Thermic sealing in femoral catheterization: First experience with the Secure Device

Background: Devices currently used to achieve hemostasis of the femoral artery following percutaneous cardiac catheterization are associated with vascular complications and remnants of artificial materials are retained at the puncture site. The Secure arterial closure Device induces hemostasis by utilizing thermal energy, which causes collagen shrinking and swelling. In comparison to established devices, it has the advantage of leaving no foreign material in the body following closing. This study was designed to evaluate the efficacy and safety of the Secure Device to close the puncture site following percutaneous cardiac catheterization. Methods: The Secure Device was evaluated in a prospective non-randomized single-center trial with patients undergoing 6 F invasive cardiac procedures. A total of 67 patients were enrolled and the device was utilized in 63 patients. Fifty diagnostic and 13 interventional cases were evaluated. Femoral artery puncture closure was performed immediately after completion of the procedure. Time to hemostasis (TTH), time to ambulation (TTA) and data regarding short-term and 30-day clinical follow-up were recorded. Results: Mean TTH was 4:30 ± 2:15 min in the overall observational group. A subpopulation of patients receiving anticoagulants had a TTH of 4:53 ± 1:43 min. There were two access site complications (hematoma > 5 cm). No major adverse events were identified during hospitalization or at the 30 day follow-up. Conclusions: The new Secure Device demonstrates that it is feasible in diagnostic and interventional cardiac catheterization. With respect to safety, the Secure Device was non-inferior to other closure devices as tested in the ISAR closure trial

Stretch-elicited Na+/H+ exchanger activation: The autocrine/paracrine loop and its mechanical counterpart

The stretch of the cardiac muscle is immediately followed by an increase in the contraction strength after which occurs a slow force increase (SFR) that takes several minutes to fully develop. The SFR was detected in a wide variety of experimental preparations including isolated myocytes, papillary muscles and/or trabeculae, left ventricle strips of failing human myocardium, in vitro isovolumic and in vivo volume-loaded hearts. It was established that the initial increase in force is due to an increase in myofilament Ca2+ responsiveness, whereas the SFR results from an increase in the Ca2+ transient. However, the mechanism(s) for this increase in the Ca2+ transient has remained undefined until the proposal of Na+/H+ exchanger (NHE) activation by stretch. Studies in multicellular cardiac muscle preparations from cat, rabbit, rat and failing human heart have shown evidence that the stretch induces a rise in intracellular Na+ ([Na+]i) through NHE activation, which subsequently leads to an increase in Ca2+ transient via reverse-mode Na+/Ca2+ (NCX) exchange. These experimental data agree with a theoretical ionic model of cardiomyocytes that predicted an increased Na+ influx and a concurrent increase in Ca2+ entry through NCX as the cause of the SFR to muscle stretch. However, there are aspects that await definitive demonstration, and perhaps subjected to species-related differences like the possibility of an autocrine/paracrine loop involving angiotensin II and endothelin as the underlying mechanism for stretch-induced NHE activation leading to the rise in [Na+]i and reverse-mode NCX.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Use of levosimendan in acute heart failure

Peer reviewe

Stretch-elicited Na+/H+ exchanger activation: The autocrine/paracrine loop and its mechanical counterpart

The stretch of the cardiac muscle is immediately followed by an increase in the contraction strength after which occurs a slow force increase (SFR) that takes several minutes to fully develop. The SFR was detected in a wide variety of experimental preparations including isolated myocytes, papillary muscles and/or trabeculae, left ventricle strips of failing human myocardium, in vitro isovolumic and in vivo volume-loaded hearts. It was established that the initial increase in force is due to an increase in myofilament Ca2+ responsiveness, whereas the SFR results from an increase in the Ca2+ transient. However, the mechanism(s) for this increase in the Ca2+ transient has remained undefined until the proposal of Na+/H+ exchanger (NHE) activation by stretch. Studies in multicellular cardiac muscle preparations from cat, rabbit, rat and failing human heart have shown evidence that the stretch induces a rise in intracellular Na+ ([Na+]i) through NHE activation, which subsequently leads to an increase in Ca2+ transient via reverse-mode Na+/Ca2+ (NCX) exchange. These experimental data agree with a theoretical ionic model of cardiomyocytes that predicted an increased Na+ influx and a concurrent increase in Ca2+ entry through NCX as the cause of the SFR to muscle stretch. However, there are aspects that await definitive demonstration, and perhaps subjected to species-related differences like the possibility of an autocrine/paracrine loop involving angiotensin II and endothelin as the underlying mechanism for stretch-induced NHE activation leading to the rise in [Na+]i and reverse-mode NCX.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control

Diabetes mellitus and the associated complications represent a global burden on human health and economics. Cardiovascular diseases are the leading cause of death in diabetic patients, who have a 2–5 times higher risk of developing heart failure than age-matched non-diabetic patients, independent of other comorbidities. Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors, such coronary artery disease, hypertension, and significant valvular disease. Hyperglycemia, hyperinsulinemia, and insulin resistance mediate the pathological remodeling of the heart, characterized by left ventricle concentric hypertrophy and perivascular and interstitial fibrosis leading to diastolic dysfunction. A change in the metabolic status, impaired calcium homeostasis and energy production, increased inflammation and oxidative stress, as well as an accumulation of advanced glycation end products are among the mechanisms implicated in the pathogenesis of diabetic cardiomyopathy. Despite a growing interest in the pathophysiology of diabetic cardiomyopathy, there are no specific guidelines for diagnosing patients or structuring a treatment strategy in clinical practice. Anti-hyperglycemic drugs are crucial in the management of diabetes by effectively reducing microvascular complications, preventing renal failure, retinopathy, and nerve damage. Interestingly, several drugs currently in use can improve cardiac health beyond their ability to control glycemia. GLP-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors have been shown to have a beneficial effect on the cardiovascular system through a direct effect on myocardium, beyond their ability to lower blood glucose levels. In recent years, great improvements have been made toward the possibility of modulating the expression of specific cardiac genes or non-coding RNAs in vivo for therapeutic purpose, opening up the possibility to regulate the expression of key players in the development/progression of diabetic cardiomyopathy. This review summarizes the pathogenesis of diabetic cardiomyopathy, with particular focus on structural and molecular abnormalities occurring during its progression, as well as both current and potential future therapies

Effects of an online information tool on post-traumatic stress disorder in relatives of intensive care unit patients: a multicenter double-blind, randomized, placebo-controlled trial (ICU-Families-Study).

PURPOSE Intensive care unit (ICU) hospitalization is challenging for the family members of the patients. Most family members report some level of anxiety and depression, sometimes even resulting in post-traumatic stress disorder (PTSD). An association has been reported between lack of information and PTSD. This study had three aims: to quantify the psychological burden of family members of critically ill patients, to explore whether a website with specific information could reduce PTSD symptoms, and to ascertain whether a website with information about intensive care would be used. METHOD A multicenter double-blind, randomized, placebo-controlled trial was carried out in Austria and Switzerland. RESULTS In total, 89 members of families of critically ill patients (mean age 47.3 ± 12.9 years, female n = 59, 66.3%) were included in the study. 46 relatives were allocated to the intervention website and 43 to the control website. Baseline Impact of Event Scale (IES) score was 27.5 ± 12.7. Overall, 50% showed clinically relevant PTSD symptoms at baseline. Mean IES score for the primary endpoint (~ 30 days after inclusion, T1) was 24 ± 15.8 (intervention 23.9 ± 17.9 vs. control 24.1 ± 13.5, p = 0.892). Hospital Anxiety and Depression Scale (HADS - Deutsch (D)) score at T1 was 12.2 ± 6.1 (min. 3, max. 31) and did not differ between groups. Use of the website differed between the groups (intervention min. 1, max. 14 vs. min. 1, max. 3; total 1386 "clicks" on the website, intervention 1021 vs. control 365). Recruitment was prematurely stopped in February 2020 due to coronavirus disease 2019 (COVID-19). CONCLUSION Family members of critically ill patients often have significant PTSD symptoms and online information on critical illness did not result in reduced PTSD symptoms

AMPK - Activated Protein Kinase and its Role in Energy Metabolism of the Heart

Adenosine monophosphate – activated kinase (AMPK) plays a key role in the coordination of the heart’s anabolic and catabolic pathways. It induces a cellular cascade at the center of maintaining energy homeostasis in the cardiomyocytes.. The activated AMPK is a heterotrimeric protein, separated into a catalytic α - subunit (63kDa), a regulating β - subunit (38kDa) and a γ - subunit (38kDa), which is allosterically adjusted by adenosine triphosphate (ATP) and adenosine monophosphate (AMP). The actual binding of AMP to the γ – subunit is the step which activates AMPK

Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+Ca^{\text{2+}} cycling

Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve

CaMKII delta C Drives Early Adaptive Ca(2+)Change and Late Eccentric Cardiac Hypertrophy

Rationale: CaMKII (Ca2+-Calmodulin dependent protein kinase) delta C activation is implicated in pathological progression of heart failure (HF) and CaMKII delta C transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca(2+)handling and CaMKII activation in hypertrophy and HF. Objective: To measure time- and location-dependent activation of CaMKII delta C signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKII delta C transgenic mice. Methods and Results: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKII delta-knockout), CaMKII delta C transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKII delta C activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKII delta activation caused a compensatory increase in sarcoplasmic reticulum Ca(2+)content, Ca(2+)transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKII delta TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca(2+)transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKII delta TG mice lacking delta B exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKII delta expression, especially for CaMKII delta C in nuclear fractions. Conclusions: We conclude that in early TAC perinuclear CaMKII delta C activation promotes adaptive increases in myocyte Ca(2+)transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKII delta C axis contributes to eccentric hypertrophy and HF