Long-Term Renal Function with Cardiac Contractility Modulation Therapy.

BACKGROUND: Cardiac implantable electrical devices are able to affect kidney function through hemodynamic improvements. The Cardiac Contractility Modulation (CCM) is a device-based therapy option for patients with symptomatic chronic heart failure (HF) despite optimized medical treatment. The long-term cardiorenal interactions for CCM treated patients are yet to be described. METHODS: CCM recipients (n=187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were evaluated in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of kidney function, and the chronic kidney disease (CKD) stage-distribution. With regard to kidney function at baseline, the patients were furthermore grouped to either advanced CKD (aCKD, CKD-stage ≥3, eGFR≤59mL/min/1.73 m2, n=107) or preserved kidney function and mild CKD (pCKD, CKD stages 1-2, eGFR≥60mL/min/1.73 m2, n=80). The groups were compared for differences regarding kidney function, New York Heart Association classification (NYHA), biventricular systolic function, HF hospitalizations and other parameters in the long-term (60 months). RESULTS: CKD stage distribution remained stable during the entire follow-up (p=0.65). An increase in serum creatinine (1.47±1 vs. 1.6±1mg/dL) with a corresponding decline of eGFR (58.2±23.4 vs. 54.2±24.4mL/min/1.73 m2, both p<.05) were seen after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3±1.3 vs. 55.3±1.2months, p=0.53) was comparable in both groups. Improvements in NYHA (3.11±0.46 vs. 2.94±0.41 to 2.28±0.8 vs. 1.94±0.6) and LVEF (24.8±7.1 vs. 22.9±6.6 to 31.1±11.4 vs. 35.5±11.1%) were likewise similar after 60 months (both p <.05). The aCKD patients suffered from more HF-hospitalizations and ventricular tachycardias during the entire follow-up period (both p<.05). CONCLUSIONS: The kidney function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experience improvements in LVEF and functional status, regardless of their kidney function before. An impaired kidney function might be associated with further cardiovascular comorbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterwards.

[Acute ischemic stroke and troponin elevation: update of the Mannheim clinical algorithm]. / Akuter ischämischer Schlaganfall und erhöhter Troponinwert ­ Update des Mannheimer Algorithmus.

Elevated high-sensitivity cardiac troponin (hs-cTn) levels should be expected in about half of all patients with acute ischemic stroke (AIS). Since those patients are at risk of increased morbidity and mortality, often attributable to cardiac causes, an adequate work-up of the underlying etiology is required. This can only be achieved by a team of cardiologists and neurologists. Since underlying causes of hs-cTn elevation in AIS patients are diverse, often atypical or silent in their clinical presentation and some, such as an accompanying myocardial infarction, can be acutely life-threatening, the work-up should follow a standardized clinical algorithm. The vast majority of hs-cTn elevations are caused by non-ischemic myocardial injury associated with AIS. This work presents a practice-oriented approach to differential diagnosis with the update of the Mannheim clinical algorithm for acute ischemic stroke and troponin elevation.

Left atrial area index provides the best prediction of atrial fibrillation in ischemic stroke patients: results from the LAETITIA observational study.

Background and aims: Left atrial (LA) enlargement has been repeatedly shown to be associated with the diagnosis of atrial fibrillation (AF). In clinical practice, several parameters are available to determine LA enlargement: LA diameter index (LADI), LA area index (LAAI), or LA volume index (LAVI). We investigated the predictive power of these individual LA parameters for AF in patients with acute ischemic stroke or transient ischemic attack (TIA). Methods: LAETITIA is a retrospective observational study that reflects the clinical reality of acute stroke care in Germany. Consecutive patient cases with acute ischemic cerebrovascular event (CVE) in 2019 and 2020 were identified from the Mannheim stroke database. Predictive power of each LA parameter was determined by the area under the curve (AUC) of receiver operating characteristic curves. A cutoff value was determined. A multiple logistic regression analysis was performed to confirm the strongest LA parameter as an independent predictor of AF in patients with acute ischemic CVE. Results: A total of 1,910 patient cases were included. In all, 82.0% of patients had suffered a stroke and 18.0% had a TIA. Patients presented with a distinct cardiovascular risk profile (reflected by a CHA2DS2-VASc score ≥2 prior to hospital admission in 85.3% of patients) and were moderately affected on admission [median NIHSS score 3 (1; 8)]. In total, 19.5% of patients had pre-existing AF, and 8.0% were newly diagnosed with AF. LAAI had the greatest AUC of 0.748, LADI of 0.706, and LAVI of 0.719 (each p < 0.001 vs. diagonal line; AUC-LAAI vs. AUC-LADI p = 0.030, AUC-LAAI vs. AUC-LAVI p = 0.004). LAAI, increasing NIHSS score on admission, and systolic heart failure were identified as independent predictors of AF in patients with acute ischemic CVE. To achieve a clinically relevant specificity of 70%, a cutoff value of ≥10.3 cm2/m2 was determined for LAAI (sensitivity of 69.8%). Conclusion: LAAI revealed the best prediction of AF in patients with acute ischemic CVE and was confirmed as an independent risk factor. An LAAI cutoff value of 10.3 cm2/m2 could serve as an inclusion criterion for intensified AF screening in patients with embolic stroke of undetermined source in subsequent studies.

[What is confirmed in the treatment of atrial fibrillation?] / Was ist gesichert in der Therapie von Vorhofflimmern?

Atrial fibrillation is the most common clinically relevant cardiac arrhythmia. Important goals in the treatment of atrial fibrillation are improvement of the quality of life, relief of symptoms and the prevention of stroke. New in the current European guidelines on atrial fibrillation from 2020 is a structured approach with the introduction of the 4S-AF scheme (4S estimation of the risk of stroke, severity of symptoms, degree of severity of atrial fibrillation load and substrate, AF atrial fibrillation) for better characterization of atrial fibrillation and the ABC pathway in the treatment. The decision on the use of anticoagulation should be made after appropriate risk stratification. Depending on the characterization and symptoms of atrial fibrillation, the planning of further treatment should be made with respect to symptom control. Based on recent studies, rhythm-maintaining treatment by means of drugs or catheter ablation is gaining in importance over a strategy purely aimed at controlling the frequency. Integral components of treatment are also the identification and treatment of comorbidities and cardiovascular risk factors as well as the modification of an unhealthy lifestyle.

Should HFrEF patients with NYHA class II expect benefit from CCM therapy? Results from the MAINTAINED observational study.

BACKGROUND: Cardiac contractility modulation (CCM) is an FDA-approved device therapy for patients with refractory systolic heart failure and normal QRS width. Randomized trials demonstrated benefits of CCM primarily for patients with severe heart failure (> NYHA class II). PURPOSE: To better understand individualized indication in clinical practice, we compared the effect of CCM in patients with baseline NYHA class II vs. NYHA class III or ambulatory IV over the 5-year period in our large clinical registry (MAINTAINED Observational Study). METHODS: Changes in NYHA class, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), NT-proBNP level, and KDIGO chronic kidney disease stage were compared as functional parameters. In addition, mortality within 3 years was compared with the prediction of the Meta-Analysis Global Group in Chronic heart failure risk score. RESULTS: A total of 172 patients were included in the analyses (10% with NYHA class II). Only patients with NYHA class III/IV showed a significant improvement in NYHA class over 5 years of CCM (II: 0.1 ± 0.6; p = 0.96 vs. III/IV: - 0.6 ± 0.6; p < 0.0001). In both groups, LVEF improved significantly (II: 4.7 ± 8.3; p = 0.0072 vs. III/IV: 7.0 ± 10.7%; p < 0.0001), while TAPSE improved significantly only in NYHA class III/IV patients (II: 2.2 ± 1.6; p = 0.20 vs. III/IV: 1.8 ± 5.2 mm; p = 0.0397). LVEF improvement was comparable in both groups over 5 years of CCM (p = 0.83). NYHA class II patients had significantly lower NT-proBNP levels at baseline (858 [175/6887] vs. 2632 [17/28830] ng/L; p = 0.0044), which was offset under therapy (399 [323/1497] vs. 901 [13/18155] ng/L; p = 0.61). Actual 3-year mortality was 17 and 26% vs. a predicted mortality of 31 and 42%, respectively (p = 0.0038 for NYHA class III/IV patients). CONCLUSIONS: NYHA class III/IV patients experienced more direct and extensive functional improvements with CCM and a survival benefit compared with the predicted risk. However, our data suggest that NYHA class II patients may also benefit from the sustained positive effects of LVEF improvement.

Treatment standards for direct oral anticoagulants in patients with acute ischemic stroke and non-valvular atrial fibrillation: A survey among German stroke units.

BACKGROUND: Acute ischemic stroke (AIS) in patients with non-valvular atrial fibrillation (AF) despite oral anticoagulation (OAC) is a complex and insufficiently investigated setting. Potential strategies range from maintaining the current OAC to changing the substance class. We have queried the specific treatment standards on German stroke units (SUs). METHODS: By means of a standardized online questionnaire via SurveyMonkey™ (San Mateo, CA, USA), all clinical heads of German SUs were asked about their treatment standards in the following clinical situations: first AIS of an OAC-naïve AF patient, AF patient with AIS despite administration of a vitamin K antagonist (VKA), AF patient with AIS despite administration of direct OAC (DOAC). In addition, the performance of specific coagulation tests in AF patients with AIS despite OAC was queried. RESULTS: 160 (48%) clinical heads of German SU responded. Data from pivotal trials (84%), own experience with substances (71%), and side-effect profiles (66%) determine the initial DOAC prescription. In case of an AIS despite OAC, 83 and 18% would switch from VKA to DOAC under certain conditions and always, respectively. Half of respondents would switch from DOAC to VKA under certain conditions, while the other half would decline. 96% would switch to an alternative DOAC. The vast majority of those who made preconditions considered concomitant diseases (92, 90, and 81%, respectively). Few would consider infarct pattern (<35%). 61% perform initial coagulation tests (only one-third substance-specific assessments); however, the majority do not use these to make further decisions. CONCLUSIONS: In the setting of an OAC-naïve AF patient with AIS, established pivotal data are most respected. In the unclear setting of an AIS despite OAC, most respondents consider concomitant diseases and give preference to switching to a (different) DOAC.

Cardiac Contractility Modulation in Patients with Ischemic versus Non-ischemic Cardiomyopathy: Results from the MAINTAINED Observational Study.

BACKGROUND: Cardiac contractility modulation (CCM) is an FDA-approved device-based therapy for patients with systolic heart failure and normal QRS width who are symptomatic despite optimal drug therapy. The purpose of this study was to compare the long-term therapeutic effects of CCM therapy in patients with ischemic (ICM) versus non-ischemic cardiomyopathy (NICM). METHODS: Changes in NYHA class, KDIGO CKD stage, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), and NT-proBNP levels were compared as functional parameters. Moreover, observed mortality rates at 1 and 3 years were compared to those predicted by the MAGGIC heart failure risk score, and observed mortality rates were compared between groups for the entire follow-up period. RESULTS: One hundred and seventy-four consecutive patients with chronic heart failure and CCM device implantation between 2002 and 2019 were included in this retrospective analysis. LVEF was significantly higher in NICM patients after 3 years of CCM therapy (35 ± 9 vs. 30 ± 9%; p = 0.0211), and after 5 years, also TAPSE of NICM patients was significantly higher (21 ± 5 vs. 18 ± 5%; p = 0.0437). There were no differences in other effectiveness parameters. Over the entire follow-up period, 35% of all patients died (p = 0.81); only in ICM patients, mortality was lower than predicted at 3 years (35 vs. 43%, p = 0.0395). CONCLUSIONS: Regarding improvement of biventricular systolic function, patients with NICM appear to benefit particularly from CCM therapy.

[Acute ischemic stroke and elevated troponin: Diagnostic work-up and therapeutic consequences]. / Akuter ischämischer Schlaganfall und Troponinerhöhung: Diagnostische Abklärung und therapeutische Konsequenzen.

Elevated troponin values are frequently detected in patients with acute ischemic stroke, requiring adequate diagnostic work-up due to the high cardiac mortality after stroke. Since dual platelet inhibition can cause secondary intracerebral hemorrhage careful consideration of invasive coronary intervention is mandatory. Based on three case reports, this review article presents a diagnostic algorithm taking into account latest findings from the literature.

Comparison of transvenous vs subcutaneous defibrillator therapy in patients with cardiac arrhythmia syndromes and genetic cardiomyopathies.

BACKGROUND: Inherited arrhythmia syndromes and genetic cardiomyopathies attribute in a significant proportion to sudden cardiac death. Implantable cardioverter defibrillators (ICDs) are the cornerstone in the prevention of sudden death in high-risk patients. However, ICD therapy is also associated with high rates of inappropriate shocks and/or device-related complications especially in young patients. OBJECTIVE: To determine the outcome of high-risk patients with inherited arrhythmia syndromes and genetic cardiomyopathies comparing two defibrillator technologies. METHOD: Between 2010 and 2018, 183 consecutive patients from two large German tertiary care centers were enrolled in the study. The majority of patients (83%) had either cardiac channelopathies or idiopathic ventricular fibrillation without cardiac structural abnormalities, while the remaining 17% had a genetic cardiomyopathy (HCM/ARVC). Eighty-six patients (47%) received a transvenous ICD (TV-ICD), while a subcutaneous ICD (S-ICD) was implanted in another 97 patients (53%). RESULTS: During a mean follow-up of 4.3 years, 30 patients had an appropriate ICD therapy (annual rate 3.8%). Fifteen patients experienced an inappropriate shock (annual rate 1.9%). Lead failure occurred in 17 (9%) patients and was less frequent in the S-ICD group (OR 0.48, 95%CI 0.38-0.62). Adverse defibrillator events, defined as a composite of inappropriate shocks and lead failure requiring surgical revision were significantly lower in the S-ICD group as compared to the TV-ICD group (OR 0.55, 95%CI 0.41-0.72). There was a non-significant trend towards lower appropriate shocks in the S-ICD group, that in combination with all-cause shocks yielded in a significantly higher freedom of any shock in the S-ICD group (RR 39%, p = 0.003). No deaths occurred during follow-up. CONCLUSION: The present data favor the use of the subcutaneous ICD for patients with inherited arrhythmia syndromes and genetic cardiomyopathies who do not need anti-bradycardia pacing.

Coronary Artery Disease in Patients Presenting With Acute Ischemic Stroke or Transient Ischemic Attack and Elevated Troponin Levels.

Background: There is little information concerning the invasive coronary angiography (ICA) findings of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) with elevated troponin levels and suspected myocardial infarction (MI). This study analyzed patient characteristics associated with ICA outcomes. Methods: A total of 8,322 patients with AIS or TIA, treated between March 2010 and May 2020, were retrospectively screened for elevated serum troponin I at hospital admission. Patients in whom ICA was performed, due to suspected type 1 MI based on symptoms, echocardiography, and ECG, were categorized according to ICA results (non-obstructive coronary artery disease (CAD): ≥1 stenosis ≥50% but no stenosis ≥80%; obstructive CAD: any stenosis ≥80% or hemodynamically relevant stenosis assessed by FFR/iwFR). Results: Elevated troponin levels were detected in 2,205 (22.5%) patients, of whom 123 (5.6%) underwent ICA (mean age 71 ± 12 years; 67% male). CAD was present in 98 (80%) patients, of whom 51 (41%) were diagnosed with obstructive CAD. Thus, ICA findings of obstructive CAD accounted for 2.3% of patients with troponin elevation and 0.6% of all stroke patients. The clinical hallmarks of myocardial ischemia, including angina pectoris (31 vs. 15%, p < 0.05) and regional wall motion abnormalities (49 vs. 32%, p = 0.07), and increased cardiovascular risk indicated obstructive CAD. While there was no association between lesion site or stroke severity and ICA findings, causal large-artery atherosclerosis was significantly more common in patients with obstructive coronary disease (p < 0.05). Conclusion: The rate of obstructive CAD in patients with stroke or TIA and elevated troponin levels with suspected concomitant type I MI is low. The cumulation of several cardiovascular risk factors and clinical signs of MI were predictive. AIS patients with large-artery atherosclerosis and elevated troponin may represent an especially vulnerable subgroup of stroke patients with risk for obstructive CAD.

Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling.

HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards 'reverse mode' leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy.

High Sensitivity Troponins Discriminate Different Morphologies of Coronary Artery Plaques Being Assessed by Coronary Computed Tomography Angiography.

BACKGROUND: This study evaluates the association between high sensitivity troponin I (hsTnI) and T (hsTnT) and the morphology of coronary artery plaques detected by coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD). METHODS: Patients undergoing CCTA were prospectively enrolled. CCTA was indicated by a low to intermediate pretest probability for CAD during routine clinical care. Within 24 hours of CCTA examination, peripheral blood samples were taken to measure hsTnI, hsTnT, and N-terminal probrain natriuretic peptide (NT-proBNP). RESULTS: A total of 99 patients were enrolled with 43% without CAD, 9% with noncalcified plaques, 28% with calcified plaques, and 19% with mixed type plaque lesions. Both hsTnI and hsTnT levels were able to discriminate significantly between the groups, especially in the presence of mixed coronary plaques (AUC range: 0.741-0.752; p = 0.0001). In multivariate logistic regression models, hsTnT, but not hsTnI, was still significantly associated with mixed coronary plaque morphology (odds ratio = 8.968; 95% CI 1.999-40.241; p = 0.004). CONCLUSIONS: Both hsTnI and hsTnT are able to discriminate between different coronary artery plaques morphologies, whereas hsTnT was significantly associated with mixed coronary plaques in patients with suspected CAD. This trial is registered with NCT03074253.

Biomarkers in Cardiomyopathies and Prediction of Sudden Cardiac Death.

BACKGROUND: Cardiomyopathies are a major cause of heart diseases in all age groups leading to heart failure and arrhythmias. Additionally, they are an important cause of sudden cardiac death (SCD) in young people. Major advances have been made in the understanding of the complex and manifold underlying pathomechanisms and their correlating blood measured biomarkers. The aim of this review is to outline the role of such biomarkers in non-ischemic cardiomyopathies and their role in the prediction of SCD. METHODS: A search in bibliographic databases was conducted. Most relevant references focusing on blood measured biomarkers in non-ischemic cardiomyopathies and biomarkers in SCD were reviewed regarding their role in pathophysiology and clinical practice. The references contain prospective and retrospective studies as well as meta-analyses. Current guidelines were analyzed concerning the implementation of biomarkers. RESULTS: Most research on the role of biomarkers in cardiomyopathies is focused on myocardial stress (natriuretic peptides), injury (troponins), inflammation, and remodelling (fibrosis marker). Various studies suggest a potential application of biomarkers in diagnostics, prognosis and treatment response. Further approaches include microRNAs or multimarker approaches. Biomarkers to delineate patients being at risk for SCD have demonstrated predictive ability and could improve risk stratification strategies. CONCLUSION: To improve the prognosis of cardiomyopathies an early onset of treatment is needed. This necessitates further research and a better integration of biomarkers in the diagnostic work-up of cardiomyopathies. Identification of patients being at risk for SCD is mandatory, however, reliable data of biomarkers are still lacking.