Background Recurrence of acute myocarditis (AM) is challenging. The management and natural history of patients who experience a recurrence of AM (Re‐AM) remain poorly characterized. The aim of this study is to investigate clinical characteristics and outcomes of patients with Re‐AM. Methods In this international multicenter study, 141 consecutive patients with biopsy‐proven or cardiac magnetic resonance‐proven Re‐AM (35 [26–45] years, 77% male, median left ventricular ejection fraction 55%) were investigated and compared with 372 consecutive patients with single acute myocarditis (S‐AM). The primary outcome was a composite of all‐cause mortality, heart transplant and major ventricular arrhythmias. Results Patients with Re‐AM had more frequently a family history of cardiomyopathy (19% in Re‐AM versus 2.8% in S‐AM, P<0.001) and a diffuse late gadolinium enhancement compared with patients with S‐AM (46% in Re‐AM versus 34% in S‐AM, P=0.019). The extent of late gadolinium enhancement also increased between the first and the second AM episode in patients with Re‐AM (P=0.001). During a median follow‐up of 33 months (interquartile range, 23–52) patients with Re‐AM had a higher risk of primary outcome (P=0.001) compared with patients with S‐AM, as well as a significantly elevated competing risk of major ventricular arrhythmias (P<0.001), which remained independently associated even after adjustment (hazard ratio, 2.15 [95% CI, 1.15–4.04], P=0.017). A family history of cardiomyopathy, autoimmune diseases, and ring‐like late gadolinium enhancement was independently associated with a higher risk of recurrent AM. Conclusions Re‐AM is a distinct clinical subgroup of AM associated with generally worse prognosis and a specific increased arrhythmic risk compared with S‐AM.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers.

Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant acquired risk factors for DCM (hypertension, diabetes, smoking habit, and/or previous alcohol and cocaine abuse) and with a family history of both DCM and sudden cardiac death. The left ventricular systolic function, as assessed by standard echocardiography, was 20%. The genetic analysis performed using TruSight Cardio panel, including 174 genes related to cardiac genetic diseases, revealed a novel nonsense TTN variant (TTN:c.103591A > T, p.Lys34531*), falling within the M-band region of the titin protein. This region is known for its important role in maintaining the structure of the sarcomere and in promoting sarcomerogenesis. The identified variant was classified as likely pathogenic based on ACMG criteria. The current results support the need of genetic analysis in the presence of a family history, even when relevant acquired risk factors for DCM may have contributed to the severity of the disease.

ACM is a rare hereditary heart disease characterized by a progressive fibro-fatty replacement of the myocardium that can affect either the right or the left ventricle or both. It is mainly caused by variants in the desmosome genes with autosomal dominant transmission and incomplete penetrance. The disease shows a wide spectrum of clinical manifestations, including ventricular arrhythmias, HF and myocarditis. The latter is considered a ‘hot phase’ in the natural history of the disease and must therefore be distinguished from the isolated AM, which is frequently due to viral infections. Our case report is an example of how an AM, as the first manifestation of the disease, helped to reach a diagnosis of ACM through the genetic analysis. In fact, the multi-parametric investigation, which also included CMR and EMB, revealed controversial aspects that led us to perform the genetic test. The latter revealed a heterozygous pathogenic variant in the PKP2 that was considered definitive proof of ACM.

To the Editor Although acute myocarditis has not been described as an adverse event in landmark trials of coronavirus disease 2019 (COVID-19) vaccines, it has been frequently reported as a rare complication in the real world.1–6 The prognosis of this self-limiting condition is generally good, but little is known about the long-term outcomes.2 This work aims to report a single-center experience giving new insights into this topic. Methods We describe four cases diagnosed with myocarditis7 at Sant’Andrea Hospital in Rome, Italy, within 24–96 h after receiving a dose of COVID-19 vaccination between 1 August and 15 October 2021. All patients underwent blood tests, ECG and echocardiography at the time of presentation. All patients underwent cardiovascular magnetic resonance (CMR) within a few weeks from the onset of symptoms. All patients received an outpatient evaluation including ECG and echocardiography after a median of 6 months. Follow-up CMR at 6 months was performed and compared with the previous one in all four patients. Results Key characteristics of each case are included in Table 1. All patients had chest pain and elevated troponin levels on presentation to the emergency department. Serum C-reactive protein levels were very low and procalcitonin levels were in the normal range in all but one patient. None developed an increase in white blood cell count or changes in erythrocyte sedimentation rate. Abnormal ECG findings were recorded only in one patient presenting nonspecific ST changes. Echocardiography demonstrated preserved left ventricular (LV) ejection fraction (EF) and no regional wall motion abnormalities in all patients; pericardial effusion was present in three patients. The two patients who underwent CMR within 4 weeks of symptom onset had findings of myocardial edema with one having also late gadolinium enhancement (LGE). Conversely, the two CMRs performed after 4 weeks of onset showed LGE without myocardial edema. Hospitalization ranged 3–4 days. All patients were treated with NSAIDs, beta blockers and ACEi. None of the patients had in-hospital sustained arrhythmias or suffered from clinical acute heart failure, and all had normal cardiac function at discharge. All were asymptomatic and had not complications or rehospitalizations during follow-up. After 6 months from the onset, none had persistent ECG changes or echocardiographic alterations and inflammatory biomarkers were in the normal range. On 6 months, follow-up, CMR findings of myocardial edema disappeared in all cases, but areas of LGE present in the acute phase persisted almost unchanged in terms of extent and distribution. Table 1 - Key characteristics of patients with acute myocarditis following coronavirus disease 2019 vaccination Case 1 Case 2 Case 3 Case 4 Age (years) 39 20 54 21 Gender Male Male Female Female Coronary artery disease risk factors No No Hypertension, dyslipidemia No Cardiovascular history Previous myocarditis No No No Known prior COVID-19 infection No No No No Symptoms Chest pain, generalized malaise Chest pain Chest pain, dyspnea Chest pain, dyspnea, fever COVID19 vaccine doses prior to symptom onset 1 1 1 2 COVID19 vaccine manufacturer Johnson & Johnson Moderna Pfizer Pfizer Days from vaccination to symptom onset 3 3 2 2 SARS-COV-2 PCR testing Negative Negative Negative Negative Serum hsTnI (pg/ml) 5734 9313 158 390 Serum BNP (pg/ml) 43 Not obtained 64 Not obtained Serum CRP (mg/dl) 1.1 0.03 0.12 5.78 Serum PCT (ng/ml) 0.02 0.02 0.02 0.06 Serum ESR (mm/h) 17 2 12 8 ECG No abnormal findings No abnormal findings Nonspecific ST changes No abnormal findings TTE LVEF (%) 57 63 61 58 Pericardial effusion No Yes Yes Yes Anatomic coronary artery assessment Not obtained Nonobstructive (ICA) Nonobstructive (ICA) Not obtained Time from clinical onset to first CMR 5 weeks 8 weeks 4 weeks 2 weeks First CMR findings LGE with sub-epicardial distribution in the mid-basal inferolateral wall (not present in the previous CMR)Pericardial enhancementNo edema LGE with mesocardial distribution in the mid-apical inferolateral wallNo edema Focal edema with sub-epicardial distribution in the basal lateral wallNo LGE LGE with sub-epicardial distribution in the basal inferolateral wallFocal and linear sub-epicardial edema in the same segments Oxygen support No No No No Length of stay (days) 4 3 4 3 Discharge medications (in addition to chronic therapy) Ibuprofen Aspirin Ibuprofen Aspirin Follow-up 6 months 6 months 6 months 6 months Time from clinical onset to second CMR 6 months 6 months 6 months 6 months Second CMR findings LGE with sub-epicardial distribution in the mid-basal inferolateral wall unchangedPericardial enhancementNo edema LGE with mesocardial distribution in the mid-apical inferolateral wall unchangedNo edema No LGENo edema LGE with sub-epicardial distribution in the basal inferolateral wall unchangedNo edema BNP, brain natriuretic peptide (normal range 0–65 pg/ml); CMR, cardiovascular magnetic resonance; CRP, C-reactive protein (normal range 0–0.5 mg/dl); COVID-19, the coronavirus disease of 2019; ESR, erythrocyte sedimentation rate (normal range 2–25 mm/h); hsTnI, high-sensitivity troponin I (normal range 0–34 pg/ml); ICA, invasive coronary angiography; LGE, late gadolinium enhancement; PCT, procalcitonin (normal range <0.05 ng/ml); TTE LVEF, transthoracic left ventricular ejection fraction. Comment Acute myocarditis following COVID-19 vaccination is a well defined clinical entity characterized in most cases by a presentation with chest pain and troponin I elevation without impairment of left ventricular ejection fraction (LVEF) and a benign in-hospital course.8,9 An atypical finding compared with other forms of myocarditis3 and in previously reported vaccine-associated10–12 is the prevalent absence of inflammatory serological changes, suggesting a noninflammatory pathophysiology. With respect to the CMR findings, all patients in acute phase met at least one of the two updated 2018 Lake Louise CMR main criteria for acute myocarditis.13 Of note, sub-epicardial LGE was a frequent finding and persisted mostly unchanged after a follow-up of 6 months. In nonvaccine-associated myocarditis, the presence of LGE is generally associated with increased risk of adverse cardiovascular events during follow-up. However, data are lacking with regard to the prognostic significance of persistent LGE in the absence of severe LV dysfunction and remodeling. In this setting, prolonged clinical and instrumental follow-up is recommended as these findings may reflect the extensive myocardial derangement potentially leading to future evolution to LV remodeling or late arrhythmias.14 Interestingly, the localization of LGE to the inferolateral LV segments on CMR was similarly seen in other case series11 and seems to carry a better prognosis compared with LGE localized to the septal segments.15 Nevertheless, further investigations are needed to determine the prognostic impact of these findings in the context of myocarditis following COVID-19 vaccination (Fig. 1).Fig. 1: Cardiovascular magnetic resonance findings. (a) Case 1 CMR on acute phase: PSIR sequences. Short-axis view, basal segments. The image shows a linear area of LGE with sub-epicardial distribution in the inferolateral wall (arrow). (b) Case 1 CMR after 6 months of follow-up: PSIR sequences. Short-axis view, basal segments. The image shows the persistence of pericardial enhancement (∗) and linear sub-epicardial LGE in the inferolateral wall of left ventricle (arrow). (c) Case 2 CMR on acute phase: PSIR sequences. Long-axis view. The image shows an area of LGE with mesocardial distribution in the mid-apical inferolateral wall (arrows). (d) Case 2 CMR after 6 months of follow-up: PSIR sequences. Long-axis view. The image shows the persistence of the area of LGE with mesocardial distribution in the mid-apical inferolateral wall (arrows). (e) Case 3 CMR on acute phase: STIR sequences. Short-axis view. The image shows focal edema with sub-epicardial distribution in the basal lateral wall (arrow). (f) Case 3 CMR after 6 months of follow-up: STIR sequences. Short-axis view, basal segments. The image shows the dissolution/disappearance of the myocardial edema previously detected in the lateral wall. (g) Case 4 CMR on acute phase: PSIR sequences. Short-axis view. The image shows a liner area of LGE with sub-epicardial distribution in the basal inferolateral wall (arrow). (h) Case 4 CMR after 6 months of follow-up: PSIR sequences. Short-axis view, basal segments. The image shows the persistence of liner area of LGE. CMR, cardiovascular magnetic resonance; LGE, late gadolinium enhancement.Conflicts of interest There are no conflicts of interest.

Objective: Although acute myocarditis has not been observed as an adverse event in landmark trials of COVID-19 vaccines, it has been reported as a rare complication in real-world. The study aims to report a single-center experience on this issue. Design and method: We identified five cases of acute myocarditis with consistent temporal association to administration of COVID-19 vaccine and described clinical, serological, echocardiographic and cardiac magnetic resonance findings both in the acute phase and after a median follow up of 6 months. Results: All five patients received a COVID-19 vaccination dose within 24 to 96 hours before the onset of symptoms. Four patients received an mRNA vaccine (Comirnaty or Spikevax) and one received the adenovirus vaccine (Janssen). Only one patient had a known prior COVID-19 infection. All patients presented with chest pain and troponin I elevation occurring after the first vaccine dose in four cases. All patients tested negative for acute COVID-19 infection by polymerase chain reaction at admission. Blood tests revealed no or only mild inflammatory serological changes. Only one patient developed an increase in white blood cell count. None had specific changes on electrocardiography and echocardiography demonstrated preserved left ventricular systolic function and no regional wall motion abnormalities in all patients. Three patients underwent coronary angiography since risk factors and troponin trends raised clinical suspicion of acute coronary syndrome, none showed evidence of obstructive coronary artery disease. All patients had a mild to moderate disease not complicated by acute heart failure or arrhythmias. Cardiac Magnetic Resonance was performed in four cases and showed myocardial oedema and late gadolinium enhancement during the acute phase with persistence of areas of late gadolinium enhancement after a median follow-up of 6 months. None had further symptoms or hospitalizations since discharge. Conclusions: Acute myocarditis following COVID-19 vaccination is a well-defined clinical entity. Our findings suggest an immune rather than inflammatory pathogenesis and a benign course without clinical complication after a median follow-up of 6 months, but further studies are needed to define the prognostic significance of persistent findings on cardiac magnetic resonance.

Background: A blunted heart rate (HR) response is associated with an impaired peak oxygen uptake (pVO(2)), a powerful outcome predictor in hypertrophic cardiomyopathy (HCM). The present multicenter study sought to determine the prognostic role for exercise-induced HR response in HCM. Methods: A total of 681 consecutive HCM outpatients on optimized treatment were recruited. The heart failure (HF) end-pointwas death due to HF, cardiac transplantation, NYHA III-IV class progression, HF worsening leading to hospitalization and severe functional deterioration leading to septal reduction. The sudden cardiac death (SCD) end-point included SCD, aborted SCD and appropriate implantable cardioverter defibrillator discharges. Results: During a median follow-up of 4.2 years (25-75th centile: 3.9-5.2), 81 patients reached the HF and 23 the SCD end-point. Covariates with independent effects on the HF end-point were left atrial diameter, left ventricular ejection fraction, maximal left ventricular outflow tract gradient and exercise cardiac power (ECP=pVO(2)*systolic blood pressure) (C-Index= 0.807) whereas the HCM Risk-SCD score and the ECP remained associated with the SCD end-point (C-Index = 0.674). When the VO2-derived variables were not pursued, peak HR (pHR) re-entered in the multivariate HF model (C-Index= 0.777) and, marginally, in the SCD model (C-index= 0.656). A pHR= 70% of the maximum predicted resulted as the best cut-off value in predicting the HF-related events. Conclusions: The cardiopulmonary exercise test is pivotal in the HCM management, however the pHR remains a meaningful alternative parameter. A pHR < 70% identified a HCM population at high risk of HF-related events, thus calling for a reappraisal of the chronotropic incompetence threshold in HCM. (c) 2018 Elsevier B.V. All rights reserved.

In hypertrophic cardiomyopathy (HC), a process of left ventricular (LV) remodeling carrying an adverse prognosis has been described. Conversely, a gradual and benign LV wall thinning has been suggested but never investigated. Therefore, we studied a HC cohort over a long period of time to evaluate the occurrence of a LV remodeling with a benign clinical course. Data of HC patients aged 18 to 65 years and without any condition known to influence LV remodeling were analyzed over a mean follow-up of 7.6 +/- 5.7 years. Of 231 HC patients (65% males, mean age 46 +/- 12 years), 47 (20%) developed LV remodeling, of whom 23 (10%) had a thinning 15% of LV maximal wall thickness from baseline without systolic dysfunction (MWT thinning); 13 (6%) progressed to a LV ejection fraction <50% (end-stage HC) and 11 (5%) developed an apical aneurysm. Follow-up length (odds ratio 1.07, 95% confidence interval 1.00 to 1.15, p = 0.06) and maximal LV wall thickness at baseline (odds ratio 1.14, 95% confidence interval 1.04 to 1.25, p = 0.004) were the main predictors of MWT thinning. Compared with patients with end-stage HC and apical aneurysm, those with MWT thinning showed lower HC-related morbidity (92% and 36% vs 22%, p = 0.003) and mortality (31% and 27% vs 4%, p = 0.02). Furthermore, they showed a combined HC-related morbidity and mortality similar to patients without LV remodeling (incidence 29/1000 vs 26/1000 patient-year, p = 0.77). In conclusion, a process of LV wall thinning with a benign outcome can occur over the long term in patients with HC. The prognostic importance of LV remodeling varies in relation to the different changes in LV morphology and function. (C) 2018 Elsevier Inc. All rights reserved.

Oxidative stress is currently viewed as a key factor in the genesis and progression of Heart Failure (HF). The aim of this study was to characterize the mitochondrial changes linked to oxidative stress generation in circulating peripheral blood mononuclear cells isolated from chronic HF patients (HF_PBMCs) in order to highlight the involvement of mitochondrial dysfunction in the pathophysiology of HF. To assess the production of reactive oxygen species (ROS), mitochondrial function and ultrastructure and the mitophagic flux in circulating PBMCs we enrolled 15 patients with HF and a control group of ten healthy subjects. The HF_PBMCs showed a mitochondrial population consisting of damaged and less functional organelles responsible of higher superoxide anion production both at baseline and under in vitro stress conditions, with evidence of cellular apoptosis. Although the mitophagic flux at baseline was enhanced in HF_PBMCs at level similar to those that could be achieved in control PBMCs only under inflammatory stress conditions, the activation of mitophagy was unable to preserve a proper mitochondrial dynamics upon stress stimuli in HF. In summary, circulating HF_PBMCs show structural and functional derangements of mitochondria with overproduction of reactive oxidant species. This mitochondrial failure sustains a leucocyte dysfunctional status in the blood that may contribute to development and persistence of stress conditions within the cardiovascular system in HF.

Background: The 12-lead surface electrocardiographic (ECG) analysis is able to provide independent predictors of prognosis in several cardiovascular settings, including hypertrophic cardiomyopathy (HCM). The present single-center study investigated the possible ability of several ECG-derived variables in stratifying sudden cardiac death (SCD) risk and, possibly, in improving the accuracy of the 2014 European Society of Cardiology guidelines. Methods: A total of 221 consecutive HCM outpatients were recruited and prospectively followed. All of them underwent a full clinical and instrumental examination, including a 12-lead surface ECG to calculate the dispersion for the following intervals: QRS, Q-Tend (QT), Q-Tpeak (QTp), Tpeak-Tend (TpTe), J-Tpeak (JTp), and J-Tend (JT). The study composite end-point was SCD, aborted SCD, and appropriate implantable cardioverter defibrillator (ICD) interventions. Results: During a median follow-up of 4.4 years (25th-75th interquartile range: 2.4-9.4 years), 23 patients reached the end-point at 5-years (3 SCD, 3 aborted SCD, 17 appropriate ICD interventions). At multivariate analysis, the spatial QT dispersion corrected according to Bazett's formula (QTcd) remains independently associated to the study endpoint over the HCM Risk-SCD score (C-index 0.737). A QTcd cutoff value of 93 ms showed the best accuracy in predicting the SCD endpoint within the entire HCM study cohort (sensitivity 56%, specificity 75%, positive predictive value 22%, negative predictive value 97%). Conclusion: Our data suggest that the QTcd might be helpful in SCD risk stratification, particularly in those HCM categories classified at low-intermediate SCD risk according to the contemporary guidelines. (C) 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

BACKGROUND:Heart failure (HF) progression and its complications represent major emergent concerns in hypertrophic cardiomyopathy (HCM). We investigated the possible adjunctive role of cardiopulmonary exercise testing (CPET) in predicting HF-related events. An exercise-derived risk model, theHYPertrophicExercise-derivedRiskHF(HYPERHF), has been developed. METHODS AND RESULTS:A multicenter cohort of 620 consecutive HCM outpatients was recruited and followed (2007 to 2015). The endpoint was death from HF, cardiac transplantation, NYHA III-IV class progression, severe functional deterioration leading to hospitalization for septal reduction, and hospitalization for HF worsening. During a median follow-up of 3.8 years (25-75th centile: 2.3-5.3 years), 84 patients reached the endpoint. Peak circulatory power (peak oxygen consumption * peak systolic blood pressure), ventilatory efficiency and left atrial diameter were independently associated with the endpoint and, accordingly, integrated into the HYPERHFmodel (C index: 0.849; best cutoff value equal to 15%). CONCLUSIONS:CPET is useful in the evaluation of HCM patients. In this context, the HYPERHFscore might allow early identification of those patients at high risk of HF progression and its complications. (Circ J 2016; 80: 2204-2211).

Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective.

BACKGROUND Growing evidence suggests that late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) is an additive marker of disease severity, and possibly of arrhythmic risk, in hypertrophic cardiomyopathy (HCM). We investigated the possible relationship between LGE and markers of myocardial repolarization dispersion in HCM. METHODS AND RESULTS Eighty-five HCM outpatients underwent CMR and short-period electrocardiogram analysis to calculate the temporal myocardial repolarization dispersion through the QT variance normalized for QT mean (QTVN) and the QT variability index (QTVI). The QT dispersion in the spatial domain was also obtained. Patients with LGE (62%) had higher left atrial volume, maximum wall thickness, and left ventricular mass (P<0.0001), as well as a greater prevalence of non-sustained ventricular tachycardia (P<0.0001) and hypotensive blood pressure response (P=0.044). Both QTVN and QTVI were higher in the group with LGE (P<0.0001). At multivariate analysis, using QTVI as the dependent variable, %LGE (P<0.0001), age (P<0.0001), left ventricular outflow obstruction (P=0.038), and sudden cardiac death risk factor burden (P=0.020) reached statistical significance. Otherwise, only %LGE (P=0.005) and left ventricular mass index (P=0.015) remained associated with QTVN. CONCLUSIONS Temporal myocardial repolarization dispersion correlates with LGE extent. Whether these variables could be useful in HCM clinical management warrants confirmation by larger prospective studies.

NSVT in ICD Patients with HCMBackgroundNonsustained ventricular tachycardia (NSVT) is a risk factor for sudden death (SD) in hypertrophic cardiomyopathy (HCM). Implantable cardioverter-defibrillators (ICDs) enable accurate assessment of NSVT burden and characteristics. In a cohort of HCM patients with ICD, we characterized Holter- and ICD-retrieved NSVT and evaluated their relationship with prognosis.Methods and ResultsWe studied a cohort of consecutive HCM patients who underwent Holter ECG before receiving a primary prevention ICD. Patients were followed from ICD implantation to the first appropriate ICD therapy. We evaluated the association of NSVT characteristics with ICD interventions. Study cohort included 51 HCM patients (28 males, mean age: 48 15 years). Thirty-four patients (66%) had NSVT at pre-ICD Holter ECG. Out of 17 patients with negative baseline Holter, 7 (41%) showed ICD-NSVT. In patients with both Holter- and ICD-NSVT, these latter were faster (199 +/- 27 bpm vs. 146 +/- 24 bpm; P < 0.001) and longer (16 +/- 8 beats vs. 10 +/- 11 beats; P = 0.008) than Holter-NSVT. During follow-up (38 +/- 24 months), 11 patients (22%) experienced appropriate ICD therapy. NSVT length in beats (hazard ratio [HR]: 1.05; 95% CI: 1.00-1.10; P = 0.02) but not heart rate (HR: 1.00; 95% CI: 0.98-1.02; P = 0.86) predicted ICD intervention. A simple index of NSVT severity (heart rate x length in beats/100 >28) predicted ICD intervention (HR: 5.45; 95% CI: 1.10-27.32; P = 0.03).ConclusionsLong-lasting and rapid NSVT recorded during continuous rhythm monitoring predict appropriate ICD intervention in high-risk HCM patients. Further studies should assess whether prolonged rhythm monitoring may assist in evaluating patients at intermediate risk of SD, in which the decision to implant an ICD needs to be individualized.

Renovascular hypertension is one of the most common forms of secondary hypertension, and its prevalence is estimated between 1 and 5% in the general hypertensive population [ [1] Piecha G. Wiecek A. Januszewicz A. Epidemiology and optimal management in patients with renal artery stenosis. J Nephrol. 2012; 25: 872-878 Crossref PubMed Scopus (24) Google Scholar ]. Amongst these conditions, renal artery stenosis (RAS), defined as >50% stenosis of the renal artery lumen, represents one of the leading causes of renovascular hypertension. It is frequently related to the presence of renal atherosclerosis (predominantly in elderly individuals), fibro-muscular dysplasia (FMD) and arteritis (more often in young women). Compared to other clinical conditions, FMD shows different aetiology, as well as different clinical presentation, prognosis and therapeutic options [ [2] Safian R.D. Textor S.C. Renal-artery stenosis. N Engl J Med. 2001; 344: 431-442 Crossref PubMed Scopus (894) Google Scholar ].

Most patients with hypertrophic cardiomyopathy (HCM) usually complain of a reduced exercise capacity, and several factors have been advocated as possible causes of this clinical feature. The present single-center study was designed to investigate exercise capacity and its main clinical determinants in HCM patients. One hundred ninety seven patients of 223 evaluated underwent a complete clinical assessment, including Doppler echocardiography, cardiopulmonary exercise test (CPET) and, in most cases, cardiac magnetic resonance. The HCM population (male 75 %; age 47 ± 16 years; NYHA class I or II 95 %; left ventricular ejection fraction 61 ± 3 %; resting left ventricular outflow tract gradient ≥30 mmHg 22 %; late gadolinium enhancement presence 58 %) showed slightly reduced mean peak oxygen uptake values (pVO2 75 ± 15 %, 23.2 ± 6.7 ml/kg/min) with a significant reduction of the achieved percentage of peak heart rate reserve (%pHRR 65 ± 20 %). Adopting a pVO2 <80 % cut-off value, 59 % of HCM patients showed a reduced exercise capacity. Age, male gender, left atrial size, chronotropic and systolic blood pressure response, ventilatory efficiency, late gadolinium enhancement presence and β-blocker therapy were independently associated with pVO2 (R 2-adjusted index 0.738). A %pHRR cut-off value of 74 % appeared to most accurately predict an impaired exercise capacity (area under curve 0.90). A great prevalence of reduced exercise capacity is present in NYHA class I–II HCM patients. Notwithstanding its multifactorial genesis, few parameters might be adopted in identifying this feature. In this context, %pHRR value might represent a reliable and easy-to-obtain tool for the clinical evaluation of HCM patients.

We are describing a case of acute prosthetic valve thrombosis, presented in emergency department with clinical findings of pulmonary embolism. This case, underlines the best diagnostic accuracy of the chest CT scan, comparison to the trans thoracic echocardiogram for the differential diagnosis.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in sarcomere protein genes. MYBPC3 mutations are reported as a frequent cause of HCM. We aimed to identify the gene mutation underlying HCM in an Italian patient and his family composed of 13 relatives. Mutation screening of 658 known mutations was performed using a rapid and efficient mutation detection system based on semiautomated MALDI-TOF mass spectrometry using the Sequenom MassArray System and iPLEX Gold genotyping chemistry. Subsequently, direct sequencing of the coding exons and flanking intronic regions was performed for the most suitable HCM genes (MYBPC3, MYH7, TNNT2, TNNI3, and TPM1) in the index patient. We found a novel MYBPC3 gene mutation: G13999T (Gln689His). No other sarcomere gene mutation was found in this family. This genetic variant, which changes the last amino acid of MYBPC3 exon 21, affects a highly conserved residue. Furthermore, the Gln689His does not appear in public databases and has never been described as a polymorphism. The potential pathogenic role of this novel mutation was underlined by its absence in a sample of healthy subjects (n = 122) from the general Italian population. In summary, a novel MYBPC3 gene mutation has been identified in a patient affected by HCM, whereas it was absent in 244 reference alleles.