Evolution and triggers of defibrillator shocks in patients with arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Implantable cardioverter-defibrillators (ICDs) can prevent sudden cardiac death due to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The aim of our study was to assess the cumulative burden, evolution and potential triggers of appropriate ICD shocks during long-term follow-up, which may help to reduce and further refine individual arrhythmic risk in this challenging disease. METHODS: This retrospective cohort study included 53 patients with definite ARVC according to the 2010 Task Force Criteria from the multicentre Swiss ARVC Registry with an implanted ICD for primary or secondary prevention. Follow-up was conducted by assessing all available patient records from patient visits, hospitalisations, blood samples, genetic analysis, as well as device interrogation and tracings. RESULTS: Fifty-three patients (male 71.7%, mean age 43±2.2 years, genotype positive 58.5%) were analysed during a median follow-up of 7.9 (IQR 10) years. In 29 (54.7%) patients, 177 appropriate ICD shocks associated with 71 shock episodes occurred. Median time to first appropriate ICD shock was 2.8 (IQR 3.6) years. Long-term risk of shocks remained high throughout long-term follow-up. Shock episodes occurred mainly during daytime (91.5%, n=65) and without seasonal preference. We identified potentially reversible triggers in 56 of 71 (78.9%) appropriate shock episodes, the main triggers representing physical activity, inflammation and hypokalaemia. CONCLUSION: The long-term risk of appropriate ICD shocks in patients with ARVC remains high during long-term follow-up. Ventricular arrhythmias occur more often during daytime, without seasonal preference. Reversible triggers are frequent with the most common triggers for appropriate ICD shocks being physical activity, inflammation and hypokalaemia in this patient population.

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy.

Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear. Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint. Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2-44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis. A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE. Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE. Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.

Impact of stroke volume assessment by integrating multi-detector computed tomography and Doppler data on the classification of aortic stenosis.

BACKGROUND: The prevalence of low flow low gradient (LFLG) severe aortic stenosis (AS) may be overrated due to underestimation of stroke volume in two-dimensional (2D) echocardiography. The implications of 3D imaging on stroke volume calculation for AS classification have not been elucidated. Integrating multi-detector computed tomography (MDCT) and Doppler data may improve diagnostic accuracy in patients with LFLG AS. METHODS: A total of 186 patients with severe AS evaluated for transcatheter aortic valve replacement were classified according to indexed stroke volume (SVI, cut-off 35mL/m2) and mean transaortic pressure gradient (cut-off 40mmHg). SVI was calculated using a) the biplane Simpson's method, b) left ventricular outflow tract (LVOT) velocity time integral (VTI) and LVOT diameter determined by 2D echocardiography, or c) LVOT VTI and LVOT area planimetered by MDCT. RESULTS: SVI assessed by the biplane Simpson's method was smaller than that obtained from 2D echocardiography LVOT diameter (29.5±0.6 vs 34.9±0.8mL/m2, p<0.001). The latter was smaller than SVI calculated by integrating MDCT and Doppler data (47.5±1.4mL/m2, p<0.001). LFLG and paradoxical LFLG severe AS were diagnosed in 42.5% and 27.4% of patients using the biplane Simpson's method, in 30.1% and 16.7% using 2D echocardiography LVOT diameter, and in 17.2% and 8.1% when integrating MDCT and Doppler data. CONCLUSIONS: The prevalence of LFLG and paradoxical LFLG severe AS was overestimated by 2.5- and 3.4-fold based on 2D echocardiography alone. Integration of MDCT and Doppler data should be considered for stroke volume assessment in the classification of severe AS.

Prognostic power of NT-proBNP in left ventricular non-compaction cardiomyopathy.

BACKGROUND: The risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. This study was designed to determine the prognostic value of NT-proBNP, left ventricular ejection fraction (LVEF), NYHA class, and exercise capacity in LVNC patients. METHODS: Cox regression analyses were performed for evaluating the prognostic value of NT-proBNP, LVEF, NYHA class, and exercise capacity on the occurrence of death or heart transplantation. 153 patients were included. RESULTS: During 1013 person-years (longest follow-up 18.5years) 23 patients (15%) died or underwent heart transplantation. We observed a significant relationship of NT-proBNP (adjusted HR 2.44, 95% CI 1.45-4.09, for every NT-proBNP doubling, p=0.0007) and LVEF (adjusted HR for age 60years: 2.68, 95% CI 1.62-4.41, p=0.0001) with the risk of death or heart transplantation. Combined covariate analysis indicated a strong influence of NT-proBNP (adjusted 2.89, 95% CI 1.33-6.26, p=0.007), whereas LVEF was no longer significant (adjusted HR 0.82, 95% CI 0.42-1.67, p=0.66) demonstrating a favorable prognostic power of NT-proBNP over LVEF. An increase in NYHA class was associated with a worse outcome, and exercise capacity revealed a trend in the same direction. For all the abovementioned analyses, similar results were obtained when assessing the values at first presentation. CONCLUSION: This study provides evidence that an increase in NT-proBNP is a strong predictor of outcome in patients with LVNC. The prognostic power of NT-proBNP is at least as good as that of LVEF, indicating that routine NT-proBNP measurement may improve risk assessment in LVNC.

Prominent left ventricular trabeculations in competitive athletes: A proposal for risk stratification and management.

BACKGROUND: Recently, an unexpectedly large prevalence of Left Ventricular Non Compaction (LVNC) has been reported in athletes, raising the question of the appropriateness of current diagnostic criteria. We sought to describe prevalence and clinical characteristics of athletes with suspected LVNC in a large cohort of Olympic athletes. METHODS: Over 29months, 2501 consecutive athletes underwent a cardiac evaluation including physical examination, ECG, exercise test and echocardiography. Additional investigations (Cardiac Magnetic Resonance and/or genetic testing) were selectively performed in athletes with abnormal ECGs, ventricular arrhythmias, borderline LV dysfunction or positive family history. RESULTS: Of the 2501 athletes, 36 (1.4%) showed prominent trabeculations suggestive for LVNC. Of these, 3 (0.1%) were considered to be affected by LVNC, based on presence of LV dysfunction (ejection fraction<50%) and/or positive family history and genetic testing; these athletes were cautiously restricted from competitions and entered a clinical follow-up program. The remaining 33 athletes, in the absence of LV impairment or familial cardiac diseases, were considered normal (n=24) or unlikely affected (n=9), regardless of the extent of the trabeculations. CONCLUSIONS: In a large athlete population, a marked LV trabecular pattern was seen in 1.4%. Only a small subset of these athletes (0.1%) showed familial, clinical and morphologic changes supporting the diagnosis of LVNC. In the vast majority of the athletes, the increased trabeculations were not associated with LV dysfunction and/or positive family history, likely representing a morphologic LV variant, deprived of clinical significance.

Lack of Accessible Data on Prosthetic Heart Valves.

Incomplete information on characteristics of prosthetic heart valves (PHV) may lead to inappropriate choices for PHV implantation (patient-prosthesis-mismatch) or erroneous interpretation of PHV function after implantation. No single and easy accessible source provides all relevant information on PHV. The aim of this study was to provide a comprehensive overview of available data for the majority of PHVs and annuloplasty rings. Information was collected by reviewing articles published on www.pubmed.org up to December 2014 and by written contact to all PHV manufacturers. Four areas of interest were defined: (1) PHV image, (2) in vivo transvalvular gradients, (3) effective orifice area (EOA) calculators and (4) PHV dimensions. Available information was classified as complete (all categories), partial (two or three categories) or minimal (one category). 108 PHV (including homografts) and 34 annuloplasty rings systems were identified. The information on PHV was complete, partial or minimal in 19.5, 61.0 and 19.5% of PHV, respectively. In 91.6% a picture of the valve could be obtained, whereas normative data for transvalvular gradients and EOA calculators were available in 63.0 and 25.0% of all PHV, respectively. The available data was summarized on a new open access webpage ( www.valveguide.ch ). There is a lack of accessible data on PHV dimensions, normal transvalvular gradients and effective orifice area calculators, although such information is of crucial importance for proper PHV assessment.

Left Ventricular Noncompaction Diagnosis and Management Relevant to Pre-participation Screening of Athletes.

Left ventricular noncompaction (LVNC) has been extensively studied over the last years, and an increasing number of cases have been reported worldwide, with a large proportion comprising young and asymptomatic subjects, including athletes. The current epidemic of LVNC is likely the consequence of several causes, that is, the increased awareness of the disease and the refined cardiovascular imaging techniques. The current diagnostic methods, based uniquely on definition of morphologic findings, do not always resolve the overlap of a physiological myocardial architecture comprising a prominent trabecular pattern from a mild phenotypic expression of the real disease. Appropriate criteria for identification and management of LVNC in athletes have, therefore, become a novel challenge for cardiologists and sport physicians, who are required to solve the question of diagnosis and appropriate management in the setting of pre-participation cardiovascular screening. Indeed, although it is important to timely identify a true myocardial disease, to reduce the burden of adverse cardiac event in a young athlete, in contrast, a misdiagnosis of LVNC may lead to unwarranted restriction of the athlete lifestyle, with detrimental psychological, social, and economic consequences. This review report has been planned, therefore, to help physicians in diagnosing and managing athletes presenting with a morphologic pattern suggestive of LVNC with specific focus on criteria for advising sport participation.

Incidence and prognosis of ventricular arrhythmias in patients with congenital left ventricular aneurysms or diverticula.

BACKGROUND: Patients with congenital left ventricular aneurysms and diverticula may present with arrhythmia. The incidence of ventricular arrhythmias and the clinical outcome of these patients have not been reported to date. METHODS: Among 250 consecutive patients with congenital left ventricular aneurysms and diverticula detected by echocardiography, the clinical outcome of patients who presented with ventricular arrhythmias or associated symptoms was investigated. RESULTS: Of 250 patients with congenital left ventricular aneurysms and diverticula, 30 had ventricular arrhythmias or syncope at initial presentation. During a follow-up of 85 months, spontaneous ventricular tachycardia occurred in 17 of these patients (57%). Ventricular tachycardia was sustained in 13, with a monomorphic pattern in 9 patients. In 82% (11 patients), ventricular tachycardia was inducible during electrophysiologic testing. In 7 patients a sustained monomorphic ventricular tachycardia with a right bundle branch block pattern similar to the clinical tachycardia was induced. Twenty patients were treated with antiarrhythmic agents. Eleven patients received an implantable cardioverter defibrillator. Appropriate device discharges were observed in 73% during a follow-up of 61 months. One patient underwent surgical resection of a congenital left ventricular aneurysm. Three patients underwent successful catheter ablation for incessant ventricular tachycardia. Of these, 2 were free of any clinically relevant arrhythmia during follow-up. Three patients died (10, 41, and 89 months after initial presentation). In 2 of them, the cause of death was attributed to ventricular arrhythmia. CONCLUSION: The clinical outcome of patients with congenital left ventricular aneurysms and diverticula and arrhythmia is variable. Clinical ventricular tachycardia in these patients is often monomorphic and usually inducible during electrophysiologic study, indicating a role for this test in risk stratification. Appropriate discharges are frequent in implantable cardioverter defibrillator recipients with congenital left ventricular aneurysms and diverticula.

Different prognostic value of functional right ventricular parameters in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: The value of standard 2-dimensional transthoracic echocardiographic parameters for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is controversial. METHODS AND RESULTS: We investigated the impact of RV fractional area change (FAC) and tricuspid annulus plane systolic excursion (TAPSE) for the prediction of major adverse cardiovascular events (MACE) defined as the occurrence of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or arrhythmogenic syncope. Among 70 patients who fulfilled the 2010 ARVC/D Revised Task Force Criteria and underwent baseline transthoracic echocardiography, 37 (53%) patients experienced MACE during a median follow-up period of 5.3 (interquartile range, 1.8-9.8) years. Average values for FAC, TAPSE, and TAPSE indexed to body surface area (BSA) decreased over time (P=0.03 for FAC, P=0.03 for TAPSE, and P=0.01 for TAPSE/BSA, each versus baseline). In contrast, median RV end-diastolic area increased (P=0.001 versus baseline). Based on the results of Kaplan-Meier estimates, the time between baseline transthoracic echocardiography and experiencing MACE was significantly shorter for patients with FAC <23% (P<0.001), TAPSE <17 mm (P=0.02), or right atrial short axis/BSA ≥25 mm/m(2) (P=0.04) at baseline. A reduced FAC constituted the strongest predictor of MACE (hazard ratio, 1.08 per 1% decrease; 95% confidence interval, 1.04-1.12; P<0.001) on bivariable analysis. CONCLUSIONS: This long-term observational study indicates that TAPSE and dilation of right-sided cardiac chambers are associated with an increased risk for MACE in patients with ARVC/D with advanced disease and a high risk for adverse events. However, FAC is the strongest echocardiographic predictor of adverse outcome in these patients. Our data advocate a role for transthoracic echocardiography in risk stratification in patients with ARVC/D, although our results may not be generalizable to lower-risk ARVC/D cohorts.

Transcatheter implantation of homologous "off-the-shelf" tissue-engineered heart valves with self-repair capacity: long-term functionality and rapid in vivo remodeling in sheep.

OBJECTIVES: This study sought to evaluate long-term in vivo functionality, host cell repopulation, and remodeling of "off-the-shelf" tissue engineered transcatheter homologous heart valves. BACKGROUND: Transcatheter valve implantation has emerged as a valid alternative to conventional surgery, in particular for elderly high-risk patients. However, currently used bioprosthetic transcatheter valves are prone to progressive dysfunctional degeneration, limiting their use in younger patients. To overcome these limitations, the concept of tissue engineered heart valves with self-repair capacity has been introduced as next-generation technology. METHODS: In vivo functionality, host cell repopulation, and matrix remodeling of homologous transcatheter tissue-engineered heart valves (TEHVs) was evaluated up to 24 weeks as pulmonary valve replacements (transapical access) in sheep (n = 12). As a control, tissue composition and structure were analyzed in identical not implanted TEHVs (n = 5). RESULTS: Transcatheter implantation was successful in all animals. Valve functionality was excellent displaying sufficient leaflet motion and coaptation with only minor paravalvular leakage in some animals. Mild central regurgitation was detected after 8 weeks, increasing to moderate after 24 weeks, correlating to a compromised leaflet coaptation. Mean and peak transvalvular pressure gradients were 4.4 ± 1.6 mm Hg and 9.7 ± 3.0 mm Hg, respectively. Significant matrix remodeling was observed in the entire valve and corresponded with the rate of host cell repopulation. CONCLUSIONS: For the first time, the feasibility and long-term functionality of transcatheter-based homologous off-the-shelf tissue engineered heart valves are demonstrated in a relevant pre-clinical model. Such engineered heart valves may represent an interesting alternative to current prostheses because of their rapid cellular repopulation, tissue remodeling, and therewith self-repair capacity. The concept of homologous off-the-shelf tissue engineered heart valves may therefore substantially simplify previous tissue engineering concepts toward clinical translation.

A novel electrocardiographic index for the diagnosis of diastolic dysfunction.

BACKGROUND: Although the assessment of diastolic dysfunction (DD) is an integral part of routine cardiologic examinations, little is known about associated electrocardiographic (ECG) changes. Our aim was to investigate a potential role of ECG indices for the recognition of patients with DD. METHODS AND RESULTS: ECG parameters correlating with echocardiographic findings of DD were retrospectively assessed in a derivation group of 172 individuals (83 controls with normal diastolic function, 89 patients with DD) and their diagnostic performance was tested in a validation group of 50 controls and 50 patients. The patient group with a DD Grade 1 and 2 showed longer QTc (422 ± 24 ms and 434 ± 32 ms vs. 409 ± 25ms, p<0.0005) and shorter Tend-P and Tend-Q intervals, reflecting the electrical and mechanical diastole (240 ± 78 ms and 276 ± 108 ms vs. 373 ± 110 ms, p<0.0001; 409 ± 85 ms and 447 ± 115 ms vs. 526 ± 119 ms, p<0.0001). The PQ-interval was significantly longer in the patient group (169 ± 28ms and 171 ± 38ms vs. 153 ± 22ms, p<0.005). After adjusting for possible confounders, a novel index (Tend-P/[PQxAge]) showed a high performance for the recognition of DD, stayed robust in the validation group (sensitivity 82%, specificity 93%, positive predictive value 93%, negative predictive value 82%, accuracy 88%) and proved a substantial added value when combined with the indexed left atrial volume (LAESVI, sensitivity 90%, specificity 92%, positive predictive value 95%, negative predictive value 86%, accuracy 91%). CONCLUSIONS: A novel electrocardiographic index Tend-P/(PQxAge) demonstrates a high diagnostic accuracy for the diagnosis of DD and yields a substantial added value when combined with the LAESVI.

Aortic regurgitation after transcatheter aortic valve implantation: mechanisms and implications.

In recent years, transcatheter aortic valve implantation (TAVI) has become an established treatment option for selected high-risk patients with severe aortic stenosis (AS). Favorable results with regard to both hemodynamics and clinical outcome have been achieved with transcatheter valves. Aortic regurgitation (AR) remains a major concern after TAVI. Echocardiography is the imaging modality of choice to assess AR in these patients due to its wide accessibility and low cost. Mostly mild residual AR has been observed in up to 70% of patients. However, as even a mild degree of AR has been associated with a decreased survival up to two years after TAVI, accurate evaluation and classification of AR is important. AR in transcatheter valves can be divided into three types according to different pathophysiological mechanisms. Besides the well-known transvalvular and paravalvular forms of regurgitation, a third form termed supra-skirtal has recently been observed. A thorough understanding of AR in transcatheter valves may allow to improve device design and implantation techniques to overcome this complication. The aim of this review is to provide an overview of the three types of AR after TAVI focussing on the different pathophysiological mechanisms.

Age- and gender-dependent left ventricular remodeling.

BACKGROUND: The effect of age and gender on left ventricular (LV) size, muscle mass, and systolic function as determined by two-dimensional echocardiography has not yet been investigated in a large population. METHODS: Normal transthoracic two-dimensional echocardiography studies of 5307 subjects (47% males) performed between March 1990 and December 2011 were analyzed. LV end-diastolic volume index (LVEDVI), LV muscle mass index (LVMMI), LV ejection fraction (LVEF), and LV fractional shortening (LVFS) were compared in different age groups. RESULTS: LVMMI increased in females from 66.4 ± 1.3 g/m(2) (7-20 years) to 76.3 ± 0.9 g/m(2) (60-80 years; P < 0.0001) and in males from 81.9 ± 1.7 g/m(2) (7-20 years) to 94.6 ± 1.3 g/m(2) (60-80 years; P < 0.0001). LVEDVI decreased in females from 49.8 ± 0.9 mL/m(2) (7-20 years) to 42.8 ± 0.6 mL/m(2) (60-80 years; P < 0.0001) and in males from 56.6 ± 0.8 mL/m(2) (7-20 years) to 49.0 ± 0.7 mL/m(2) (60-80 years; P < 0.0001). A significant increase in LVEF was observed with age (P < 0.0001 for both genders), but it was more pronounced in females (62 ± 0.5% [age 7-20 years] vs. 65 ± 0.3% [age 60-80 years]) than in males (62 ± 0.5% [age 7-20 years] vs. 64 ± 0.3% [age 60-80 years]). Similarly, LVFS increased in females from 37.7 ± 0.5% (7-20 years) to 42.4 ± 0.4% (60-80 years; P < 0.001) and in males from 37.3 ± 0.5% (7-20 years) to 39.4 ± 0.5% (60-80 years; P < 0.001). CONCLUSIONS: LVEF, LVFS, and LVMMI increase with advancing age, in particular in females. In contrast, LVEDVI decreases with age. These findings indicate that the LV undergoes a lifelong remodeling.