamber dilation, and depressed ejection fraction. CONCLUSIONS: The telomere-telomerase axis, population-doubling time, and insulin-like growth factor-1 receptor expression in CSCs, together with a high circulating level of insulin-like growth factor-1, represent a novel biomarker able to predict the evolution of ischemic cardiomyopathy following revascularization.

Vascular endothelial growth factor (VEGF-a) in Fabry disease: association with cutaneous and systemic manifestations with vascular involvement.

INTRODUCTION: Fabry disease is an X-linked inherited metabolic disorder characterized by the deficiency of lysosomal α-galactosidase A enzyme. This leads to the accumulation, into lysosomes through the body, of glycosphingolipids, mainly Gb3. Skin involvement and progressive multi-organ failure are usually observed. Endothelium is the preferential target of the Gb3 storage that determines endothelial dysfunction and vasculopathy leading to the clinical manifestations of the disease. The serum levels of Vascular Endothelial Growth Factor-A (VEGF-A), a specific endothelial cell mitogen, were analyzed in Fabry patients to explore a possible association to the clinical manifestations with vascular involvement. METHODS: Thirty-five patients with a biochemical and genetic diagnosis of Fabry disease, along with an age-gender-matched healthy control group, were enrolled. Serum samples were collected and analyzed by ELISA. The genetic mutations, the specific organ dysfunction, and the cardiovascular risk factors such as dyslipidaemia, diabetes, smoking habits and hypertension were evaluated in Fabry patients. RESULTS: The mean serum level of VEGF-A in Fabry patients group was significantly higher than in the control group (P=0.006). A statistical significant association, between VEGF-A levels and the skin manifestation including angiokeratomas, sweating abnormalities and Fabry Facies was found. An association was also found between high VEGF-A and specific GLA mutations, the male gender, the renal and neurological manifestations, the presence of eye vessels tortuosity, smoking habit and hypertension. CONCLUSIONS: We detected increased VEGF-A levels in patients with Fabry disease compared to the controls, and we hypothesized that this could be a response to the vascular damage characterising this lysosomal disorder. However, further studies are necessary to clarify the role of VEGF-A in Fabry.

Imaging of scar in patients with ventricular arrhythmias of right ventricular origin: cardiac magnetic resonance versus electroanatomic mapping.

INTRODUCTION: Assessment of late gadolinium enhancement (LGE) at cardiac magnetic resonance is often used to detect scar in patients with arrhythmias of right ventricular (RV) origin. Recently, electroanatomic mapping (EAM) has been shown to reliably detect scars corresponding to different cardiomyopathic substrates. We compared LGE with EAM for the detection of scar in patients with arrhythmias of RV origin. METHODS AND RESULTS: Thirty-one patients with RV arrhythmias and biopsy-proven structural heart disease (18 ARVC and 13 myocarditis), and 5 with idiopathic RV outflow tract arrhythmias underwent LGE analysis and EAM with scar validation through EAM-guided endomyocardial biopsy. EAM scars were present in 23 (64%) patients (all with structural heart disease), whereas LGE was present only in 12 (33%). In 2 cases, EAM provided a false-positive diagnosis of a small scar in the basal perivalvular area. LGE correctly diagnosed EAM scar in 48% of patients, resulting in high positive (92%) but low negative (50%) predictive values. The distribution of LGE was significantly associated with the distribution of EAM scars (P < 0.001 in the free wall, P = 0.003 in the outflow tract, and P = 0.023 in the posterior/inferior wall). Presence of LGE reflected a higher extension of EAM scars (34.4 ± 16.5% vs 7.9 ± 10.1% of the RV area, P < 0.001). At receiver operating characteristic (ROC) analysis, an extension of scar ≥20% of the RV area was the best cut-off value to detect LGE (sensitivity 83%, specificity 92%). Of note, LGE missed 10 of 11 (91%) patients with EAM scars <20% of RV area. CONCLUSIONS: LGE is significantly less sensitive than EAM in identifying RV cardiomyopathic substrates. Absence of LGE does not rule out the presence of small scars, and EAM with biopsy should be considered to increase the diagnostic yield.

Concealed cardiomyopathies in competitive athletes with ventricular arrhythmias and an apparently normal heart: role of cardiac electroanatomical mapping and biopsy.

BACKGROUND: The diagnosis of subtle structural heart disease in competitive athletes with ventricular arrhythmias (VAs) and an apparently normal heart is challenging. Three-dimensional electroanatomic mapping (EAM) has been demonstrated to reliably identify low-voltage areas that correspond to different cardiomyopathic substrates. OBJECTIVE: The purpose of this study was to test whether EAM may help in the diagnosis of concealed cardiomyopathies in athletes with VAs and an apparently normal heart. METHODS: We studied 13 consecutive competitive athletes (12 males, age 30 ± 13 years) who had documentation of VAs within the previous 6 months on 12-lead electrocardiogram (ECG), 24-hour Holter ECG, or ECG exercise testing and who were judged as having a structurally normal heart after a thorough noninvasive evaluation, including signal-averaged ECG, transthoracic echocardiogram, and cardiac magnetic resonance imaging. Depending on the presumed site of VA origin according to 12-lead ECG criteria, patients underwent right or left ventricular EAM and EAM-guided endomyocardial biopsy. RESULTS: Presenting arrhythmias included sustained ventricular tachycardia (n = 3), multiple episodes of nonsustained ventricular tachycardia (n = 7), and frequent ventricular ectopic beats (>1,000 during 24 hours; n = 3). Three patients had a history of syncope. Twelve (92%) patients had at least one low-voltage region at EAM, which corresponded at EAM-guided endomyocardial biopsy to the histological diagnosis of active myocarditis in seven patients and of arrhythmogenic right ventricular cardiomyopathy in five. In one patient the histological evidence of contraction band necrosis allowed the unmasking of caffeine and ephedrine abuse. CONCLUSIONS: Electroanatomical substrate mapping may help diagnose concealed myocardial diseases in competitive athletes presenting with recent-onset VAs and an apparently normal heart. Further studies are warranted to assess the prognostic implications of such subtle myocardial abnormalities.

Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus.

AIMS: Diabetes mellitus (DM) is associated with high incidence of first and recurrent cardiovascular events, especially acute coronary syndromes (ACSs); however, the mechanisms involved are still unknown. We sought to investigate the role of CD4(+)CD28(null)T-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM. METHODS AND RESULTS: CD4(+)CD28(null)T-cell frequency was analysed by flow-cytometry in 60 DM patients without overt cardiovascular disease (cDM), in 166 ACS patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and in 60 healthy individuals. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4+CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4+CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4+CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28(null)T-cells ≥4% and highest in those without DM and CD4+CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features. CONCLUSIONS: In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

Noninvasive diagnosis of electroanatomic abnormalities in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: The diagnostic reliability and pathophysiologic relevance of different noninvasive diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) are undefined. We tested the association between noninvasive diagnostic criteria for ARVC and the presence of low-voltage areas (LVAs) detected at electroanatomic voltage mapping (EAM). METHODS AND RESULTS: Noninvasive diagnostic criteria, including ECG, signal-averaged ECG (SAECG), and cardiac magnetic resonance (CMR) criteria, were compared with the presence and location of LVAs detected at right ventricular (RV) EAM in 17 patients (9 men) aged 50 ± 16 years with biopsy specimen-proven ARVC. LVAs were found in 15 (88%) patients. Patients with surface ECG abnormalities showed a higher degree of RV involvement than those without ECG abnormalities (number of LVAs, 1.8 ± 0.5 versus 0.9 ± 0.6, respectively; P < 0.01). A significant association was found between SAECG abnormalities and LVAs in the RV outflow tract (P = 0.03) but not between SAECG parameters and LVAs in other RV regions. Among CMR findings, RV delayed enhancement was more significantly associated with the distribution of LVAs (free wall, P < 0.01; outflow tract, P < 0.01; posteroinferior wall, P = 0.02). Regional RV dysfunction also showed a good correlation with LVAs, with the most significant association being found with the free wall (P = 0.01), whereas RV fat infiltration at CMR was not correlated with LVAs. CONCLUSION: In patients with ARVC, SAECG abnormalities correlate with the presence of LVAs selectively in the RV outflow tract, whereas surface ECG abnormalities are associated with a more diffuse RV involvement. Myocardial delayed enhancement is the CMR finding more strongly associated with LVAs, thus supporting the appropriateness of its inclusion among diagnostic criteria for ARVC.

A case of early drug-eluting stent fracture.

Although stent fracture following femoro-popliteal intervention is well recognized, coronary stent fracture represents an underrecognized entity. Its incidence is low but it represents an important clinical entity as it may complicate with stent thrombosis causing acute coronary syndromes, or may predispose to instent restenosis. Although coronary stent fracture may involve both bare metal stents (BMS) and drug-eluting stents (DES), a recent analysis of the literature indicates that reports of stent fracture have increased since DES was introduced. Furthermore, chronic stretch at specific vessel sites as bends may lead to late occurrence of fracture. We present the case of a patient with a non-ST-segment elevation acute coronary syndrome caused by the early fracture of an everolimus-eluting stent (Xience®) implanted only three days before.

Immunomodulator activity of 3-hydroxy-3-methilglutaryl-CoA inhibitors.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA are best known for their lipid-lowering effects but they also possess immunomodulatory properties that are, at least in part, independent of changes in serum cholesterol. Some recent clinical trials (eg. PROVE-IT) have shown that statins exert beneficial cardiovascular effects independently of the resultant level of LDL cholesterol. These "pleiotropic" effects seem to be due to inhibition of prenylation of several proteins such as the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins are able to modulate immune responses by modulating cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Over the past decade, a large number of studies reported a prominent role of inflammation and immune response in atherosclerosis, thus, the ability of statins to modulate immune-inflammatory processes could explain their cardiovascular beneficial effects beyond lipid-lowering effects. Moreover, various studies demonstrated beneficial effects of statins in inflammatory and auto-immune diseases, such as rheumatoid arthritis, multiple sclerosis and others. The purpose of this review is to summarize clinical and experimental evidence of immunomodulatory properties of these drugs, highlighting their clinical and, thus, therapeutic implications.