Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation

Aims: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in pre‐transplant characteristics and outcomes after HTx. Methods and results: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in all‐cause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46–62; 24.6% women), 49 732 events occurred during a median follow‐up of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11–3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44–0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12–1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17–1.32; P < 0.001) or VAD (OR 1.53, CI 1.45–1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13–1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62–2.00; P < 0.001). There were no differences in all‐cause mortality, cardiovascular mortality, and graft failure between sexes. Conclusions: In this US transplant registry, men and women differed in pre‐transplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized post‐HTx management and care

Incidence of premature battery depletion in subcutaneous cardioverter-defibrillator patients: insights from a multicenter registry.

BACKGROUND The subcutaneous ICD established its role in the prevention of sudden cardiac death in recent years. The occurrence of premature battery depletion in a large subset of potentially affected devices has been a cause of concern. The incidence of premature battery depletion has not been studied systematically beyond manufacturer-reported data. METHODS Retrospective data and the most recent follow-up data on S-ICD devices from fourteen centers in Europe, the US, and Canada was studied. The incidence of generator removal or failure was reported to investigate the incidence of premature S-ICD battery depletion, defined as battery failure within 60 months or less. RESULTS Data from 1054 devices was analyzed. Premature battery depletion occurred in 3.5% of potentially affected devices over an observation period of 49 months. CONCLUSIONS The incidence of premature battery depletion of S-ICD potentially affected by a battery advisory was around 3.5% after 4 years in this study. Premature depletion occurred exclusively in devices under advisory. This is in line with the most recently published reports from the manufacturer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04767516

Inhibition of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) improves contractility in human end-stage failing myocardium

In den vergangenen Jahren avancierte die Herzinsuffizienz zu einer der häufigsten Todesursachen und kostenintensivsten Krankheiten. Bekannterweise ist die Ca2+/Calmodulin-abhängige Proteinkinase II (CaMKII) in der Herzinsuffizienz sowohl in ihrer Aktivität als auch in ihrer Expression erhöht, jedoch ist ihre funktionelle Rolle bei dieser noch nicht hinreichend geklärt. In dieser Dissertation konnten zum ersten Mal detaillierte Expressionsanalysen der CaMKII in humanen terminal insuffizienten Herzen und die Folgen der CaMKII-Inhibition auf die Myokardkontraktilität untersucht werden.Die Expressionsanalysen zeigten, dass die Proteinexpression der CaMKIIδ sowohl ihrer nukleären Splicevariante CaMKIIδB als auch ihrer zytosolischen Splicevariante CaMKIIδC und die CaMKIIγ-Expression bei Patienten mit dilatativer Kardiomyopathie (DCM) und ischämischer Kardiomyopathie (ICM) im linken und rechten Ventrikel in humanen terminal insuffizienten Herzen im Vergleich zu gesunden Herzen erhöht sind. Die Inhibition der CaMKII-Überexpression mit KN-93 und AIP bewirkte einen signifikant positiv inotropen Effekt in Muskelstreifenexperimenten. Signifikante Effekte auf die diastolische Spannung und die Relaxationskinetik der Muskelstreifen konnten nicht detektiert werden. Darüber hinaus wies das verbesserte Post-Pausen-Verhalten der Muskelstreifen und die durchgeführten Caffein-induzierten Ca2+-Transienten auf einen verbesserten Sarkoplasmatischen Retikulum (SR)-Ca2+-Stoffwechsel unter CaMKII-Inhibition hin. Di! e Hypothese, ob der verbesserte SR-Ca2+-Gehalt auf einem reduzierten SR-Ca2+-Leck beruhen könne, wurde mit Hilfe der konfokalen Laserfluoreszenzmikroskopie überprüft. Durch CaMKII-Inhibition konnte das SR-Ca2+-Leck signifikant vermindert werden und bestätigte somit die erhobene Hypothese. Darüber hinaus war die Ryanodinrezeptor Typ 2 (RyR2)-Phosphorylierung an Ser-2809 und an der für die CaMKII-spezifischen RyR2-Phosphorylierungsstelle an Ser-2815 nach CaMKII-Hemmung signifikant vermindert. Diese reduzierte RyR2-Hyperphosphorylierung durch CaMKII-Inhibition zog wahrscheinlich eine verminderte Öffnungswahrscheinlichkeit der RyR2 nach sich.Zusammenfassend erscheint die Inhibition der CaMKII bzw. die Inhibition des SR-Ca2+-Lecks durch vermehrte CaMKII-abhängige Phosphorylierung der RyR2 eine mögliche neue und vielversprechende Therapieoption in der Herzinsuffizienz

Role of Toll-like receptors and interferon regulatory factors in different experimental heart failure models of diverse etiology: IRF7 as novel cardiovascular stress-inducible factor.

Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor. Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy. In addition, we investigated for the first time comprehensive TLR and IRF gene and protein expression under basal conditions in murine and human cardiac tissue. We found that Tlr4, Tlr9 and Irf7 displayed highest gene expression under basal conditions, indicating their significant role in first-line defense in the murine and human heart. Moreover, induction of TLRs and IRFs clearly differs between the various experimental HF models of diverse etiology and the concomitant inflammatory status. In the HF model of acute viral-induced myocarditis, TLR and IRF activation displayed the uppermost gene expression in comparison to the remaining experimental HF models, indicating the highest amount of myocardial inflammation in myocarditis. In detail, Irf7 displayed by far the highest gene expression during acute viral infection. Interestingly, post myocardial infarction TLR and IRF gene expression was almost exclusively increased in the infarct zone after myocardial ischemia (Tlr2, Tlr3, Tlr6, Tlr7, Tlr9, Irf3, Irf7). With one exception, Irf3 showed a decreased gene expression in the remote zone post infarction. Finally, we identified Irf7 as novel cardiovascular stress-inducible factor in the pathologically stressed heart. These findings on TLR and IRF function in the inflamed heart highlight the complexity of inflammatory immune response and raise more interesting questions for future investigation

Seasonal trends of incidence and outcomes of cardiogenic shock : findings from a large, nationwide inpatients sample with 441,696 cases

Background!#!Outcome data about the use of tranexamic acid (TXA) in civilian patients in mature trauma systems are scarce. The aim of this study was to determine how severely injured patients are affected by the widespread prehospital use of TXA in Germany.!##!Methods!#!The international TraumaRegister DGU® was retrospectively analyzed for severely injured patients with risk of bleeding (2015 until 2019) treated with at least one dose of TXA in the prehospital phase (TXA group). These were matched with patients who had not received prehospital TXA (control group), applying propensity score-based matching. Adult patients (≥ 16) admitted to a trauma center in Germany with an Injury Severity Score (ISS) ≥ 9 points were included.!##!Results!#!The matching yielded two comparable cohorts (n = 2275 in each group), and the mean ISS was 32.4 ± 14.7 in TXA group vs. 32.0 ± 14.5 in control group (p = 0.378). Around a third in both groups received one dose of TXA after hospital admission. TXA patients were significantly more transfused (p = 0.022), but needed significantly less packed red blood cells (p ≤ 0.001) and fresh frozen plasma (p = 0.023), when transfused. Massive transfusion rate was significantly lower in the TXA group (5.5% versus 7.2%, p = 0.015). Mortality was similar except for early mortality after 6 h (p = 0.004) and 12 h (p = 0.045). Among non-survivors hemorrhage as leading cause of death was less in the TXA group (3.0% vs. 4.3%, p = 0.021). Thromboembolic events were not significantly different between both groups (TXA 6.1%, control 4.9%, p = 0.080).!##!Conclusion!#!This is the largest civilian study in which the effect of prehospital TXA use in a mature trauma system has been examined. TXA use in severely injured patients was associated with a significantly lower risk of massive transfusion and lower mortality in the early in-hospital treatment period. Due to repetitive administration, a dose-dependent effect of TXA must be discussed

Predictive value of long-term changes of growth differentiation factor-15 over a 27-year-period for heart failure and death due to coronary heart disease

<div><p>Background</p><p>Growth differentiation factor-15 (GDF-15), Cystatin C and C-reactive protein (CRP) have been discussed as biomarkers for prediction of cardiac diseases. The aim of this study was to investigate the predictive value of single and repeated measurements of GDF-15 compared to Cystatin C and CRP for incidence of heart failure (HF) and death due to coronary heart disease (CHD) in the general population.</p><p>Methods and results</p><p>Levels of GDF-15, CRP and Cystatin C were determined in three repeated measurements collected 5 years apart in the DAN-MONICA (Danish-Multinational MONitoring of trends and determinants in Cardiovascular disease) cohort (participants at baseline n = 3785). Cox regression models adjusted for cardiovascular risk factors revealed significantly increased hazard ratios (HR) for GDF-15 for incident HF 1.36 (HR per interquartile range (IQR) increase, 95% confidence interval (CI): 1.16; 1.59) and for death from CHD 1.51 (HR per IQR increase, 95% CI: 1.31, 1.75) (both with p<0.001). Joint modeling of time-to-event and longitudinal GDF-15 over a median 27-year follow-up period showed that the marker evolution was positively associated with death of CHD (HR per IQR increase 3.02 95% CI: (2.26, 4.04), p < 0.001) and HF (HR per IQR increase 2.12 95% CI: (1.54, 2.92), p<0.001). However using Cox models with follow-up time starting at the time of the third examination, serial measurement of GDF-15, modeled as changes between the measurements, did not improve prediction over that of the most recent measurement.</p><p>Conclusions</p><p>GDF-15 is a promising biomarker for prediction of HF and death due to CHD in the general population, which may provide prognostic information to already established clinical biomarkers. Repeated measurements of GDF-15 displayed only a slight improvement in the prediction of these endpoints compared to a single measurement.</p></div

Longitudinal biomarker measurements: Hazard ratios for death from CHD estimated by joint models.

<p>Longitudinal biomarker measurements: Hazard ratios for death from CHD estimated by joint models.</p

Gene expression levels of the intracellular localized TLRs <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> in different HF models of diverse etiology.

<p>Cardiac tissue of healthy and diseased C57BL/6J mice was used for TaqMan based gene expression analysis of the plasma membrane localized TLRs <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i>. Expression levels of cardiac tissue from control mice are shown as white boxes, from diseased animals as red, blue, green, or yellow boxes corresponding to the analyzed heart failure model. In viral-induced myocarditis (shown in red), gene expression of <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> was highly increased 7 days after infection compared to healthy controls. However, <i>Tlr3</i>, <i>Tlr7</i> and <i>Tlr9</i> displayed the highest increase during acute myocarditis and the initially increased gene expression levels returned almost with exception to basal levels 28 days after infection. Moreover, in the model of myocardial infarction (shown in blue), gene expression of <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> was highly increased 5 days post infarction in the infarct zone when compared to the remote zone. In addition, the TLRs <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> showed the highest increase in gene expression levels after myocardial ischemia. In the remote zone, no increased TLR gene expression was observed. In STZ-induced diabetic cardiomyopathy (shown in green), a decreased gene expression of <i>Tlr8</i> in comparison to their healthy controls was detected; the remaining TLRs displayed no changes in gene expression levels. In the heart failure model caused by chronic AngII-infusion for 21 days (shown in yellow) only the intracellular localized <i>Tlr3</i> displayed a significant decrease when compared to their controls. Data are presented as relative mRNA expression in fold change to the corresponding untreated control using the formula 2^−ΔΔCt. * = significantly different compared to corresponding control; ^# = significantly different compared to VM (acute—7 days) or RZ (remote zone).</p

Gene and protein expression of plasma membrane and intracellular localized TLRs and of the IFN regulatory factors IRF3 and IRF7 in murine and human cardiac tissue under basal conditions.

<p>Cardiac tissue of healthy C57BL/6J wildtype mice was used for TaqMan based gene expression analysis of various TLRs and their IFN regulatory factors <i>Irf3</i> and <i>Irf7</i> under basal conditions. Gene expressions of <i>Tlr4</i>, <i>Tlr9</i>, <i>Irf3</i> and <i>Irf7</i> were highly expressed when compared to the remaining TLRs under basal conditions in murine cardiac tissue. The highest gene expression under basal condition was detected for <i>Irf7</i>. In addition, we detected similar human protein expression patterns when compared with murine gene expression in cardiac tissue under basal conditions. Data are presented in box plots as absolute mRNA expression normalized to the house keeping gene <i>Cdkn1b</i> and human protein abundance are presented as rhombus sign on the right-hand of each mRNA expression.</p