Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer.

BACKGROUND: In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown. OBJECTIVES: The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40). METHODS: Echocardiographic surveillance was performed in 299 CCS from the Emma Children's Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS. RESULTS: Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up. CONCLUSIONS: In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified.

Zoonotic Endocarditis in a Man, the Netherlands.

In 2017, endocarditis caused by Streptococcus equi subspecies zooepidemicus was diagnosed in a man in the Netherlands who had daily contact with horses. Whole-genome sequencing of isolates from the man and his horses confirmed the same clone, indicating horse-to-human transmission. Systematic reporting of all zoonotic cases would help with risk assessment.

Transaortic Aortic Valve Implantation in 100 Patients: Follow-up to 3 Years.

OBJECTIVE: Transaortic aortic valve implantation (TAo-AVI) through the ascending aorta is a novel technique and is used as an alternative in patients with poor femoral access. Although early results have been promising, no midterm data have been published yet. To determine whether this approach is an acceptable treatment option, we analyzed the first 100 cases performed at our institution with a follow-up to 3 years. METHODS: Between July 2011 and January 2015, a total of 100 patients with high-risk or inoperable aortic valve stenosis were treated with TAo-AVI. Preoperative patient data were collected and analyzed retrospectively. All surviving patients were seen for clinical and echocardiographic examination for follow-up. RESULTS: Median follow-up was 15 months. Device success was accomplished in 94 patients (94%). There were no access site complications. The 30-day mortality rate was 9%. Stroke occurred in a total of six patients (6%). Survival at 1-, 2-, and 3 years was 75%, 62%, and 58%, respectively. CONCLUSIONS: Our results show that TAo-AVI is a promising alternative to transapical implantation for treating severe inoperable aortic valve stenosis.

Predictors of outcome in patients undergoing MitraClip implantation: An aid to improve patient selection.

BACKGROUND: MitraClip implantation (MCI) reduces mitral regurgitation (MR) and symptoms in patients considered inoperable or with high-surgical risk. Data to determine the benefit from MCI for an individual patient are limited. The aim of this study is to determine predictors associated with the prognosis after MCI to improve the patient selection for this procedure. METHODS: We included 84 consecutive patients (age: 76 ± 10 years, 51% male) who underwent MCI in our institution for symptomatic severe MR. All patients underwent transthoracic echocardiography before MCI; clinical and echocardiographic follow-up was obtained after MCI. RESULTS: The 2-year survival was 81%. Predictors for two-year mortality in multi-variate analysis were baseline NT-proBNP ≥ 5000 µg/L (HR: 5.4, 95% CI: 1.8-16.2), previous valve surgery (HR: 4.5, 95% CI: 1.7-12.2), tricuspid regurgitation (TR)≥ grade 3 prior to MCI (HR: 2.8, 95% CI: 1.2-6.8) and absence of MR reduction after MCI (HR: 2.1, 95% CI: 1.2-3.8). The 2-year survival of patients with 0, 1 or ≥ 2 of these predictors was: 87%; 78% and 38% respectively (log-rank p < 0.001). The functional class at 1 month and mid-term follow-up was worse in patients with two or more of these predictors present at baseline compared to patients with zero or one of these predictors (1 month: p = 0.007 and mid-term: p < 0.001). CONCLUSION: Heart failure, previous valve surgery, co-presence of TR and the degree of MR reduction after MCI are the independent predictors of survival and functional status after MCI in high risk patients. The pre-procedural characteristics may be used to optimize patient selection, while maximal MR reduction should be attempted to optimize the outcome of MCI.

Long-term benefits of exercise training in patients with a systemic right ventricle.

OBJECTIVES: The aim of the present study is to determine the long-term effects of a ten-week exercise training program in adult patients with a systemic right ventricle. METHODS: All patients who participated in a 2009 randomized controlled trial were approached. At approximately three years of follow-up from initial baseline, patients underwent cardiopulmonary exercise testing, filled out two quality of life questionnaires, and NT proBNP levels were measured. All examinations were performed according to the protocols of the 2009 trial. In addition, patients were asked about their current sports habits. RESULTS: Of the 54 patients who were randomized in the 2009-trial 40 participated in the current re-evaluation (male 50%, ccTGA 35%, age 36 ± 10 years, intervention group n=22, control group n=18). After three years, no persistent effect of exercise training on V'O2peak training remained (-2% of predicted, 95% CI -3% to 5%; p=.56). However, patients who already participated in regular sports or exercise at baseline (n=23/40 (58%)) showed higher V'O2peak of 13% of predicted (95% CI 4% to 23%; p>.01) and a decrease of 62% in plasma NT-proBNP (95% CI -115% to -10%; p>.03) during follow-up, when compared to patients who did not. Moreover, sports were associated with a lower incidence of clinical events (p=.032). CONCLUSION: Short-term beneficial effects of exercise training did not persist over a three-year follow-up period. However, sports participation at baseline was associated with better exercise capacity, lower neurohormone levels, and increased event-free survival.

Percutaneous mitral valve repair preserves right ventricular function.

BACKGROUND: Chronic mitral regurgitation (MR) often leads to diminished right ventricular (RV) function due to long-standing pressure and volume overload. Surgical intervention often adds to the preexisting RV dysfunction. Percutaneous mitral valve (MV) repair can reduce MR, but to what extent this affects the right ventricle is unknown. METHODS: Consecutive patients scheduled for percutaneous MV repair using the MitraClip system underwent transthoracic echocardiography at baseline and at 1- and 6-month follow-up. RV systolic function was evaluated using five echocardiographic parameters. RV afterload was evaluated using systolic pulmonary arterial pressure and the mean MV pressure gradient. Residual MR was defined as grade ≥ 3 and mitral stenosis (MS) as a mean MV pressure gradient ≥ 5 mm Hg. RESULTS: Sixty-eight patients (52% men; mean age, 75 ± 10 years) were included. Six months after MitraClip implantation, there were no significant changes in any of the RV parameters. MR decreased (P < .01) and the mean MV pressure gradient increased during follow-up (2.3 ± 1.4 mm Hg at baseline vs 4.5 ± 2.7 mm Hg at 6 months, P < .01). Patients with both residual MR and MS 6 months after MitraClip implantation showed significantly higher systolic pulmonary arterial pressure values (P < .01) and lower New York Heart Association functional classes (P < .01) compared with patients without residual MR or MS. CONCLUSIONS: Percutaneous MV repair, in contrast to surgical repair or replacement, does not negatively affect RV function. After repair, RV afterload and New York Heart Association functional class are improved in the case of successful repair but adversely affected in the presence of both residual MR and MS.

Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and Mortality rAtes.

BACKGROUND: Hospital admissions for acute decompensated heart failure (ADHF) are frequent and are accompanied by high percentages of mortality and readmissions. Brain natriuretic peptide (BNP) and the inactive N-terminal fragment of its precursor proBNP (NT-proBNP) are currently the best predictors of prognosis in heart failure (HF) patients. In the setting of chronic HF, studies that performed guidance of therapy by NT-proBNP have had only limited success. For patients with ADHF, retrospective studies have shown that a reduction in NT-proBNP of ≤30% during admission is a significant predictor of HF readmissions and mortality. These data suggest a role for NT-proBNP guidance in the setting of ADHF admissions. STUDY DESIGN: The PRIMA II is an investigator-initiated, multicenter, randomized, controlled, prospective 2-arm trial that investigates the impact of inhospital guidance for ADHF treatment by a predefined NT-proBNP target (>30% reduction during admission) on the reduction of readmission and mortality rates within 180 days. Consenting ADHF patients with NT-proBNP levels of >1,700 ng/L are eligible. After achieving clinical stability, a total of 340 patients are randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point is dual, that is, a composite of all-cause mortality and readmission for HF in 180 days and the number of days alive out of hospital in 180 days. Secondary end points are readmissions and/or mortality in 180 days, cost effectiveness of hospitalization days in 180 days, readmissions and mortality in 90 days, and quality of life. CONCLUSION: The PRIMA II trial aims at providing scientific evidence for the use of NT-proBNP-guided therapy compared with conventional treatment in patients admitted for ADHF.

Mitral inflow patterns after MitraClip implantation at rest and during exercise.

BACKGROUND: MitraClip implantation reduces mitral regurgitation effectively but decreases mitral valve area, creating iatrogenic mitral stenosis. Evaluation with transesophageal echocardiography intraprocedurally is necessary to measure mitral regurgitation and mitral valve pressure gradient (MVPG) to determine whether it is necessary and safe to place more clips. The aim of this study was to investigate whether these intraprocedural hemodynamics represent postprocedural measurements and whether exercise is affected by the stenosis. METHODS: In this retrospective single-center study, 51 patients who underwent MitraClip implantation were included. Measurements were performed intraprocedurally using transesophageal echocardiography and postprocedurally using transthoracic echocardiography. In 23 of these patients, exercise echocardiography was performed at follow-up. RESULTS: Intraprocedural mean MVPG was 3.0 ± 1.6 mm Hg and increased to 4.3 ± 2.2 mm Hg postprocedurally (P < .001). During exercise, mean MVPG increased significantly compared with rest conditions (from 3.6 ± 1.7 to 6.3 ± 2.7 mm Hg, P < .001). Six patients had mean resting MVPGs ≥ 5 mm Hg at follow-up and had higher systolic pulmonary artery pressure (sPAPs) than patients with mean MVPGs < 5 mm Hg (47 ± 7 vs 35 ± 12 mm Hg, P = .035). Higher MVPG and sPAP did not lead to more symptoms of heart failure. Receiver operating characteristic curve analysis showed an estimated cutoff point for intraprocedural pressure half-time of 91 msec to identify patients with mitral stenosis and sPAP ≥ 50 mm Hg postprocedurally. CONCLUSIONS: Mean MVPG during MitraClip implantation measured by TEE underestimates the hemodynamics in daily life, of which operators should be aware when deciding on placing one or more clips. Pressure half-time seems to be the most robust parameter compared with mean and maximum MVPG and may contribute to this decision. Patients with higher mean MVPGs after MitraClip implantation have higher sPAPs at follow-up. However, more symptoms of heart failure were not detected at follow-up.

SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.

BACKGROUND: Mutations in SCN5A are identified in approximately 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. METHODS AND RESULTS: Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. CONCLUSIONS: Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels.

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.

BACKGROUND: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. OBJECTIVES: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. METHODS: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with 90% (M(inactive)) peak I(Na) reduction were analyzed separately. RESULTS: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group. CONCLUSION: In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Exclusion of multiple candidate genes and large genomic rearrangements in SCN5A in a Dutch Brugada syndrome cohort.

BACKGROUND: The Brugada syndrome is an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. Screening for mutations in the cardiac Na+ channel-encoding gene SCN5A uncovers a mutation in approximately 20% of Brugada syndrome cases. Genetic heterogeneity and/or undetected SCN5A mutations, such as exon duplications and deletions, could be involved in the remaining 80% mutation-negative patients. OBJECTIVES: Thirty-eight SCN5A mutation-negative Dutch Brugada syndrome probands were studied. The SCN5A gene was investigated for exon duplication and deletion, and a number of candidate genes (Caveolin-3, Irx-3, Irx-4, Irx-5, Irx-6, Plakoglobin, Plakophilin-2, SCN1B, SCN2B, SCN3B, and SCN4B) were tested for the occurrence of point mutations and small insertions/deletions. METHODS: We used a quantitative multiplex approach to determine SCN5A exon copy numbers. Mutation analysis of the candidate genes was performed by direct sequencing of polymerase chain reaction-amplified coding regions. RESULTS: No large genomic rearrangements in SCN5A were identified. No mutations were found in the candidate genes. Twenty novel polymorphisms were identified in these genes. CONCLUSION: Large genomic rearrangements in SCN5A are not a common cause of Brugada syndrome. Similarly, the studied candidate genes are unlikely to be major causal genes of Brugada syndrome. Further studies are required to identify other genes responsible for this syndrome.

Clinical aspects and prognosis of Brugada syndrome in children.

BACKGROUND: Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and augmented risk of sudden cardiac death. Little is known about the clinical presentation and prognosis of this disease in children. METHODS AND RESULTS: Thirty children affected by Brugada syndrome who were <16 years of age (mean, 8+/-4 years) were included. All patients displayed a type I ECG pattern before or after drug provocation challenge. Diagnosis of Brugada syndrome was made under the following circumstances: aborted sudden death (n=1), syncope of unexplained origin (n=10), symptomatic supraventricular tachycardia (n=1), suspicious ECG (n=1), and family screening for Brugada syndrome (n=17). Syncope was precipitated by fever in 5 cases. Ten of 11 symptomatic patients displayed a spontaneous type I ECG. An implantable cardioverter-defibrillator was implanted in 5 children; 4 children were treated with hydroquinidine; and 1 child received a pacemaker because of symptomatic sick sinus syndrome. During a mean follow-up of 37+/-23 months, 1 child experienced sudden cardiac death, and 2 children received an appropriate implantable cardioverter-defibrillator shock; all of them were symptomatic and had manifested a type I ECG spontaneously. One child had a cardioverter-defibrillator infection that required explantation of the defibrillator. CONCLUSIONS: In the largest population of children affected by Brugada syndrome described to date, fever represented the most important precipitating factor for arrhythmic events, and as in the adult population, the risk of arrhythmic events was higher in previously symptomatic patients and in those displaying a spontaneous type I ECG.

Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome.

INTRODUCTION: Provocation tests with sodium channel blockers are often required to unmask ECG abnormalities in Brugada syndrome (BrS). However, their diagnostic value is only partially established, while life-threatening ventricular arrhythmias during these tests were reported. We aimed to establish sensitivity, specificity, and safety of flecainide testing, and to predict a positive test outcome from the baseline ECG. METHODS AND RESULTS: We performed 160 tests with flecainide in subjects determined to be at risk for BrS. P wave width, PQ duration, QRS width, S wave amplitude and duration in leads II-III, in addition to ST morphology and J point elevation in V1-V3 were measured before and after flecainide administration. Moreover, leads were positioned over the third intercostal space (V1(IC3)-V2(IC3)). Flecainide tests were considered positive if criteria from the First Consensus Report on BrS were fulfilled. In 64 cases, the test was positive, while 95 were negative (1 test was prematurely interrupted). The sensitivity and specificity, calculated in SCN5A-positive probands and their family members, were 77% and 80%, respectively. Baseline ECGs exhibited significant group differences in P, PQ, and QRS duration, J point elevation (leads V1-V2 and V1(IC3)-V2(IC3)), and S duration in II, but an attempt to predict the outcome of flecainide testing from these baseline ECG parameters failed. No malignant arrhythmias were observed. CONCLUSION: Flecainide testing is a valid and safe tool to identify SCN5A-related BrS patients. Baseline ECGs do not predict test outcomes, but point to conduction slowing as a core mechanism in BrS.

Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?

After its recognition as a distinct clinical entity, Brugada syndrome is increasingly recognized worldwide as an important cause of sudden cardiac death. Brugada syndrome exhibits autosomal dominant inheritance with SCN5A, which encodes the cardiac sodium channel, as the only gene with a proven involvement in 20-30% of patients. Its signature feature is ST segment elevation in right precordial ECG leads and predisposition to malignant ventricular tachyarrhythmias. The pathophysiological mechanism of ST elevation and ventricular tachyarrhythmia, two phenomena strongly related, is controversial. Here, we review clinical and experimental studies as they provide evidence to support or disprove the two hypotheses on the mechanism of Brugada syndrome that currently receive the widest support: (1) nonuniform abbreviation of right ventricular epicardial action potentials ("repolarization disorder"), (2) conduction delay in the right ventricular outflow tract ("depolarization disorder"). We also propose a schematic representation of the depolarization disorder hypothesis. Moreover, we review recent evidence to suggest that other derangements may also contribute to the pathophysiology of Brugada syndrome, in particular, right ventricular structural derangements. In reviewing these studies, we conclude that, similar to most diseases, it is likely that Brugada syndrome is not fully explained by one single mechanism. Rather than adhering to the notion that Brugada syndrome is a monofactorial disease, we should aim for clarification of the contribution of various pathophysiological mechanisms in individual Brugada syndrome patients and tailor therapy considering each of these mechanisms.