Comparative Analysis of Mitochondria Surrounding the Intercalated Discs in Heart Diseases-An Ultrastructural Pilot Study.

BACKGROUND: Mitochondria play a crucial role in adapting to fluctuating energy demands, particularly in various heart diseases. This study investigates mitochondrial morphology near intercalated discs in left ventricular (LV) heart tissues, comparing samples from patients with sinus rhythm (SR), atrial fibrillation (AF), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). METHODS: Transmission electron microscopy was used to analyze mitochondria within 0-3.5 µm and 3.5-7 µm of intercalated discs in 9 SR, 10 AF, 9 DCM, and 8 ICM patient samples. Parameters included mean size in µm2 and elongation, count, percental mitochondrial area in the measuring frame, and a conglomeration score. RESULTS: AF patients exhibited higher counts of small mitochondria in the LV myocardium, resembling SR. DCM and ICM groups had fewer, larger, and often hydropic mitochondria. Accumulation rates and percental mitochondrial area were similar across groups. Significant positive correlations existed between other defects/size and hydropic mitochondria and between count/area and conglomeration score, while negative correlations between count and size/other defects and between hydropic mitochondria and count could be seen as well. CONCLUSION: Mitochondrial parameters in the LV myocardium of AF patients were similar to those of SR patients, while DCM and ICM displayed distinct changes, including a decrease in number, an increase in size, and compromised mitochondrial morphology. Further research is needed to fully elucidate the pathophysiological role of mitochondrial morphology in different heart diseases, providing deeper insights into potential therapeutic targets and interventions.

Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx).

The relationship between oxidative stress and cardiac stiffness is thought to involve modifications to the giant muscle protein titin, which in turn can determine the progression of heart disease. In vitro studies have shown that S-glutathionylation and disulfide bonding of titin fragments could alter the elastic properties of titin; however, whether and where titin becomes oxidized in vivo is less certain. Here we demonstrate, using multiple models of oxidative stress in conjunction with mechanical loading, that immunoglobulin domains preferentially from the distal titin spring region become oxidized in vivo through the mechanism of unfolded domain oxidation (UnDOx). Via oxidation type-specific modification of titin, UnDOx modulates human cardiomyocyte passive force bidirectionally. UnDOx also enhances titin phosphorylation and, importantly, promotes nonconstitutive folding and aggregation of unfolded domains. We propose a mechanism whereby UnDOx enables the controlled homotypic interactions within the distal titin spring to stabilize this segment and regulate myocardial passive stiffness.

Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions.

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH-iPSC-CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm2 vs. 538.9 ± 23.8 µm2, p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH-iPSC-CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O2·s-1·mg-1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies.

Changes in healthcare seeking and lifestyle in old aged individuals during COVID-19 lockdown in Germany: the population-based AugUR study.

BACKGROUND: Containment measures in the COVID-19 pandemic protected individuals at high risk, particularly individuals at old age, but little is known about how these measures affected health-related behavior of old aged individuals. We aimed to investigate the impact of the spring 2020 lockdown in Germany on healthcare-seeking and health-related lifestyle in the old aged and to identify susceptible subgroups. METHODS: We conducted a follow-up survey among the pre-pandemically well-characterized participants of our AugUR cohort study, residents in/around Regensburg aged 70+ years and relatively mobile. A self-completion questionnaire on current behavior, perceived changes, and SARS-Cov-2 infection was mailed in May 2020, shortly before contact restrictions ended. Pre-pandemic lifestyle and medical conditions were derived from previous study center visits. RESULTS: Among 1850 survey participants (73-98 years; net-response 89%), 74% were at increased risk for severe COVID-19 according to medical conditions; four participants reported SARS-CoV-2 infection (0.2%). Participants reported changes in behavior: 29% refrained from medical appointments, 14% increased TV consumption, 26% reported less physical activity, but no systematic increase of smoking or alcohol consumption. When comparing during- and pre-lockdown reports of lifestyle within participant, we found the same pattern as for the reported perceived changes. Women and the more educated were more susceptible to changes. Worse QOL was perceived by 38%. CONCLUSIONS: Our data suggest that the spring 2020 lockdown did not affect the lifestyle of a majority of the mobile old aged individuals, but the substantial proportions with decreased physical activity and healthcare-seeking are markers of collateral damage.

Alterations of the renin angiotensin system in human end-stage heart failure before and after mechanical cardiac unloading by LVAD support.

Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the ß-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, ß-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, ß-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and ß-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and ß-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.

Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Cardiac unloading by LVAD support differentially influences components of the cGMP-PKG signaling pathway in ischemic and dilated cardiomyopathy.

Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively. Then the expressions of key components of the cGMP-PKG signaling pathway were determined by polymerase chain reaction (ANP; BNP; natriuretic peptide receptor A, NPR-A; natriuretic peptide receptor C, NPR-C; neprilysin; NOS3; soluble guanylyl cyclase, sGC; PDE5; cGMP-dependent protein kinase G, PKG) and enzyme-linked immunosorbent assay (cGMP), respectively. Patients were predominantly male, 52 ± 10 years old, were receiving recommended heart failure therapy, and had their donor organ implanted after 351 ± 317 days of LVAD support. Except for more DCM patients with ICD therapy, no significant differences were detected between ICM and DCM, which also applies to the expression of cGMP-PKG pathway components at baseline. After LVAD support, ANP, NPR-C, and cGMP were significantly down-regulated and neprilysin, PDE5, and PKG I expressions were reduced with borderline significance in DCM, but not in ICM patients. Multiple significant correlations were found for expression differences (i.e., expression at LVAD implantation minus expression at heart transplantation) both in DCM and ICM, even though there was a closer connection between the NO and NP side of the cGMP-PKG pathway in DCM patients. Furthermore, duration of LVAD support negatively correlated with expression differences of PKG I, PDE5, and sGC in ICM, but not in DCM. Originating from the same activation level at LVAD implantation, cardiac unloading significantly alters key components of the cGMP-PKG pathway in DCM, but not in ICM patients. This etiology-specific regulation should be considered when analyzing therapeutic interventions with effects on this signaling pathway.

3D vena contracta area after MitraClip© procedure: precise quantification of residual mitral regurgitation and identification of prognostic information.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is increasingly performed in patients with severe mitral regurgitation (MR). Post-procedural MR grading is challenging and an unsettled issue. We hypothesised that the direct planimetry of vena contracta area (VCA) by 3D-transoesophageal echocardiography allows quantifying post-procedural MR and implies further prognostic relevance missed by the usual ordinal scale (grade I-IV). METHODS: Based on a single-centre PMVR registry containing 102 patients, the association of VCA reduction and patients' functional capacity measured as six-minute walk distance (6 MW) was evaluated. 3D-colour-Doppler datasets were available before, during and 4 weeks after PMVR. RESULTS: Twenty nine patients (age 77.0 ± 5.8 years) with advanced heart failure (75.9% NYHA III/IV) and severe degenerative (34%) or functional (66%) MR were eligible. VCA was reduced in all patients by PMVR (0.99 ± 0.46 cm2 vs. 0.22 ± 0.15 cm2, p < 0.0001). It remained stable after median time of 33 days (p = 0.999). 6 MW improved after the procedure (257.5 ± 82.5 m vs. 295.7 ± 96.3 m, p < 0.01). Patients with a decrease in VCA less than the median VCA reduction showed a more distinct improvement in 6 MW than patients with better technical result (p < 0.05). This paradoxical finding was driven by inferior results in very large functional MR. CONCLUSIONS: VCA improves the evaluation of small residual MR. Its post-procedural values remain stable during a short-term follow-up and imply prognostic information for the patients' physical improvement. VCA might contribute to a more substantiated estimation of treatment success in the heterogeneous functional MR group.

Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure.

PURPOSE OF REVIEW: In highly prevalent cardiac diseases, new therapeutic approaches are needed. Since the first description of oxidative stress in heart failure, reactive oxygen species (ROS) have been considered as attractive drug targets. Though clinical trials evaluating antioxidant vitamins as ROS-scavenging agents yielded neutral results in patients at cardiovascular risk, the knowledge of ROS as pathophysiological factors has considerably advanced in the past few years and led to novel treatment approaches. Here, we review recent new insights and current strategies in targeting mitochondrial calcium handling and ROS in heart failure. RECENT FINDINGS: Mitochondria are an important ROS source, and more recently, drug development focused on targeting mitochondria (e.g. by SS-31 or MitoQ). Important advancement has also been made to decipher how the matching of energy supply and demand through calcium (Ca2+) handling impacts on mitochondrial ROS production and elimination. This opens novel opportunities to ameliorate mitochondrial dysfunction in heart failure by targeting cytosolic and mitochondrial ion transporters to improve this matching process. According to this approach, highly specific substances as the preclinical CGP-37157, as well as the clinically used ranolazine and empagliflozin, provide promising results on different levels of evidence. Furthermore, the understanding of redox signalling relays, resembled by catalyst-mediated protein oxidation, is about to change former paradigms of ROS signalling. Novel methods, as redox proteomics, allow to precisely analyse key regulatory thiol switches, which may induce adaptive or maladaptive signalling. Additionally, the generation of genetically encoded probes increased the spatial and temporal resolution of ROS imaging and opened a new methodological window to subtle, formerly obscured processes. These novel insights may broaden our understanding of why previous attempts to target oxidative stress have failed, and at the same time provide us with new targets for drug development.

The German AugUR study: study protocol of a prospective study to investigate chronic diseases in the elderly.

BACKGROUND: The majority of patients suffering from chronic health disabilities is beyond 70 years of age. Typical late-onset chronic diseases include those affecting the heart, the kidney, cancer, and conditions of the eye such as age-related macular degeneration. These diseases disable patients for many years and largely compromise autonomy in daily life. Due to challenges in recruiting the elderly, the collection of population-based epidemiological data as a prerequisite to understand associated risk factors and mechanisms is commonly done in the general population within an age-range of 20 to 70 years. METHODS/DESIGN: We establish the German AugUR study (Age-related diseases: understanding genetic and non-genetic influences - a study at the University of Regensburg), a prospective study in the mobile elderly general population in and around Regensburg in eastern Bavaria. In the long term, we aim to recruit 3,000 persons of Caucasian ethnicity with at least 70 years of age via residents' registration offices and conduct 3-year follow-ups. The study protocol includes a standardized interview regarding social and life-style factors, medication history, quality-of-life, and existing diagnoses of common diseases. The participants undergo medical examinations for ophthalmological, cardiovascular or diabetes-related conditions, and general measurements of body shape and fitness. The program is particularly tailored for the elderly. Biobanking of whole blood, serum, plasma, and urine is conducted and standard laboratory measurements are performed in fresh samples. DISCUSSION: AugUR is specifically designed as a research platform to host studies of late onset diseases. Consequently, this platform will help (1) to unravel the genetic and non-genetic etiology of disease development and progression, (2) to serve as control group of elderly individuals for comparisons with various patient groups, (3) to derive prevalence and incidence data on chronic diseases, and (4) to provide clinical reference parameters for the elderly mobile general population. This data will foster our understanding of disease mechanisms, which may ultimately help to improve prevention, diagnosis, and therapy for frequent chronic diseases. Here we present the baseline study protocol of AugUR.

Experimental heart failure induces alterations of the lung proteome--insight into molecular mechanisms.

BACKGROUND: Heart failure (CHF) is characterized by dyspnea and pulmonary changes. The underlying molecular adaptations are unclear, but might provide targets for therapeutic interventions. We therefore conceived a study to determine molecular changes of early pulmonary stress failure in a model of tachycardia-induced heart failure. METHODS: CHF was induced in rabbits by progessive right ventricular pacing (n=6). Invasive blood pressure measurements and echocardiography were repeatedly performed. Untreated animals served as controls (n=6). Pulmonary tissue specimens were subjected to two-dimensional gel electrophoresis, and differentially expressed proteins were identified by mass spectrometry. Selected proteins were validated by Western Blot analysis and localized by immunohistochemical staining. RESULTS: CHF animals were characterized by significantly altered functional, morphological, and hemodynamic parameters. Upon proteomic profiling, a total of 33 proteins was found to be differentially expressed in pulmonary tissue of CHF animals (18 up-regulated, and 15 down-regulated) belonging to 4 functional groups: 1. proteins involved in maintaining cytoarchitectural integrity, 2. plasma proteins indicating impaired alveolar-capillary permeability, 3. proteins with antioxidative properties, and 4. proteins participating in the metabolism of selenium compounds CONCLUSION: Experimental heart failure profoundly alters the pulmonary proteome. Our results supplement the current knowledge of pulmonary stress failure by specifying its molecular fundament.

[Case report: Aneurysmatic subarachnoid hemorrhage -- complicated course due to coincidental manifestation of an inverted Tako-Tsubo-cardiomyopathy]. / Kasuistik: Aneurysmatische Subarachnoidalblutung - Komplizierter Verlauf mit inverser Tako-Tsubo-Kardiomyopathie.

We report the case of a patient who suffered a serious subarachnoid hemorrhage with a cardialaffection and development of an inverted Tako-Tsubo-cardiomyopathy. To avoid apparent cerebral ischemia due to severe cerebral vasospasm after exhaustion of conservative therapeutic options a temporarily endovascular therapy with continuous intra-arterial application of Nimodipine was necessary. In the overall protracted and complicated course the special challenge were the therapeutic efforts to avoid apparent cerebral ischemia in context to the significant cardial affection.

Cardiovascular Risk Factor Control in 70- to 95-Year-Old Individuals: Cross-Sectional Results from the Population-Based AugUR Study.

Cardiovascular risk factors such as high glucose, LDL-cholesterol, blood pressure, and impaired kidney function are particularly frequent in old-aged individuals. However, population-based data on the extent of cardiovascular risk factor control in the old-aged population is limited. AugUR is a cohort of the mobile "70+"-year-old population of/near Regensburg, recruited via population registries. We conducted cross-sectional analyses assessing the proportion of AugUR participants with LDL-cholesterol, HbA1c, or blood pressure beyond recommended levels and their association with impaired creatinine- and cystatin-based estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m2) or urine albumin-creatinine ratio (UACR, ≥30 mg/g). Among 2215 AugUR participants, 74.7% were taking lipid-, glucose-, blood-pressure-lowering, or diuretic medication. High LDL-cholesterol at ≥116 mg/dL was observed for 76.1% (51.1% among those with prior cardiovascular events). We found HbA1c ≥ 7.0% for 6.3%, and high or low systolic blood pressure for 6.8% or 26.5%, respectively (≥160, <120 mmHg). Logistic regression revealed (i) high HbA1c levels associated with increased risk for impaired kidney function among those untreated, (ii) high blood pressure with increased UACR, and (iii) low blood pressure with impaired eGFR, which was confined to individuals taking diuretics. Our results provide important insights into cardiovascular risk factor control in individuals aged 70-95 years, which are understudied in most population-based studies.

Proteomic profiling implies mitochondrial dysfunction in tachycardia-induced heart failure.

BACKGROUND/OBJECTIVES: Molecular mechanisms of congestive heart failure as reflected by alterations of protein expression patterns are still incompletely analyzed. We therefore investigated intraventricular (ie, left ventricular congestive heart failure [LV-CHF] vs. LV-control [CTRL], and right ventricular [RV]-CHF vs. RV-CTRL) and interventricular (ie, LV-CHF vs. RV-CHF, and LV-CTRL vs. RV-CTRL) protein expression differences in an animal model. METHODS: The model of rapid ventricular pacing in rabbits was combined with a proteomic approach using 2-dimensional gel electrophoresis. Identification of proteins was done by matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS). RESULTS: Rapid ventricular pacing-induced heart failure was characterized by LV dilatation, dysfunction, and hypotension as well as by increased BNP gene expression. By comparing LV-CHF vs. LV-CTRL, proteins were found to be underexpressed at 3 crucial points of cellular energy metabolism. In RV-CHF vs. RV-CTRL, proteins belonging to respiratory chain complexes were underexpressed, but additionally a disturbance in the nitric oxide-generating enzymatic apparatus was seen. Regarding the interventricular analyses, a stronger expression of energetic pathways was accompanied by an underexpression of contractile and stress response proteins in failing left vs. right ventricles. Finally, significant protein expression differences were found in LV-CTRL vs. RV-CTRL reflecting a higher expression of contractile, stress response, and respiratory chain proteins in LV tissue. CONCLUSIONS: In tachycardia-induced heart failure, significant inter- and intraventricular protein expression patterns were found with a predominance of proteins, which are involved in cellular energy metabolism.

Self-report of chronic diseases in old-aged individuals: extent of agreement with general practitioner medical records in the German AugUR study.

BACKGROUND: To estimate prevalence and incidence of diseases through self-reports in observational studies, it is important to understand the accuracy of participant reports. We aimed to quantify the agreement of self-reported and general practitioner-reported diseases in an old-aged population and to identify socio-demographic determinants of agreement. METHODS: This analysis was conducted as part of the AugUR study (n=2449), a prospective population-based cohort study in individuals aged 70-95 years, including 2321 participants with consent to contact physicians. Self-reported chronic diseases of participants were compared with medical data provided by their respective general practitioners (n=589, response rate=25.4%). We derived overall agreement, over-reporting/under-reporting, and Cohen's kappa and used logistic regression to evaluate the dependency of agreement on participants' sociodemographic characteristics. RESULTS: Among the 589 participants (53.1% women), 96.9% reported at least one of the evaluated chronic diseases. Overall agreement was >80% for hypertension, diabetes, myocardial infarction, stroke, cancer, asthma, bronchitis/chronic obstructive pulmonary disease and rheumatoid arthritis, but lower for heart failure, kidney disease and arthrosis. Cohen's kappa was highest for diabetes and cancer and lowest for heart failure, musculoskeletal, kidney and lung diseases. Sex was the primary determinant of agreement on stroke, kidney disease, cancer and rheumatoid arthritis. Agreement for myocardial infarction and stroke was most compromised by older age and for cancer by lower educational level. CONCLUSION: Self-reports may be an effective tool to assess diabetes and cancer in observational studies in the old and very old aged. In contrast, self-reports on heart failure, musculoskeletal, kidney or lung diseases may be substantially imprecise.

Distribution and specificity of high-sensitivity cardiac troponin T in older adults without acute cardiac conditions: cross-sectional results from the population-based AugUR study.

OBJECTIVE: European guidelines recommended a uniform upper reference limit of high-sensitivity cardiac troponin T (hsTnT) to rule out non-ST segment elevation myocardial infarction. Our study aimed to provide a hsTnT reference distribution and to assess the specificity of the 14 ng/L cut-off value in the mobile population ≥70 years of age. DESIGN: A cross-sectional analysis was performed in the German AugUR study (Altersbezogene Untersuchungen zur Gesundheit der University of Regensburg). SETTING: Study population was the mobile population aged 70+ years living in the city and county of Regensburg, Germany. PARTICIPANTS: A random sample was derived from the local population registries of residence. Of the 5644 individuals invited, 1133 participated (response ratio=20.1%). All participants came to the study centre and were mentally and physically mobile to conduct the protocol (face-to-face interview, blood draw and standardised transthoracic echocardiography). None of the participants was in an acute state of myocardial infarction. RESULTS: Among the 1129 individuals with hsTnT measurements (overall median=10.0 ng/L(25th, 75th percentile)=(7.0, 15.0 ng/L)), hsTnT was higher among the older individuals and higher among men (men 70-74 years median=9.6 ng/L (7.2, 13.1 ng/L); men 90-95 years median=21.2 ng/L (14.6, 26.0 ng/L); women 70-74 years median=6.3 ng/L (4.7, 8.7 ng/L); and women 90-95 years median=18.0 ng/L (11.0, 21.0 ng/L)). In participants with impaired kidney function (eGFRcrea <60 mL/min/1.73 m2), hsTnT was elevated (median=13.6 ng/L (9.4, 20.6 ng/L)).Specificity of recommended upper reference limit, 14 ng/L, is 68%. Most false positives were among men aged >79 years (specificity=34%). In a healthy subgroup (n=96, none of the following: overt heart disease, impaired renal function, blood pressure >160/100 mm Hg, left ventricular hypertrophy and diastolic/systolic dysfunction), specificity was 90%. CONCLUSION: In the elderly population without acute myocardial infarction, hsTnT further increases with age showing different levels for men and women. The specificity of the 14 ng/L cut-off is considerably lower than 99%, even in healthy subjects.

Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone.

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non-COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Skeletal muscle alterations in tachycardia-induced heart failure are linked to deficient natriuretic peptide signalling and are attenuated by RAS-/NEP-inhibition.

BACKGROUND: Heart failure induced cachexia is highly prevalent. Insights into disease progression are lacking. METHODS: Early state of left ventricular dysfunction (ELVD) and symptomatic systolic heart failure (HF) were both induced in rabbits by tachypacing. Tissue of limb muscle (LM) was subjected to histologic assessment. For unbiased characterisation of early and late myopathy, a proteomic approach followed by computational pathway-analyses was performed and combined with pathway-focused gene expression analyses. Specimen of thoracic diaphragm (TD) served as control for inactivity-induced skeletal muscle alterations. In a subsequent study, inhibition of the renin-angiotensin-system and neprilysin (RAS-/NEP) was compared to placebo. RESULTS: HF was accompanied by loss of protein content (8.7±0.4% vs. 7.0±0.5%, mean±SEM, control vs. HF, p<0.01) and a slow-to-fast fibre type switch, establishing hallmarks of cachexia. In ELVD, the enzymatic set-up of LM and TD shifted to a catabolic state. A disturbed malate-aspartate shuttle went well with increased enzymes of glycolysis, forming the enzymatic basis for enforced anoxic energy regeneration. The histological findings and the pathway analysis of metabolic results drew the picture of suppressed PGC-1α signalling, linked to the natriuretic peptide system. In HF, natriuretic peptide signalling was desensitised, as confirmed by an increase in the ratio of serum BNP to tissue cGMP (57.0±18.6pg/ml/nM/ml vs. 165.8±16.76pg/ml/nM/ml, p<0.05) and a reduced expression of natriuretic peptide receptor-A. In HF, combined RAS-/NEP-inhibition prevented from loss in protein content (8.7±0.3% vs. 6.0±0.6% vs. 8.3±0.9%, Baseline vs. HF-Placebo vs. HF-RAS/NEP, p<0.05 Baseline vs. HF-Placebo, p = 0.7 Baseline vs. HF-RAS/NEP). CONCLUSIONS: Tachypacing-induced heart failure entails a generalised myopathy, preceding systolic dysfunction. The characterisation of "pre-cachectic" state and its progression is feasible. Early enzymatic alterations of LM depict a catabolic state, rendering LM prone to futile substrate metabolism. A combined RAS-/NEP-inhibition ameliorates cardiac-induced myopathy independent of systolic function, which could be linked to stabilised natriuretic peptide/cGMP/PGC-1α signalling.

Long-term outcomes and predictors of recurrence after pulmonary vein isolation with multielectrode ablation catheter in patients with atrial fibrillation.

PURPOSE: Despite various techniques used in atrial fibrillation ablation, recurrence of atrial arrhythmias still constitutes a clinical problem. The aim of this study was to document the long-term outcomes of pulmonary vein isolation with a ring-shaped ablation catheter (PVAC). METHODS: All consecutive patients presenting with paroxysmal or persistent atrial fibrillation (pxAF or perAF, respectively) treated with PVAC (first generation) were enrolled. After standard follow-up during the first year, all patients were contacted for long-term follow-up. In addition to the patient's medical history, 3-day Holter monitoring was performed. Endpoints were atrial fibrillation-related symptoms, ECG documentation of atrial fibrillation or other left atrial arrhythmias and reablation. RESULTS: In total, 125 patients (78% with pxAF) were enrolled. All but two pulmonary veins (0.4% of 485 pulmonary veins) could be successfully isolated. At 12 months, 83% of patients in the pxAF group and 53% of patients in the perAF group were free from symptoms. The mean long-term follow-up was 51 ±â€Š14 months. Regarding long-term efficacy, 56% of patients in the pxAF group and 28% of patients in the perAF group were free from any recurrence at 72 months. Independent predictors of event-free survival were perAF (hazard ratio 2.76, P = 0.001) and the existence of mild valvular disease (hazard ratio 2.69, P = 0.001). No significant complication due to PVAC occurred, especially no ischemic stroke. CONCLUSION: Long-term follow-up indicated for the first time in such a considerable cohort that pulmonary vein isolation with PVAC is a safe and very efficient method for treating pxAF - despite known microembolism issues. Patients with perAF receive less benefit from PVAC and ablation therapy should be reserved to pxAF. Significantly, even mild valvular disease was an independent predictor of atrial fibrillation recurrence.

Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure.

BACKGROUND: Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF). METHODS AND RESULTS: By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP-inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment. CONCLUSIONS: This study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS-/NEP-inhibition can beneficially influence mitochondrial key pathways.