Search

The EF-hand calcium (Ca2+) sensor protein S100A1 combines inotropic with antiarrhythmic potency in cardiomyocytes (CMs). Oxidative posttranslational modification (ox-PTM) of S100A1's conserved, single-cysteine residue (C85) via reactive nitrogen species (i.e., S-nitrosylation or S-glutathionylation) has been proposed to modulate conformational flexibility of intrinsically disordered sequence fragments and to increase the molecule's affinity toward Ca2+. Considering the unknown biological functional consequence, we aimed to determine the impact of the C85 moiety of S100A1 as a potential redox switch. We first uncovered that S100A1 is endogenously glutathionylated in the adult heart in vivo. To prevent glutathionylation of S100A1, we generated S100A1 variants that were unresponsive to ox-PTMs. Overexpression of wild-type (WT) and C85-deficient S100A1 protein variants in isolated CM demonstrated equal inotropic potency, as shown by equally augmented Ca2+ transient amplitudes under basal conditions and β-adrenergic receptor (βAR) stimulation. However, in contrast, ox-PTM defective S100A1 variants failed to protect against arrhythmogenic diastolic sarcoplasmic reticulum (SR) Ca2+ waves and ryanodine receptor 2 (RyR2) hypernitrosylation during βAR stimulation. Despite diastolic performance failure, C85-deficient S100A1 protein variants exerted similar Ca2+-dependent interaction with the RyR2 than WT-S100A1. Dissecting S100A1's molecular structure-function relationship, our data indicate for the first time that the conserved C85 residue potentially acts as a redox switch that is indispensable for S100A1's antiarrhythmic but not its inotropic potency in CMs. We, therefore, propose a model where C85's ox-PTM determines S100A1's ability to beneficially control diastolic but not systolic RyR2 activity. NEW & NOTEWORTHY: S100A1 is an emerging candidate for future gene-therapy treatment of human chronic heart failure. We aimed to study the significance of the conserved single-cysteine 85 (C85) residue in cardiomyocytes. We show that S100A1 is endogenously glutathionylated in the heart and demonstrate that this is dispensable to increase systolic Ca2+ transients, but indispensable for mediating S100A1's protection against sarcoplasmic reticulum (SR) Ca2+ waves, which was dependent on the ryanodine receptor 2 (RyR2) nitrosylation status. [ABSTRACT FROM AUTHOR]

Aims: Takotsubo syndrome (TTS) is an acute heart failure (AHF) syndrome mimicking the symptoms of acute myocardial infarction. Impaired outcome has been shown, making risk stratification and novel therapeutic concepts a necessity. We hypothesized insulin resistance with elevated plasma glucose and potentially myocardial glucose deprivation to contribute to the pathogenesis of TTS and investigated the therapeutic benefit of insulin in vivo. Methods and results: First, we retrospectively analysed patient data of n = 265 TTS cases (85.7% female, mean age 71.1 ± 14.1 years) with documented initial plasma glucose from the Department of Cardiology of the University Hospital Heidelberg in Germany (May 2011 to May 2021). Median split of the study population according to glucose levels (≤123 mg/dL vs. >123 mg/dL) yielded significantly elevated mean heart rate (80.75 ± 18.96 vs. 90.01 ± 22.19 b.p.m., P < 0.001), left ventricular end‐diastolic pressure (LVEDP, 18.51 ± 8.35 vs. 23.09 ± 7.97 mmHg, P < 0.001), C‐reactive protein (26.14 ± 43.30 vs. 46.4 ± 68.6 mg/L, P = 0.006), leukocyte count (10.12 ± 4.29 vs. 15.05 ± 9.83/nL, P < 0.001), peak high‐sensitive Troponin T (hs‐TnT, 515.44 ± 672.15 vs. 711.40 ± 736.37 pg/mL, P = 0.005), reduced left ventricular ejection fraction (EF, 34.92 ± 8.94 vs. 31.35 ± 8.06%, P < 0.001), and elevated intrahospital mortality (2.3% vs. 12.1%, P = 0.002) in the high‐glucose group (Student's t‐test, Mann–Whitney U test, or chi‐squared test). Linear regression indicated a significant association of glucose with HR (P < 0.001), LVEDP (P = 0.014), hs‐TnT kinetics from admission to the next day (P < 0.001), hs‐TnT the day after admission (P < 0.001), as well as peak hsTnT (P < 0.001). Logistic regression revealed significant association of glucose with a composite intrahospital outcome including catecholamine use, respiratory support, and resuscitation [OR 1.010 (1.004–1.015), P = 0.001]. To further investigate the potential role of glucose in TTS pathophysiology experimentally, we utilized an in vivo murine model of epinephrine (EPI)‐driven reversible AHF. For this, male mice underwent therapeutic injection of insulin (INS, 1 IU/kg) or/and glucose (GLU, 0.5 g/kg) after EPI (2.5 mg/kg), both of which markedly improved mean EF (EPI 34.3% vs. EPI + INS + GLU 43.7%, P = 0.025) and significantly blunted mean hs‐TnT (EPI 14 393 pg/mL vs. EPI + INS 6864 pg/mL at 24 h, P = 0.039). Particularly, insulin additionally ameliorated myocardial pro‐inflammatory gene expression, suggesting an anti‐inflammatory effect of acute insulin therapy. Conclusions: Elevated initial plasma glucose was associated with adverse outcome‐relevant parameters in TTS and may present a surrogate parameter of heightened catecholaminergic drive. In mice, insulin‐ and glucose injection both improved EPI‐induced AHF and myocardial damage, indicating insulin resistance rather than detrimental effects of hyperglycaemia itself as the underlying cause. Future studies will investigate the role of HbA1c as a risk stratifier and of insulin‐based therapy in TTS. [ABSTRACT FROM AUTHOR]

Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS. [ABSTRACT FROM AUTHOR]

Background: High‐altitude pulmonary hypertension (HAPH) has a prevalence of approximately 10%. Changes in cardiac morphology and function at high altitude, compared to a population that does not develop HAPH are scarce. Methods: Four hundred twenty‐one subjects were screened in a hypoxic chamber inspiring a FiO2 = 12% for 2 h. In 33 subjects an exaggerated increase in systolic pulmonary artery pressure (sPAP) could be confirmed in two independent measurements. Twenty nine of these, and further 24 matched subjects without sPAP increase were examined at 4559 m by Doppler echocardiography including global longitudinal strain (GLS). Results: SPAP increase was higher in HAPH subjects (∆ = 10.2 vs. ∆ = 32.0 mm Hg, p <.001). LV eccentricity index (∆ =.15 vs. ∆ =.31, p =.009) increased more in HAPH. D‐shaped LV (0 [0%] vs. 30 [93.8%], p =.00001) could be observed only in the HAPH group, and only in those with a sPAP ≥50 mm Hg. LV‐EF (∆ = 4.5 vs. ∆ = 6.7%, p =.24) increased in both groups. LV‐GLS (∆ = 1.2 vs. ∆ = 1.1 –%, p =.60) increased slightly. RV end‐diastolic (∆ = 2.20 vs. ∆ = 2.7 cm2, p =.36) and end‐systolic area (∆ = 2.1 vs. ∆ = 2.7 cm2, p =.39), as well as RA end‐systolic area index (∆ = −.9 vs. ∆ =.3 cm2/m2, p =.01) increased, RV‐FAC (∆ = −2.9 vs. ∆ = −4.7%, p =.43) decreased, this was more pronounced in HAPH, RV‐GLS (∆ = 1.6 vs. ∆ = −.7 –%, p =.17) showed marginal changes. Conclusions: LV and LA dimensions decrease and left ventricular function increases at high‐altitude in subjects with and without HAPH. RV and RA dimensions increase, and RV longitudinal strain increases or remains unchanged in subjects with HAPH. Changes are negligible in those without HAPH. [ABSTRACT FROM AUTHOR]

Aims: Oncological patients suspected at risk for cardiotoxicity are recommended to undergo intensified cardiological surveillance. We investigated the value of cardiac biomarkers and patient‐related risk factors [age, cardiovascular risk factors (CVRFs), and cardiac function] for the prediction of all‐cause mortality (ACM) and the development of cardiotoxicity. Methods and results: Between January 2016 and December 2020, patients with oncological diseases admitted to the Cardio‐Oncology Unit at the Heidelberg University Hospital were included. They were evaluated by medical history, physical examination, 12‐lead electrocardiogram, 2D echocardiography, and cardiac biomarkers [high‐sensitivity cardiac troponin T (hs‐cTnT) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP)]. The primary endpoint was defined as ACM and the secondary endpoint was defined as cardiotoxicity, as defined by the European Society of Cardiology. Of the 1971 patients enrolled, the primary endpoint was reached by 490 patients (25.7%) with a median of 363.5 [interquartile range (IQR) 121.8, 522.5] days after presentation. Hs‐cTnT of ≥ 7 ng/L [odds ratio (OR) 1.82, P < 0.001] and NT‐proBNP (OR 1.98, P < 0.001) were independent predictors of ACM, while reduced left ventricular ejection fraction was not associated with increased ACM (P = 0.85). The secondary endpoint was reached by 182 patients (9.2%) with a median of 793.5 [IQR 411.2, 1165.0] days. Patients with multiple CVRFs (defined as high risk, n = 886) had an increased risk of cardiotoxicity (n = 100/886, 11.3%; hazard ratio 1.57, P = 0.004). They showed elevated baseline values of hs‐cTnT (OR 1.60, P = 0.006) and NT‐proBNP (OR 4.00, P < 0.001) and had an increased risk of ACM (OR 1.43, P = 0.031). Conclusions: In cancer patients, CVRF accumulation predicts cardiotoxicity whereas elevated hs‐cTnT or NT‐proBNP levels are associated with ACM. Accordingly, less intensive surveillance protocols may be warranted in patients with low cardiac biomarker levels and absence of CVRFs. [ABSTRACT FROM AUTHOR]