Abstract Background Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but ...genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). Objectives The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. Methods The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. Results SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 ( HCN4 )-G482R mutation and a common cysteine and glycine-rich protein 3 ( CSRP3 )-W4R variant were identified. HCN4 -G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3 -W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3 -W4R. Conclusions The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.
Objectives This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and ...Patient Outcomes) trial. Background In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS). Methods A clinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, excluded silent MI. Results Overall, 1,299 (610 ticagrelor, 689 clopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 clopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 clopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% clopidogrel; hazard ratio HR: 0.84; 95% confidence interval CI: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00). Conclusions In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with clopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome PLATO; NCT00391872 )
Objectives The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) ...amyloidosis. Background AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease. Methods Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation. Results After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were −10.65% for LS and −11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers. Conclusions In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters.
Abstract Objectives This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the ...detection of microvasculopathy. Background Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. Methods Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. Results Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density ( r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). Conclusions CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.
Stratification of patients with atrial fibrillation (AF) according to mechanistic and prognostic criteria may optimize the effectiveness and safety of catheter ablation. In women, AF is associated ...with more severe symptoms and worse prognosis.
We sought to assess sex-related differences in catheter ablation procedures and outcome in a large cohort of patients with AF.
A total of 3652 patients (1198 women 33%; 2454 men 67%) included in the German Ablation Registry were analyzed. Periprocedural parameters and outcome at 12-month follow-up were compared between male and female patients.
Women were older at the time of ablation (women: 63.6 years; men: 59.1 years; P < .0001) and exhibited a higher prevalence of paroxysmal AF (women: 72%; men: 61%; P < .0001). They were less often affected by cardiovascular disease and reduced left ventricular function. Energy application duration and overall procedure duration were shorter in women. Conversely, the rate of major inhospital complications was increased in female patients (1.9% vs 0.8%; P = .023) and mainly driven by major bleeding events. At follow-up, women experienced higher AF recurrence rates (women: 50%; men: 45%; P = .017) and more often received oral medication for rhythm and rate control. In addition, the rate of pacemaker implantation was higher in the female cohort. Women more frequently reported femoral access site complications (women: 6%; men: 3%; P < .001). Overall, male patients were more often free from AF-related symptoms and satisfied with the treatment.
Catheter ablation of AF was associated with a distinct sex-related outcome and complication profile that requires consideration in clinical practice.
Background The incremental prognostic value of admission measurements of biomarkers beyond clinical characteristics and extent of coronary artery disease (CAD) in patients treated with primary ...percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is unclear. Methods Centrally analyzed plasma for biomarker measurements was available in 5,385 of the STEMI patients treated with PPCI in the PLATO trial. Extent of CAD was graded by operators in association with PPCI. We evaluated the prognostic value of high-sensitivity cardiac troponin T, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15) beyond clinical characteristics and extent of CAD using Cox proportional hazards analyses, C-index, and net reclassification improvement (NRI). Outcomes were cardiovascular death (CVD) and spontaneous myocardial infarction (MI). Results Angiographic data on extent of CAD improved the prediction of CVD compared to clinical risk factors alone, increasing the C-index from 0.760 to 0.778, total NRI of 0.31. Biomarker information provided additional prognostic value for CVD beyond clinical risk factors and extent of CAD, C-indices ranging from 0.792 to 0.795 for all biomarkers, but with a higher NRI for NT-proBNP. Extent of CAD and high-sensitivity cardiac troponin T were not associated with spontaneous MI. The prediction of spontaneous MI beyond clinical characteristics and extent of CAD (C-index 0.647) was improved by both NT-proBNP (C-index 0.663, NRI 0.22) and GDF-15 (C-index 0.652, NRI 0.05). Conclusions Biomarker measurement on admission is feasible and provides incremental risk stratification in patients with STEMI treated with PPCI, with NT-proBNP and GDF-15 being most valuable due to the association with both CVD and spontaneous MI.
Direct oral anticoagulants (DOACs) are effective for stroke prevention in nonvalvular atrial fibrillation (AF). Cardioversion (CV) is frequently performed in patients with AF or flutter. To further ...explore the safety profile of DOACs in the context of CV, we sought to assess the prevalence of intracardiac thrombi under DOAC therapy in comparison with treatment with vitamin K antagonists. A total of 672 transesophageal echocardiograms performed in 643 patients with a history of nonvalvular AF were analyzed. The median CHA2 DS2 -VASc score was 4. Cases were stratified according to anticoagulation with dabigatran (n = 79), rivaroxaban (n = 122), phenprocoumon (n = 180), or bridging therapy (n = 287). In a subgroup analysis, only patients receiving phenprocoumon with an international normalized ratio ≥2 on the day of the investigation or on DOAC therapy for ≥3 weeks were considered. The prevalence of intracardiac thrombi under phenprocoumon was significantly higher than under DOACs (phenprocoumon, 17.8%; all DOACs, 3.9%; dabigatran, 3.8%; rivaroxaban, 4.1%) and showed no significant difference to bridging therapy (12.5%). In patients with sufficient short-term anticoagulation, similar differences between DOAC and phenprocoumon groups were observed (phenprocoumon, 18.4%; all DOACs, 3.8%; dabigatran, 0%; rivaroxaban, 6.6%). The influence of anticoagulation medication on thrombus rates was confirmed after adjusting for baseline intergroup differences regarding left atrial size and CHA2 DS2 -VASc score. In conclusion, the prevalence of intracardiac thrombi was lower under DOAC therapy than under phenprocoumon in this high-risk patient cohort. Safety of CV during DOAC treatment requires further prospective evaluation.
Objectives The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). In this study we investigated whether inhibition of “mammalian target ...of rapamycin” (mTOR) attenuates left ventricular (LV) remodeling after MI. Background Therapeutic strategies to inhibit remodeling are currently limited to inhibition of neurohumoral activation. The mTOR-dependent signaling mechanisms are centrally involved in remodeling processes and provide new therapeutic opportunities. Methods Everolimus (RAD) treatment was initiated on the day after or 3 days after induction of myocardial infarction (MI) in rats. Results After 28 days, RAD-treated animals had reduced post-MI remodeling, with improved LV function and smaller LV end-diastolic diameters (8.9 ± 0.3 mm vs. 11.4 ± 0.2 mm, p < 0.05), end-diastolic volumes (304 ± 30 μl vs. 414 ± 16 μl, p < 0.05), and cardiac myocyte size (−40% vs. vehicle, p < 0.05). Infarct size was significantly reduced compared with vehicle-treated animals. The mTOR inhibition increased autophagy and concomitantly decreased proteasome activity in the border zone of the infarcted myocardium. Measurement of autophagic flux demonstrated that RAD did not decrease autophagosome clearance. When RAD treatment was initiated 3 days after MI, adverse remodeling was still attenuated and increased autophagy was still present. Sustained improvement of LV function was observed 3 months after MI, even when RAD treatment was discontinued after 1 month. Conclusions Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI.
The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was ...associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a β2 agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before β2 agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel.
Dilation of the ascending aorta was detected in 20 of 26 (77%) HCN4 mutation-positive patients in whom we could obtain images with diagnostic quality sufficient to assess the ascending aorta. Because ...our data suggested that dilation of the aorta in HCN4 mutation carriers displays an age-dependent penetrance, this was subsequently tested. Because aortic diameter is correlated with age in the general population (where the aortic diameter increases with 0.19 mm/year; p < 2e-16) (4) we used a multiple regression model to assess whether there was an additive effect of HCN4 mutation carriership on increase in aortic dilation with increasing age. ...we here report on multiple families harboring HCN4 mutations, who show significant dilation of the aorta ascendens, besides the recently established combined phenotype of bradycardia, NCCM, and mitral valve disease.
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