Compound Mutation in Cardiac Sarcomere Proteins Is Associated with Increased Risk for Major Arrhythmic Events in Pediatric Onset Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype–phenotype association regarding clinical outcome and disease progression in pediatric onset HCM. Medical charts from forty-nine patients with pediatric HCM who had undergone genetic testing were reviewed for retrospective analysis. Demographic, clinical, transthoracic echocardiographic, electrocardiographic, long-term electrocardiogram, cardiopulmonary exercise test, cardiac magnetic resonance, and medication data were recorded. Childhood onset HCM was diagnosed in 29 males and 20 females. Median age at last follow-up was 18.7 years (range 2.6–51.7 years) with a median follow-up time since diagnosis of 8.5 years (range 0.2–38.0 years). Comparison of patients carrying mutations in distinct genes and comparison of genotype-negative with genotype-positive individuals, revealed no differences in functional classification, LV morphology, hypertrophy, systolic and diastolic function, fibrosis and cardiac medication. Patients with compound mutations had a significantly higher risk for major arrhythmic events than a single-mutation carrier. No association between affected genes and disease severity or progression was identified in this cohort.

Acute myocardial infarction: Development and application of an ICD-10-CM-based algorithm to a large U.S. healthcare claims-based database

Background Healthcare administrative claims data hold value for monitoring drug safety and assessing drug effectiveness. The U.S. Food and Drug Administration Biologics Effectiveness and Safety Initiative (BEST) is expanding its analytical capacity by developing claims-based definitions—referred to as algorithms—for populations and outcomes of interest. Acute myocardial infarction (AMI) was of interest due to its potential association with select biologics and the lack of an externally validated International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) algorithm. Objective Develop and apply an ICD-10-CM-based algorithm in a U.S. administrative claims database to identify and characterize AMI populations. Methods A comprehensive literature review was conducted to identify validated AMI algorithms. Building on prior published methodology and consistent application of ICD-9-CM codes, an ICD-10-CM algorithm was developed via forward-backward mapping using General Equivalence Mappings and refined with clinical input. An AMI population was then identified in the IBM® MarketScan® Research Databases and characterized using descriptive statistics. Results and discussion Between 2014–2017, 2.83–3.16 individuals/1,000 enrollees/year received ≥1 AMI diagnosis in any healthcare setting. The 2015 transition to ICD-10-CM did not result in a substantial change in the proportion of patients identified. Average patient age at first AMI diagnosis was 64.9 years, and 61.4% of individuals were male. Unspecified chest pain, hypertension, and coronary atherosclerosis of native coronary vessel/artery were most commonly reported within one day of AMI diagnosis. Electrocardiograms were the most common medical procedure and beta-blockers were the most commonly ordered cardiac medication in the one day before to 14 days following AMI diagnosis. The mean length of inpatient stay was 5.6 days (median 3 days; standard deviation 7.9 days). Findings from this ICD-10-CM-based AMI study were internally consistent with ICD-9-CM-based findings and externally consistent with ICD-9-CM-based studies, suggesting that this algorithm is ready for validation in future studies.

Factors Affecting Health-Related Quality of Life After the Arterial Switch Operation

Background: Long-term morbidity and mortality outcomes of the arterial switch operation (ASO) in patients with transposition of the great arteries and Taussig-Bing anomaly are excellent. With an increasing number of patients reaching adolescence and adulthood, more attention is directed toward quality of life. Our study aimed to determine the health-related quality of life (hrQoL) outcomes in patients after the ASO and identify factors influencing their hrQoL. Methods: In this cross-sectional study, hrQoL of patients after ASO was assessed with the German version of the Short Form-36 (SF-36) and the potential association of specified clinical factors was analyzed. Patients of at least 14 years of age who underwent ASO in our institution from 1983 were considered eligible. Results: Of the 355 questionnaires sent to eligible patients, 261 (73%) were available for analysis. Compared to the reference population, patients who had undergone ASO had a significantly higher score in all subscales of the SF-36 except for vitality ( P < .01). Patients with an implanted pacemaker ( P = .002), patients who required at least one reoperation ( P < .001), and patients currently taking cardiac medication ( P < .004) or oral anticoagulation ( P = .036) had lower physical component scores compared to patients without these factors. Conclusions: Patients’ self-assessed and self-reported hrQoL after ASO (using German version of the Short Form 36) is very good. In this population, hrQoL is influenced by reoperation, the need for a pacemaker, and current cardiac medication or anticoagulant use. The development of strategies designed to mitigate or minimize the requirements for, and/or impact of these factors may lead to better hrQoL in this patient population.

Is It Possible for Children in Duchenne Muscular Dystrophy to Preserve Cardiac Function with Medical Assistance?

In patients with Duchenne muscular dystrophy (DMD), death secondary to cardiac or respiratory failure typically occurs in the second or third decade without treatment. Although cardiac dysfunction is treated with standard heart-failure strategies, it remains insufficient in DMD children. The purpose of this study was to evaluate the efficiency of cardiac medication and noninvasive ventilator support in DMD cardiomyopathy children with analyzing echocardiographic data. Forty-eight DMD children patients were included and divided into 2 groups by left ventricular (LV) ejection fraction (EF) at the time of initial treatment. Group 1: LV EF ≥ 45% and Group 2: LV EF < 45%. p-values were calculated using a Linear mixed model to estimate the association between cardiac medications and echocardiographic measurements. Before and after cardiac medications, the change values were significantly different in interventricular septal thickness at end diastole (IVSd), interventricular septal thickness at end systole (IVSs), left ventricular internal diameter end systole (LVIDs), left ventricular posterior wall thickness end diastole (LVPWd), ejection fraction (EF), fractional shortening (FS), deceleration time (DT), DT slope, Lat A’ and Lat E/E’ (p < 0.05). Group 2 patients revealed to take more kinds of cardiac medications than Group 1 (p < 0.05) including ACEIs, beta-blocker, and inotropics, then LV EF was better preserved in Group 2 than Group 1. It is certainly helpful to take individualized medical combination therapy including inotropic agents for cardiomyopathy in DMD children patients with EF < 45%.

Length of Initial Prescription at Hospital Discharge and Long-Term Medication Adherence for Elderly, Post-Myocardial Infarction Patients: Protocol for an Interrupted Time Series Study

Background Based on high-quality evidence, guidelines recommend the long-term use of secondary prevention medications post-myocardial infarction (MI) to avoid recurrent cardiovascular events and death. Unfortunately, discontinuation of recommended medications post-MI is common. Observational evidence suggests that prescriptions covering a longer duration at discharge from hospital are associated with greater long-term medication adherence. The following is a proposal for the first interventional study to evaluate the impact of longer prescription duration at discharge post-MI on long-term medication adherence. Objective The overarching goal of this study is to reduce morbidity and mortality among post-MI patients through improved long-term cardiac medication adherence. The specific objectives include the following. First, we will assess whether long-term cardiac medication adherence improves among elderly, post-MI patients following the implementation of (1) standardized discharge prescription forms with 90-day prescriptions and 3 repeats for recommended cardiac medication classes, in combination with education and (2) education alone compared to (3) usual care. Second, we will assess the cost implications of prolonged initial discharge prescriptions compared with usual care. Third, we will compare clinical outcomes between longer (>60 days) versus shorter prescription durations. Fourth, we will collect baseline information to inform a multicenter interventional study. Methods We will conduct a quasiexperimental, interrupted time series design to evaluate the impact of a multifaceted intervention to implement longer duration prescriptions versus usual care on long-term cardiac medication adherence among post-MI patients. Intervention groups and their corresponding settings include: (1) intervention group 1: 1 cardiac center and 1 noncardiac hospital allocated to receive standardized discharge prescription forms supporting the dispensation of 90 days’ worth of cardiac medications with 3 repeats, coupled with education; (2) intervention group 2: 4 sites (including 1 cardiac center) allocated to receive education only; and (3) control group: all remaining hospitals within the province that did not receive an intervention (ie, usual care). Administrative databases will be used to measure all outcomes. Adherence to 4 classes of cardiac medications — statins, beta blockers, angiotensin system inhibitors, and secondary antiplatelets (ie, prasugrel, clopidogrel, or ticagrelor) — will be assessed. Results Enrollment began in September 2017, and results are expected to be analyzed in late 2020. Conclusions The results have the potential to redefine best practices regarding discharge prescribing policies for patients post-MI. A policy of standardized maximum-duration prescriptions at the time of discharge post-MI is a simple intervention that has the potential to significantly improve long-term medication adherence, thus decreasing cardiac morbidity and mortality. If effective, this low-cost intervention to implement longer duration prescriptions post-MI could be easily scaled. Trial Registration ClinicalTrials.gov NCT03257579; https://clinicaltrials.gov/ct2/show/NCT03257579 International Registered Report Identifier (IRRID) DERR1-10.2196/18981

Aortic coarctation in pregnancy: outcomes and predictors for cardiovascular and hypertensive complications. Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC)

Background Pregnancy in women with repaired aortic coarctation (CoA) has a moderately increased risk (mWHO II-III) of an adverse cardiovascular, obstetric or fetal event, but prospective data to validate this estimated risk is scarce. Purpose We examined maternal and fetal outcomes in pregnant women with unrepaired and repaired CoA to identify predictors of adverse outcomes. Methods Pregnancies in women with CoA were selected from the worldwide prospective Registry of Pregnancy and Cardiac Disease (ROPAC, n=5739). The frequency and predictors of major adverse cardiac events (MACE, defined as maternal cardiac death, heart failure, atrial fibrillation/flutter, ventricular tachyarrhythmia, endocarditis, thromboembolic events, aortic dissection and acute coronary syndrome), and hypertensive complications (defined as pregnancy-induced hypertension, (pre)eclampsia or HELLP syndrome) were analyzed. Results Of 303 pregnancies in women with CoA (median age 30 years, median pregnancy duration 39 weeks), 10% were in women with unrepaired CoA and 27% in women with pre-existing hypertension. There were no maternal deaths. There were 4 neonatal deaths of which 3 occurred after a spontaneous extreme preterm birth. MACE occurred in 4.3% of pregnancies, predominantly involving heart failure (3.3%). MACE rate was similar in unrepaired vs repaired CoA (3.4% vs 4.4%, p=0.814). Predictors of MACE included pre-pregnancy clinical signs of heart failure (OR 31.8, 95% CI 6.8–147.7), LVEF &lt;40% (OR 10.4, 95% CI 1.8–59.5), NYHA class &gt;1 (OR 11.4, 95% CI 3.6–36.3), cardiac medication use (OR 4.9, 95% CI 1.3–18.3) and living in an emerging country (OR 4.88, 95% CI 1.58–15.07). Hypertensive complications occurred in 6.3%, more often in the subgroup with pre-existing hypertension (11% vs 5%, p=0.040). Pre-existing hypertension was the only predictor (OR 2.6, 95% CI 1.01–6.6). Caesarean section was performed in 50% of the total cohort. Conclusions Pregnancies in women with CoA are safe, well tolerated and MACE and hypertensive complication rates are low. These findings support mWHO risk score reevaluation to mWHO II for women with CoA without cardiac impairment. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): ESC EURObservational Research Programme (EORP)

Pregnancy outcomes in women with mechanical heart valves

Background Mechanical heart valves (MHV) and their absolute need for adequate anticoagulation poses a challenge for pregnancy, either due to warfarin fetotoxicity or an increased risk of maternal thromboembolism. This represents a unique patient (P) group where data is scarce and maternal and fetal risks and benefits must be carefully weighed. Purpose To assess maternal and perinatal outcomes in women with MHV on different anticoagulant regimens and compare them with patients with other types of valvular heart disease (VHD). Methods A retrospective analysis of 131 pregnancies in 83 women with VHD (mean age 26.5±5.6 years) was carried out in a tertiary referral centre from 2000 to 2019. 92 pregnancies with VHD, including 11 with biological prosthetic valves, and 39 pregnancies in 22 P with MHV were identified. The main outcome measures were major maternal complications and perinatal outcome. Results MHV implanted were in mitral position (89.7%), aortic (2.6%), or both (7.7%). History of rheumatic heart disease was identified in 16 P (72.7%) and a congenital etiology was present in 2 P (9.1%). 9 P (40.9%) were on warfarine and 13 P (59.1%) on acenocumarol. Regarding anticoagulation strategy, 21 P (65.6%) remained on oral anticoagulation and 10 P (31.3%) had been switched to some form of heparin during part or the entire pregnancy. Mechanical valve thrombosis complicated pregnancy in 4 patients (10.2%), all cases on heparin, and resulted in maternal death in 1 P. MHV P had more hemorrhagic complications (15.4 vs 2.2%, p=0.004) requiring transfusion or surgical revision. MHV P tended to experience more NHYA class worsening demanding initiation or intensification of cardiac medication (17.9 vs 5.4%, p=0.023). Also in the MHV group there was a higher incidence of miscarriage (46.2 vs 12.0%, p≤0.0005), comprising spontaneous abortion (31.6 vs 7.6%, p&lt;0.0005) and fetal malformations (18.4 vs 5.4%, p=0.028), including warfarin embryopathy (10.3 vs 1.1%, p=0.012). The live birth rate was higher in women on heparin compared with those on warfarin (85.9 vs 79.2%, p=0.002). The presence of multivalve disease (p=0.04), mechanical protheses (p&lt;0.001), ACO (p&lt;0.001) and previous impaired LVEF (p=0.02) were related to miscarriage. In multivariate analysis, ACO was the unique independent predictor of unsuccessful pregnancy (p=0.01). Only 29% of the patients with an MHV had a pregnancy free of serious adverse events compared with other types of VHD (81.5%, p&lt;0.0005). Conclusions MHV remains a challenging condition for pregnancy with only 29% chance of experiencing an uncomplicated pregnancy with a live birth. The increased morbimortality warrant extensive prepregnancy counseling with prosthesis type discussion,centralization of care and further larger studies to come up with evidence-based recommendations. Funding Acknowledgement Type of funding source: None

Lower peak systolic blood pressure during exercise testing predicts higher risk of all-cause mortality even when accounting for exercise capacity and other confounders

Background The risk associated with an exaggerated systolic blood pressure (SBP) response during exercise testing is controversial. In part, this may be due to the confounding effect of exercise capacity, as achieving a high workload is related to both better survival and higher peak SBP. Purpose We aimed to determine the prognostic value of the SBP response at clinical exercise testing, with and without accounting for exercise capacity and other important confounders, for predicting all-cause mortality. Methods We analysed data from 10,245 subjects aged 18–85 years (54% male), referred for bicycle ergometer exercise testing at a single hospital between 2005 and 2015. Resting SBP, peak SBP, peak Watt as well as the first and last SBP and corresponding Watt during exercise were retrieved. The slope of the increase in SBP per increment in Watt between the first and last measurement during exercise (the SBP/Watt-slope) was calculated. Survival status was determined from the National Cause of Death register up until April 2019. Cox proportional hazard ratios for all-cause mortality were calculated in males and females for peak SBP and the SBP/Watt-slope, and natural cubic spline models (with three knots) were computed to explore the risk of death based on a continuum of each SBP measure. The models were adjusted for age, SBP at rest, a diagnosis of diabetes, hypertension, baseline cardiovascular disease (ICD10 Chapter IX) and the use of cardiac and/or antihypertensive medications. In additional analyses, peak SBP and the SBP/Watt-slope were adjusted for peak Watt or exercise capacity (% predicted), respectively. Results Over a median follow-up of 7.9 (IQR 5.7) years, 890 (8.7%) subjects died. Compared to survivors, subjects who died were older (69±10 vs 57±14 years, p&lt;0.001), had lower age-adjusted exercise capacity (82±15 vs 92±17% pred. Watt, p&lt;0.001), and had lower peak SBP (193±28 vs 196±26 mmHg, p=0.002). The SBP/Watt-slope was on average 21% higher in those who died (0.64±0.36 vs 0.53±0.27 mmHg/Watt, p&lt;0.001). An exercise peak SBP &lt;190 mmHg in females and &lt;210 mmHg in males was associated with increased risk of all-cause death, after adjusting for age, prevalent comorbidities, cardiac medication and exercise capacity at baseline (Figure 1). After adjusting for maximal workload, higher peak SBP was associated with increased risk of dying in females, but not in males. An SBP/Watt-slope &gt;0.5 mmHg/Watt was associated with higher risk of death in both sexes, although not when adjusting for exercise capacity. Conclusion Achieving a lower peak SBP was associated with increased risk of all-cause mortality in both sexes. This persisted after accounting for exercise capacity and other important confounders. In females, but not in males, there was also an increased risk of death associated with higher peak SBP. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): County Council of Ostergotland