Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.

Endoplasmic reticulum (ER) stress induction of cell death is implicated in cardiovascular diseases. Sustained activation of ER-stress induces the unfolded protein response (UPR) pathways, which in turn activate three major effector proteins. We previously reported a missense homozygous mutation in FBXO32 (MAFbx, Atrogin-1) causing advanced heart failure by impairing autophagy. In the present study, we performed transcriptional profiling and biochemical assays, which unexpectedly revealed a reduced activation of UPR effectors in patient mutant hearts, while a strong up-regulation of the CHOP transcription factor and of its target genes are observed. Expression of mutant FBXO32 in cells is sufficient to induce CHOP-associated apoptosis, to increase the ATF2 transcription factor and to impair ATF2 ubiquitination. ATF2 protein interacts with FBXO32 in the human heart and its expression is especially high in FBXO32 mutant hearts. These findings provide a new underlying mechanism for FBXO32-mediated cardiomyopathy, implicating abnormal activation of CHOP. These results suggest alternative non-canonical pathways of CHOP activation that could be considered to develop new therapeutic targets for the treatment of FBXO32-associated DCM.

Transcatheter mitral valve-in-valve implantation for failed bioprosthesis.

OBJECTIVE: This study is a report of clinical and echocardiographic outcomes of experience with transapical mitral valve-in-valve (VIV) replacement. METHODS: Eleven patients with a mean age of 63.7±13.0 years who underwent transapical mitral VIV implantation for a failed bioprosthesis at a single institution were enrolled. All of the patients were considered high-risk for surgical intervention, with a Society of Thoracic Surgery predicted risk of mortality of 14.2±17.6%, and a mean European System for Cardiac Operative Risk Evaluation (EuroSCORE II) of 10.5±6.1%. RESULTS: Transapical mitral VIV implantation was successful in all of the patients. Edwards, Sapien XT and Sapien 3 valves (Edwards Lifesciences Corp., Irvine, CA, USA) were used in 8 (73%), 2 (18%), and 1 (9%) patients, respectively. Size 26 valves were used in 6 (55%) patients while size 29 valves were used in 5 (45%) patients. All of the patients (11, 100%) had no or only trace mitral regurgitation at the end of the procedure. The mean length of hospital stay was 19±8.0 days. The survival was 100% at 14 days, and 90% at 30 days and at 4 years. One patient died as a result of multiorgan failure on day 16 of intensive care unit stay. The mean mitral valve gradient across the percutaneous valve was 2.26±1.047 mmHg, and the mean valve area was 2.20±0.14 cm2. Through the 4 years follow up, the New York Heart Association class of the 10 patients remaining improved to class II with no readmission for heart failure. All of the patients were on coumadin with a target international normalized ratio of 2-3. CONCLUSION: In high-risk patients, transapical mitral VIV implantation can be performed with a high success rate and considerable improvement in clinical status.

Diagnostic Accuracy of Dobutamine Stress Echocardiography for Detection of Cardiac Allograft Vasculopathy in Orthotopic Heart Transplant Patients.

OBJECTIVE: Cardiac allograft vasculopathy is one of the leading causes of late graft failure and subsequent death in orthotopic heart transplant. Although invasive coronary angiography is the gold standard modality for detection of cardiac allograft vasculopathy, dobutamine stress echocardiography has been recently frequently used as an alternative. Our aim was to evaluate the diagnostic performance of dobutamine stress echocardiography for detection of cardiac allograft vasculopathy in transplant patients. METHODS: A retrospective analysis was conducted using a total of 150 dobutamine stress echocardiographic exams that were performed on 99 patients in our institution, with paired coronary angiogram and no acute rejection, within a median of 538 [interquartile range 371-816] days. Sensitivity and specificity of dobutamine echocardiography to detect allograft vasculopathy was evaluated. Allograft vasculopathy was defined as Grade 1 or higher based on ISHLT criteria. A positive dobutamine stress echo result was defined by new or worsening wall motion abnormality. RESULTS: Median age of the population at transplant was 34 [interquartile range 22-46] years; 76 (77%) patients were male. Allograft vasculopathy was present in 31 (20.6%) out of 150 coronary angiograms. Only 7 (4.6%) of that number were positive on dobutamine stress echocardiography. Sensitivity and specificity for allograft vasculopathy detection was 3% and 94%, respectively. Out of 7 false positive dobutamine stress echocardiograms, two were in patients with myocardial bridging. Two patients with mild acute rejection had both negative dobutamine stress echo. CONCLUSIONS: Overall, positivity of dobutamine stress echocardiography in patients after heart transplant is low. It has high specificity, but very low sensitivity for detection of cardiac allograft vasculopathy. Dobutamine stress echocardiography should only be cautiously used as an alternative to coronary angiography.

Protein arginine methyltransferase 6 mediates cardiac hypertrophy by differential regulation of histone H3 arginine methylation.

Heart failure remains a major cause of hospitalization and death worldwide. Heart failure can be caused by abnormalities in the epigenome resulting from dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing lysine acetylation and methylation of histones have been the topic of many investigations, the role of arginine methyltransferases has been overlooked. In an effort to understand regulatory mechanisms implicated in cardiac hypertrophy and heart failure, we assessed the expression of protein arginine methyltransferases (PRMTs) in the left ventricle of failing human hearts and control hearts. Our results show a significant up-regulation of protein arginine methyltransferase 6 (PRMT6) in failing human hearts compared to control hearts, which also occurs in the early phase of cardiac hypertrophy in mouse hearts subjected to pressure overload hypertrophy induced by trans-aortic constriction (TAC), and in neonatal rat ventricular myocytes (NRVM) stimulated with the hypertrophic agonist phenylephrine (PE). These changes are associated with a significant increase in arginine 2 asymmetric methylation of histone H3 (H3R2Me2a) and reduced lysine 4 tri-methylation of H3 (H3K4Me3) observed both in NRVM and in vivo. Importantly, forced expression of PRMT6 in NRVM enhances the expression of the hypertrophic marker, atrial natriuretic peptide (ANP). Conversely, specific silencing of PRMT6 reduces ANP protein expression and cell size, indicating that PRMT6 is critical for the PE-mediated hypertrophic response. Silencing of PRMT6 reduces H3R2Me2a, a mark normally associated with transcriptional repression. Furthermore, evaluation of cardiac contractility and global ion channel activity in live NRVM shows a striking reduction of spontaneous beating rates and prolongation of extra-cellular field potentials in cells expressing low-level PRMT6. Altogether, our results indicate that PRMT6 is a critical regulator of cardiac hypertrophy, implicating H3R2Me2a as an important histone modification. This study identifies PRMT6 as a new epigenetic regulator and suggests a new point of control in chromatin to inhibit pathological cardiac remodeling.

A rare case of takotsubo syndrome within the first day after heart transplantation.

A 39-year-old woman underwent heart transplantation (HTx) for advanced heart failure. The donor was a 36-year-old young woman without past medical history. The first day after HTx, T-waves changes were noted. Echocardiography revealed akinesia/dyskinesia of all basal segments of the two ventricles. Coronary catheterization plus biopsy were done 7 days later showing no coronary obstruction, no rejection and complete recovery of wall motion abnormalities on echocardiogram, suggesting biventricular inverted takotsubo syndrome (TTS). This is a case of TTS during the first day after HTx, with completely denervated heart but because of the inotropic drug support it still represents a target for catecholamine-induced cardiac dysfunction.

Three-Dimensional Echocardiographic Imaging of a Gerbode Defect Complicating Transcatheter Aortic Valve Replacement.

We describe a case of a 77-year-old male who underwent transcatheter aortic valve implantation (TAVR) with Edwards SAPIEN XT size 26 mm for severe aortic stenosis. Postprocedural transesophageal echocardiography (TEE) showed left-to-right shunt between the left ventricular outflow tract just below the bioprosthesis and the right atrium across the atrioventricular septum (Gerbode defect). Three-dimensional echocardiography (3DE) allowed a detailed anatomical imaging of the shape and the location of a small, circular, atrioventricular defect that was a type II, direct, supravalvular, Gerbode-type defect. This is the third report of a Gerbode defect after TAVR whose diagnosis has important implications on clinical decision-making. TEE plays a key role; its diagnostic ability is enriched by the additional value of 3DE.

Management of immediate partial bioresorbable vascular scaffold stent thrombosis.

Bioresorbable vascular scaffold (BVS) stents have been proposed recently as an elegant technique for treatment of coronary artery disease. However, perspective that these "dissolvable" stents will replace conventional metallic stents in broad spectrum of clinical conditions and patient categories in the near future has been moderated by non-negligible incidence of stent thrombosis (ST). Mechanical factors, such as strut thickness and malapposition have been implicated in increased risk of BVS ST. Presently described is case of immediate partial BVS ST in a young male related to technical procedural problem, rather than mechanical problem. Glycoprotein IIb/IIIa inhibitors associated with anticoagulation resulted in complete resolution of thrombus and facilitated successful patient outcome.

FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. RESULTS: We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. CONCLUSION: Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM.

Thrombolytic Therapy as the Management of Mitral Transcatheter Valve-in-Valve Implantation Early Thrombosis.

A 70-year-old male underwent mitral transcatheter valve-in-valve implantation for a failed bioprosthesis implanted 11 years earlier. In the first days following the procedure, he developed thrombosis of the new bioprosthesis with restricted cusp motion. The transmitral mean gradient increased significantly despite effective anticoagulation therapy using unfractionated heparin infusion. Low dose and slow infusion of alteplase resulted in resolution of the thrombus and normalisation of cusp motion. Thereafter long-term anticoagulation using a vitamin K antagonist was instituted and the patient remained asymptomatic.

Echocardiography detects elevated left ventricular filling pressures in heart transplant recipients.

Diastolic dysfunction is a recognized complication in heart transplant (HTx) recipients that limits exercise capacity and is a risk factor for mortality. We investigated the ability of echocardiography to detect elevated pulmonary capillary wedge pressure (mean PCWP>15 mmHg) in HTx recipients. This retrospective study comprised HTx recipients with echocardiography and right heart catheterization within 24 hours (n = 100, 113 investigations). Echocardiographic assessment was performed using mitral inflow (E/A ratio, deceleration time [DT], isovolumic relaxation time [IVRT]), tissue Doppler (E/E' lateral) parameters, and the Doppler-estimated pulmonary artery systolic pressure (Doppler PASP). The right atrial pressure (RAP) was estimated based on size and the effect of respiration or sniffing on the inferior vena cava diameter. Cutoff values were determined from a derivation group (n = 57, receiver operator characteristic curve analysis) and evaluated in a test group (n = 56). Elevated PCWP were found in 38%. The RAP and PCWP were both normal in 58 investigations and elevated in 39 investigations (concordance rate of 86.6%). The presence of signs of increased RAP by echocardiography or with three of five parameters (E/A, DT, IVRT, E/E' lateral, and Doppler PASP) reaching the cutoff values ruled in elevated PCWP with positive likelihood ratios ranging from 15.3 to 9. With normal RAP by echocardiography or none of the other parameters reaching cutoff values elevated PCWP can be ruled out with negative likelihood ratios ranging from 0.07 to 0.19. In conclusion, elevated PCWP in HTx recipients can be assessed using echocardiography.

Pressure reflection in the pulmonary circulation by echocardiography in patients with left heart disease indicates reactive pulmonary hypertension.

OBJECTIVES: The two hemodynamic profiles in left heart disease (LHD) with pulmonary hypertension (PH), passive PH with increased pulmonary venous pressure and reactive PH with increased pulmonary vascular resistance (PVR > 3 Wood units, WU), are difficult to distinguish non-invasively. We hypothesized that echocardiographic signs of pressure reflection (PR) in the pulmonary circulation can be used to diagnose reactive PH. MATERIAL AND METHODS: The study comprised 122 patients divided into three groups: patients without PH (No PH, n = 61), patients with LHD, PH and normal PVR (passive PH, n = 29) and patients with LHD, PH and increased PVR (reactive PH, n = 32). Echocardiography and right heart catheterization were performed within 24 h. Three parameters were selected related to PR [the acceleration of flow in the right ventricular outflow tract (RVOT), the interval and the augmentation of pressure between peak RVOT flow and peak RV pressure]. Cutoff values aiming at ruling in (high positive likelihood ratio, PLR) and ruling out (low negative likelihood ratio, NLR) increased PVR were determined using receiver operator characteristic (ROC) curves. RESULTS: The proportions of the patients with PH and PVR > 3 WU were 50% and 29%. Twenty-one percent had both increased pulmonary capillary wedge pressure and PVR. The area under the ROC curve for the PR parameters was 0.82-0.89. The PLR with ruling in cutoff values ranged from 4.7 to 9.4. The NLR with ruling out cutoff values ranged from 0.20 to 0.12. CONCLUSIONS: Echocardiographic assessment of PR in patients with LHD can be used to identify or exclude reactive PH.

A high-volume heart transplantation center in an Islamic country.

Cardiac transplants are performed sporadically or not at all in the majority of predominantly Muslim countries in the Middle East. We examined our experience in 76 patients who underwent heart transplantation between January 2005 and May 2010 in our center in Saudi Arabia. Excluded were 50 transplants performed between 1989 and 2004, due to incomplete data. Primary outcomes were complications, 30-day and late mortality rates, and 1-year survival. The heart transplant activity between 2005 and 2010 (15.0 per year) was 4.5-fold higher than that between 1989 and 2004 (3.3 per year). There were 61 (80%) men and 15 (20%) women, with a mean age of 35 years (range, 13-57 years). The mean waiting list time was 64 days (range, 1-262 days), and hospital stay was 30 days (range, 12-166 days). Major complications were infection (10), low-grade rejection (9), reoperation for hemorrhage (8), and sternal dehiscence (2). The 30-day mortality was 7.8% (6/76). Actuarial survival was 87.4% at 1 year and 81.5% at 3 years. A hospital in a Muslim country can increase cardiac transplant activity with excellent 30-day mortality and early survival comparable to that in worldwide counterparts.

Seventeen years' clinical and echocardiographic follow up of mitral balloon valvuloplasty in 520 patients, and predictors of long-term outcome.

BACKGROUND AND AIM OF THE STUDY: Long-term echocardiographic follow up studies of mitral balloon valvuloplasty (MBV) are scarce. The study aim was to assess the long-term results (up to 17 years) of MBV and to identify predictors of restenosis and event-free survival. METHODS: The immediate and long-term clinical and echocardiographic results for 520 consecutive patients (mean age 31 +/- 11 years) who underwent successful MBV for severe mitral stenosis (MS) and were followed up for a mean of 7.3 +/- 4.35 years (range: 1 to 17 years) after MBV, were reported. RESULTS: Immediately after MBV, the mitral valve area (MVA) was increased from 0.92 +/- 0.17 to 1.96 +/- 0.29 cm2 (p < 0.0001). Restenosis occurred in 133 patients (25.6%), and was less frequent (16.7%) in patients with a low mitral echo score (MES < or = 8). Actuarial freedom from restenosis at 10, 15, and 17 years was 73 +/- 2%, 43 +/- 4%, and 23 +/- 6%, respectively, and was significantly higher in patients with MES < or = 8 (84 +/- 2%, 52 +/- 6%, and 36 +/- 9%, respectively; p < 0.001). Event-free survival (death, redo MBV, mitral valve replacement, NYHA class III or IV) at 10, 15, and 17 years was 82 +/- 2%, 45 +/- 5%, and 31 +/- 6% respectively, and was significantly higher for patients with MES < or = 8 (90 +/- 2%, 60 +/- 5%, and 51 +/- 8%, respectively; p < 0.001). Cox regression analysis identified MES > 8 (p < 0.0001) and post-procedure MVA (p = 0.044) as predictors of restenosis, and MES < or = 8 (p < 0.0001), age (p < 0.0001), and post-procedure MVA (p = 0.016) as predictors of event-free survival. CONCLUSION: MBV provides excellent long-term results for selected patients with MS. The long-term outcome of this procedure can be predicted from the baseline clinical and echocardiographic characteristics of the mitral valve.

Immediate and intermediate results of intracoronary stand-alone bolus administration of eptifibatide during coronary intervention (ICE) study.

BACKGROUND: This study evaluated the immediate and intermediate results of intracoronary (i.c.) eptifibatide administration during percutaneous coronary intervention (PCI). Several studies tested intravenous (i.v.) bolus and continuous administration of eptifibatide during PCI. However, limited data are available regarding giving eptifibatide as i.c. bolus alone during PCI. METHODS: We studied clinical outcomes of 376 patients who received coronary stent(s) and eptifibatide by 3 applications during PCI and were followed up over 24 months. Group A (119 patients) had i.c. eptifibatide bolus only, group B (119 patients) had i.c. bolus and i.v. infusion, and group C (138 patients) had i.v. bolus and infusion. The standard 2 boluses of eptifibatide 180 microg/kg were given either via i.c. or i.v. route, and only groups B and C received i.v. infusion at 2 microcg x kg(-1) x min(-1) for 18 to 24 hours. RESULTS: There were 256 males and 120 females, with a mean age of 57 +/- 11 years. Among them, 52% were diabetic. The 6-, 12-, and 24-month cumulative composite end point of death and myocardial infraction was lower in group A (2.5%) compared with group C (10.8%, odds ratio [OR] 4.3, P = .029) and group B (5.8%, OR 2.6, P = .17). Compared with group A, target vessel revascularization was 3-fold in group C (OR 3.3, P = .001) and 2-fold in group B (OR 2.0, P = .061). Bleeding was significantly higher in group C (OR 5.4, P < .0001) and group B (OR 3.4, P = .007) compared with group A. Rehospitalization was significantly lower in group A (10.9%) compared with group B (16.8%) and group C (28%) (P = .0009). CONCLUSION: The i.c.-bolus-alone application of eptifibatide may be safer and superior to the i.v. route, and continuous infusion may not be necessary. Large-scale prospective randomized trials are needed to further validate these findings.

Overview of exercise stress testing.

Exercise stress testing is a non-invasive, safe and affordable screening test for coronary artery disease (CAD), provided there is careful patient selection for better predictive value. Patients at moderate risk for CAD are best served with this kind of screening, with the exception of females during their reproductive period, when a high incidence of false positive results has been reported. Patients with a high pretest probability for CAD should undergo stress testing combined with cardiac imaging or cardiac catheterization directly. Data from the test, other than ECG changes, should be taken into consideration when interpreting the exercise stress test since it has a strong prognostic value, i.e. workload, heart rate rise and recovery and blood pressure changes. Only a low-level exercise stress test can be performed early post myocardial infarction (first week), and a full exercise test should be delayed 4 to 6 weeks post uncomplicated myocardial infarction. The ECG interpretation with myocardial perfusion imaging follows the same criteria, but the sensitivity is much lower and the specificity is high enough to overrule the imaging part.

Immediate and long-term results of percutaneous mitral balloon valvotomy in asymptomatic or minimally symptomatic patients with severe mitral stenosis.

The purpose of this study was to evaluate the safety and value of percutaneous mitral balloon valvotomy (PMBV) in asymptomatic or minimally symptomatic patients with severe mitral stenosis (MS). There are very limited data supporting the concept of PMBV in asymptomatic or minimally symptomatic patients with severe MS. We analyzed the results of 539 consecutive patients with severe MS who underwent PMBV at our hospital. Patients were divided according to their symptoms at the time of PMBV into group A (55 patients), who had few or no symptom (NYHA class 1 or 2), and group B (484 patients), who had severe symptom (NYHA class 3 or 4). Patients had clinical and echocardiographic follow-up for 0.5-15 years. There was no significant difference in baseline characteristics between the two groups. The immediate mitral valve area (MVA) was equal in both groups. The follow-up MVA was larger in group A (1.9 +/- 0.38 vs. 1.7 +/- 0.4 cm(2); P = 0.002), and restenosis occurred in 11% in group A vs. 23% in group B (P = 0.023). Actuarial freedoms from restenosis at 5, 10, and 13 years were significantly higher for group A than for group B (97% +/- 2%, 77% +/- 9%, 77% +/- 9% vs. 85% +/- 1%, 62% +/- 3%, 39% +/- 5%; P = 0.0018). Atrial fibrillation at follow-up was encountered in 11% in group A vs. 20% in group B (P = 0.042). There was a significant reduction of the left atrial size in both groups. Event-free survivals at 5, 10, and 13 years were higher for group A than for group B (97% +/- 2%, 80% +/- 9%, 80% +/- 9% vs. 86% +/- 1%, 65% +/- 3%, 42% +/- 3%; P = 0.0018). This study demonstrated excellent immediate results of PMBV in asymptomatic or minimally symptomatic patients with severe MS and long-term results are better compared to the reported natural history of such patients. We recommend mitral balloon valvotomy (MBV) for patients with severe MS with few or no symptoms, provided the valve morphology is suitable for MBV.