Introduction: Cardiopulmonary exercise testing (CPET) has repeatedly been reported to reliably predict adverse outcomes in different forms of heart failure. However, it has not been elucidated in detail in cardiac amyloidosis (CA). Therefore, we evaluated the predictive value of CPET parameters in patients with CA regarding disease severity and prediction of mortality. Methods: Twenty-seven consecutive patients with CA were assessed noninvasively, including electrocardiography, echocardiography, CPET, and laboratory tests. Clinical data were correlated with CPET findings. Univariate and multivariate analyses were performed to evaluate predictors of mortality. Results: Within median follow-up period of 38 (IQR 43) months 19 (70%) deaths occurred. Patient initially presented with signs and symptoms of congestive heart failure NYHA 3 (IQR 1), reduced exercise capacity (peak V’O₂ 15.2 mL/kg body weight) and inefficient ventilation in CPET (V’E/V’CO₂ slope (30 (IQR 3)), markedly elevated cardiac biomarkers (NT-proBNP 1791 (IQR 3249) ng/mL) and echocardiographic signs of morphological (septum thickness 18 (IQR 6) mm) and functional cardiac involvement (TAPSE 19 (IQR 8) mm). Patients with peak V’O₂ below median value presented with significantly longer QTc interval when compared to patients with peak V’O₂ above the median. Further these patients tend to have more pronounced impairment of longitudinal function as indicated by lower MAPSE, TAPSE, and elevation of cardiac biomarkers. Multivariate analysis revealed peak V'O₂ slope as the only independent predictor of survival. Conclusions: We identified reduced peak V'O₂ as an independent predictor of mortality in patients with cardiac involvement in different forms of systemic amyloidosis.

Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimoto...

Elevated interleukin-6 levels are associated with impaired outcome in cardiac transthyretin amyloidosis

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine.

Introduction: Cardiac transthyretin amyloidosis (ATTR) is a progressive, fatal disease leading to heart failure due to accumulation of amyloid fibrils in the interstitial space and may occur as a hereditary (ATTRv) or wild-type (ATTRwt) form. Guidelines recommend the use of ACE inhibitors (ACEis) and beta-blockers (BBs) as heart failure therapy (HFT) in all patients with symptomatic heart failure and reduced ejection fraction, independent of the underlying etiology. However, the prognostic benefit of ACEis and BBs in ATTR has not been elucidated in detail yet. We thus sought to retrospectively investigate the outcome of patients with ATTRwt or ATTRv under HFT. Methods: Medical records of 403 patients with cardiac ATTR (ATTRwt: n = 268, ATTRv: n = 135) were screened for long-term medication as well as clinical, laboratory, electrocardiographic and echocardiographic data. Patients were assessed between 2005 and 2020 at the University Hospital Heidelberg. Kaplan–Meier analysis was used to analyze potential differences in survival among different subgroups. Results: The mean follow-up was 28 months. In total, 43 patients (32%) with ATTRv and 140 patients (52%) with ATTRwt received HFT. Survival was significantly shorter in patients receiving HFT in ATTRv (46 vs. 83 months, p = 0.0007) vs. non-HFT. A significantly better survival was observed in patients with comorbidities (coronary artery disease, arterial hypertension) and HFT among ATTRwt patients (p = 0.004). No significant differences in survival were observed in the other subgroups. Conclusions: Survival analysis revealed a potential benefit of HFT in patients with ATTRwt and cardiac comorbidities such as coronary artery disease and/or arterial hypertension. In contrast, HFT should be used with caution in patients with ATTRv.