Jennifer Franke

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUNDnThe natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood.nnnMETHODSnThe International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome.nnnRESULTSnOf 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.nnnCONCLUSIONSnPatients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

Atlas of the clinical genetics of human dilated cardiomyopathy

AIMnNumerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort.nnnMETHODS AND RESULTSnIn this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes.nnnCONCLUSIONnThis is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction

Aims Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI. Methods and results After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733–0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793–0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05). Conclusion The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Alterations in cardiac DNA methylation in human dilated cardiomyopathy.

Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome‐wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase‐type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass‐spectrometric analysis and bisulphite‐sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

AIMSnDilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM.nnnMETHODS AND RESULTSnApplying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors.nnnCONCLUSIONnThe present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Assessment of myocardial deformation with cardiac magnetic resonance strain imaging improves risk stratification in patients with dilated cardiomyopathy.

AIMSnTo investigate the prognostic impact of left-ventricular (LV) cardiac magnetic resonance (CMR) deformation imaging in patients with non-ischaemic dilated cardiomyopathy (DCM) compared with late-gadolinium enhancement (LGE) quantification and LV ejection fraction (EF).nnnMETHODS AND RESULTSnA total of 210 subjects with DCM were examined prospectively with standard CMR including measurement of LGE for quantification of myocardial fibrosis and feature tracking strain imaging for assessment of LV deformation. The predefined primary endpoint, a combination of cardiac death, heart transplantation, and aborted sudden cardiac death, occurred in 26 subjects during the median follow-up period of 5.3 years. LV radial, circumferential, and longitudinal strains were significantly associated with outcome. Using separate multivariate analysis models, global longitudinal strain (average of peak negative strain values) and mean longitudinal strain (negative peak of the mean curve of all segments) were independent prognostic parameters surpassing the value of global and mean LV radial and circumferential strain, as well as NT-proBNP, EF, and LGE mass. A global longitudinal strain greater than -12.5% predicted outcome even in patients with EF < 35% (P < 0.01) and in those with presence of LGE (P < 0.001). Mean longitudinal strain was further investigated using a clinical model with predefined cut-offs (EF < 35%, presence of LGE, NYHA class, mean longitudinal strain greater than -10%). Mean longitudinal strain exhibited an independent prognostic value surpassing that provided by NYHA, EF, and LGE (HR = 5.4, P < 0.01).nnnCONCLUSIONnLV longitudinal strain assessed with CMR is an independent predictor of survival in DCM and offers incremental information for risk stratification beyond clinical parameters, biomarker, and standard CMR.

Optimization of pharmacotherapy in chronic heart failure: is heart rate adequately addressed?

The aim of the study is to evaluate the use of beta-blockers in chronic heart failure (CHF) and the extent of heart rate reduction achieved in clinical practice and to determine differences in outcome of patients who fulfilled select inclusion criteria of the SHIFT study according to resting heart rate modulated by beta-blocker therapy. We evaluated an all-comer population of our dedicated CHF outpatient clinic between 2006 and 2010. For inclusion, individually optimized doses of guideline-recommended pharmacotherapy including beta-blockers had to be maintained for at least 3xa0months and routine follow-up performed at our outpatient CHF-clinic thereafter. Treatment dosages of beta-blockers, and demographic and clinical profiles including resting heart rate were assessed. The outcome of patients who fulfilled select inclusion criteria of the SHIFT study (left-ventricular ejection fraction (LVEF) ≤35xa0%, sinus rhythm, NYHA II–IV) and were followed-up for at least 1xa0year was stratified according to resting heart rates:xa0≥75 versusxa0<75xa0bpm andxa0≥70 versusxa0<70xa0bpm. The composite primary endpoint was defined as all-cause death or hospital admission for worsening heart failure during 12-month follow-up. In total, 3,181 patients were assessed in regard to treatment dosages of beta-blockers, and demographic and clinical profiles including resting heart rate. Of the overall studied population, 443 patients fulfilled all inclusion criteria and entered outcome analysis. Median observation time of survivors was 27.5xa0months with 1,039.7 observation-years in total. Up-titration to at least half the evidence-based target dose of beta-blockers was achieved in 69xa0% and full up-titration in 29xa0% of these patients. Patients with increased heart rates were younger, more often male, exhibited a higher NYHA functional class and lower LVEF. The primary endpoint occurred in 21xa0% of patients in thexa0≥70xa0bpm group versus 9xa0% of patients in the group with heart ratesxa0<70xa0bpm (pxa0<0.01). Likewise, comparing the groupsxa0≥75 and <75xa0bpm, the primary endpoint was significantly increased in the group of patients with heart ratesxa0≥75xa0bpm 27 vs. 12.2xa0%; pxa0<xa00.01). 5-year event-free survival was significantly lower among patients with heart rates ≥70xa0bpm as compared to those withxa0<70xa0bpm (log-rank test pxa0<xa00.05) and among patients in thexa0≥75xa0bpm group versusxa0<75xa0bpm group (log-rank test pxa0<xa00.01). In conclusion, in clinical practice, 53xa0% of CHF patients have inadequate heart rate control (heart ratesxa0≥75xa0bpm) despite concomitant beta-blocker therapy. In this non-randomized cohort, adequate heart rate control under individually optimized beta-blocker therapy was associated with improved mid- and long-term clinical outcome up to 5xa0years. As further up titration of beta-blockers is not achievable in many patients, the administration of a selective heart rate lowering agent, such as ivabradine adjuvant to beta-blockers may pose an opportunity to further modulate outcome.

A decade of developments in chronic heart failure treatment: a comparison of therapy and outcome in a secondary and tertiary hospital setting

AimsTo investigate determinants and temporal developments of treatment strategies, 5-year survival and heart transplantation rates between patients treated at secondary and tertiary hospitals.Methods and resultsBaseline characteristics, treatment and follow-up data from 2,023 patients with chronic systolic heart failure due to ischaemic or dilated cardiomyopathy enrolled between 1995 and 2005 (996 patients treated at a secondary hospital vs. 1,027 patients treated at a tertiary hospital) were prospectively compared. Patients treated at the secondary hospital setting were twice as likely to have ischaemic cardiomyopathy compared to the tertiary hospital setting as the underlying cause of heart failure (59.7% vs. 33.0%, respectively) and were almost a decade older (mean age 65.2 vs. 56.7xa0years, respectively). The use of guideline-recommended therapy increased in both centres over time. In direct temporal comparison, both guideline-adherent pharmacological therapy and device therapy were implemented earlier at the tertiary hospital. Survival rates were significantly lower among patients treated at the secondary hospital (log-rank test Pxa0<xa00.0001). The combined endpoint of all-cause mortality and heart transplantation, however, was not significantly different after adjustment for differences in baseline characteristics (Pxa0=xa00.44).ConclusionThis study demonstrates the marked disparity between the patient cohorts with chronic systolic heart failure presenting at secondary and tertiary hospitals. Though patient characteristics—particularly age, aetiology of heart failure and the time of implementation of pharmacological and device treatment of heart failure—differed significantly, after adjustment for differences in baseline characteristics, no substantial difference in the combined endpoint of all-cause mortality and HTX was found during the 5-year follow-up period.

Implementation of pharmacotherapy guidelines in heart failure: experience from the German Competence Network Heart Failure

AimTo evaluate the implementation of current pharmacotherapy guidelines of heart failure and to identify factors associated with high pharmacotherapy guideline adherence in heart failure patients.Methods and resultsWe pooled data from seven studies performed in the context of the German Competence Network Heart Failure selecting patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) <45% (nxa0=xa02,682). The quality of pharmacotherapy was evaluated by calculating the guideline adherence indicator (GAI), which considers three (GAI-3) or five (GAI-5) of the recommended heart failure substance classes and accounts for respective contraindications. GAI-3 was categorized as perfect (GAIxa0=xa0100%: 71% of the cohort), medium (GAIxa0=xa050–99%: 22%), and poor adherence (GAI <50%: 7%). In ordinal regression, the following factors were positively associated with perfect adherence: history of revascularization (odds ratio 1.59, 95% confidence interval 1.27–1.98), prior ICD implantation (2.29, 1.76–2.98), and LV ejection fraction <30% (1.45, 1.19–1.76), whereas age (per 10xa0years; 0.82, 0.77–0.89), NYHA III/IV (0.15, 0.12–0.18), unknown duration of heart failure (0.69, 0.53–0.89), and antidepressant medication (0.61, 0.42–0.88) were negatively associated with perfect adherence. Better GAI-3 at baseline predicted favorable changes of LV ejection fraction and end-diastolic diameter after 1xa0year. One-year mortality risk was closely related to GAI-3 in both groups of NYHA functional class I/II (excellent vs. poor GAI-3: 7.2 vs. 14.5%, log rankxa0=xa00.004) and class III/IV (13.5 vs. 21.5%, log rankxa0=xa00.005).ConclusionsThis large pooled analysis showed that a high level of guideline adherence is achievable in the context of clinical studies. Those receiving and tolerating optimal pharmacotherapy experience a better prognosis. Nevertheless, the implementation of heart failure medication needs further improvement in female and elderly patients, especially those in NYHA functional class >II and patients with LVEF ≥30%.

ECG Criteria to Differentiate Between Takotsubo (Stress) Cardiomyopathy and Myocardial Infarction

Background ECG criteria differentiating Takotsubo cardiomyopathy (TTC) from mainly anterior myocardial infarction (MI) have been suggested; however, this was in small patient populations. Methods and Results Twelve‐lead admission ECGs of consecutive 200 TTC and 200 MI patients were compared in dichotomized groups based on the presence or absence of ST‐elevation MI (STEMI versus STE‐TTC and non‐ST elevation MI versus non ST‐elevation‐TTC). When comparing STEMI and STE‐TTC, ST‐elevation in –aVR was characteristic of STE‐TTC with a sensitivity/specificity of 43% and 95%, positive predictive value (PPV) 91%, and a negative predictive value (NPV) 62% (P<0.001); when ST‐elevation in –aVR is accompanied by ST‐elevation in inferior leads, sensitivity/specificity were 14% and 98% (PPV was 89% and NPV 52%) (P=0.001), and 12% and 100% when associated with ST‐elevation in anteroseptal leads (PPV 100%, NPV 52%) (P<0.001). On the other hand, STEMI was characterized by ST‐elevation in aVR (sensitivity/specificity of 31% and 95% P<0.001, PPV 85% and NPV 59%) and ST‐depression in V2‐V3‐V4 (sensitivity/specificity of 24% and 100% P<0.001, PPV 100% and NPV 76%). When comparing non‐ST elevation MI and non ST‐elevation‐TTC, T‐inversion in leads I‐aVL‐V5‐V6 had a sensitivity/specificity of 17% and 97% for non ST‐elevation‐TTC (PPV 83% and NPV 55%) (P<0.001), and ST‐elevation in –aVR with T‐inversion in any lead was also specific for non ST‐elevation‐TTC (sensitivity/specificity of 8% and 100%, PPV 100% and NPV 53%) (P=0.006). In non‐ST elevation MI patients, the presence of ST‐depression in V2‐V3 was specific (sensitivity/specificity of 11% and 99%, PPV 91% and NPV 51%) (P=0.01). Conclusions ECG on admission can differentiate between TTC and acute MI, with high specificity and positive predictive value. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01947621.