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.

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.

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.

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.