[ARENA-Project atrial fibrillation in the Rhein-Neckar region]. / ARENA ­ Projekt Vorhofflimmern in der Rhein-Neckar-Region.

Atrial fibrillation (AF) is the most common form of cardiac tachyarrhythmia. It is estimated that in the Rhein-Neckar region approximately 40,000-50,000 out of 2 million people are affected. Due to demographic changes in the near future there will be a significant increase in the prevalence of AF within the next decades. The ARENA project was initiated by the Foundation Institute for Cardiac Infarction Research (IHF) Ludwigshafen in cooperation with cardiological and neurological departments of neighboring hospitals, resident doctors and pharmacies to improve the awareness and care of patients with AF. The particular aim is the prevention of stroke as one of the most dreaded complications. The project focusses on the following three subtopics: interventions, medication, migration. The aim of the intervention project is to raise awareness of AF as a risk factor for stroke and to improve the diagnostic work-up and care for patients with diagnosed or unknown AF. The subproject medication focusses on the adherence of patients with AF to the prescribed antithrombotic medication. To evaluate differences concerning patients with and without a migration background the subproject migration was initiated.

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies.

Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wild-type desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 × 1012 AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wild-type desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.

A closer look at right ventricular 3D volume quantification by transthoracic echocardiography and cardiac MRI.

AIM: To compare right ventricular (RV) volumetry using state-of-the-art three-dimensional (3D) transthoracic echocardiography (3DE) and cardiac magnetic resonance imaging (CMR) near-simultaneously in a clinical setting. MATERIALS AND METHODS: Forty-seven consecutive patients received comprehensive echocardiography including 3DE within 30 minutes of CMR. RV volumetry was performed offline with semi-automated 3D endocardial border tracing as well as manual delineation of the compacted myocardium in short-axis views by CMR. RESULTS: Forty-two examinations (89%) could be analysed offline by 3D RV reconstruction. Mean RV volumes assessed by CMR and 3DE were 215±63 and 127±42 ml for end-diastole (RV-EDV), as well as 110±43 and 62±27 ml for end-systole (RV-ESV). RV-EDV, RV-ESV, and RV stroke volume measured by 3DE were significantly lower than RV volumetry by CMR. Mean bias were -88, -48, and -41 ml, respectively. Mean RV ejection fraction (-EF) showed a non-significant deviation of +2% between 3DE and CMR and the correlation coefficient was r=0.58 for RV-EF. CONCLUSION: RV-EF can be assessed reliably using transthoracic 3DE in patients with good image quality; however, absolute RV volumes measured by 3DE show a systematic deviation to CMR volumetry that has been previously neglected and requires careful interpretation regarding anatomical cardiac imaging.

Transient elevation of high-sensitive troponin T after Cardioband implantation.

BACKGROUND: The Cardioband system enables percutaneous surgical-like direct mitral valve annuloplasty and, thereby, repair of severe functional mitral valve regurgitation (MR) in patients with advanced systolic heart failure (HF) and dilation of the left ventricular (LV) annulus. Since the device is anchored by screws in the LV annulus, limited myocardial injury is likely to occur. METHODS AND RESULTS: Five patients (Society of Thoracic Surgeons score: 2.7 ± 0.7%) with severe HF (LV ejection fraction [LVEF]: 17 ± 1%; LV end-diastolic diameter [LVEDD]: 71 ± 3 mm) were treated with the Cardioband (sizes C-F) receiving 14-17 screws in the LV annulus region. Myocardial injury was monitored by measuring high-sensitive cardiac troponin T (hsTnT) levels and by echocardiography. All patients showed significant periprocedural increase in hsTnT levels. Peak hsTnT concentration was reached between day 1 and day 6 (593 ± 141 pg/ml). None of the patients showed clinical signs of myocardial infarction, ST-segment elevation, new onset of deteriorated myocardial wall motion, or new ventricular tachycardia. hsTnT levels normalized in all patients after 14 days (hsTnT on day 0: 34 ± 6 pg/ml vs. hsTnT on day 14: 36 ± 6 pg/ml; p = 0.604). This nonischemic hsTnT kinetics was compared to a sixth patient who experienced proximal damage of the left circumflex artery (LCX) and ST-segment elevation during the Cardioband procedure, followed by immediate repair of the LCX, avoiding structural damage of the LV. CONCLUSION: Cardioband implantation is accompanied by significant elevation of hsTnT without causing structural myocardial damage or clinical symptoms such as worsening of LV function, new-onset LV regions exhibiting reduced wall motion, or ventricular tachycardia.

SPMSQ for risk stratification of older patients in the emergency department : An exploratory prospective cohort study.

BACKGROUND: Risk stratification of older patients in the emergency department (ED) is seen as a promising and efficient solution for handling the increase in demand for geriatric emergency medicine. Previously, the predictive validity of commonly used tools for risk stratification, such as the identification of seniors at risk (ISAR), have found only limited evidence in German geriatric patient samples. Given that the adverse outcomes in question, such as rehospitalization, nursing home admission and mortality, are substantially associated with cognitive impairment, the potential of the short portable mental status questionnaire (SPMSQ) as a tool for risk stratification of older ED patients was investigated. OBJECTIVE: To estimate the predictive validity of the SPMSQ for a composite endpoint of adverse events (e.g. rehospitalization, nursing home admission and mortality). METHOD: This was a prospective cohort study with 260 patients aged 70 years and above, recruited in a cardiology ED. Patients with a likely life-expectancy below 24 h were excluded. Follow-up examinations were conducted at 1, 3, 6 and 12 month(s) after recruitment. RESULTS: The SPMSQ was found to be a significant predictor of adverse outcomes not at 1 month (area under the curve, AUC 0.55, 95% confidence interval, CI 0.46-0.63) but at 3 months (AUC 0.61, 95% CI 0.54-0.68), 6 months (AUC 0.63, 95% CI 0.56-0.70) and 12 months (AUC 0.63, 95% CI 0.56-0.70) after initial contact. CONCLUSION: For longer periods of observation the SPMSQ can be a predictor of a composite endpoint of adverse outcomes even when controlled for a range of confounders. Its characteristics, specifically the low sensitivity, make it unsuitable as an accurate risk stratification tool on its own.

[Cardiac troponins and beyond in acute coronary syndrome]. / Kardiales Troponin und mehr beim akuten Koronarsyndrom.

Cardiac biomarkers are an integral component of the diagnostic work-up of patients with suspected acute coronary syndrome (ACS). Cardiac troponin (cTn) is the most sensitive diagnostic biomarker for patients with ACS and enables the differentiation of acute non-ST-elevation myocardial infarction (NSTEMI) from unstable angina. All cardiac and non-cardiac differential diagnoses must be taken into consideration. The use of cTn has a prognostic value in a multitude of acute and chronic diseases apart from ACS. Highly sensitive cTn (hsTn) assays should be preferentially used. Point-of-care (POC) troponin assays can be used for rule-in of acute MI but are generally not useful for rule-out of MI due to their lack of sensitivity compared to hsTn assays. This, however, may change with recent developments of newer and improved POC troponin assays. For exclusion of MI using hsTn assays, there are various protocols available, such as the instant rule-out with undetectable hsTn levels at admission or normal hsTn/cTn levels combined with normal copeptin levels or rule-out with serial controls of hsTn after 1, 2 or 3 h. This article provides an overview of guideline-recommended rule-out protocols for patients with suspected ACS and discusses recent advances in POC troponin assays.

[Cardiomyopathy in a 22-year-old man with a long history of methamphetamine abuse]. / Kardiomyopathie bei einem 22-Jährigen mit langjährigem Methamphetaminkonsum.

This article presents the case of a 22-year-old male patient with cardiomyopathy associated with a long history of methamphetamine abuse. Echocardiography revealed a dilated cardiomyopathy with highly reduced systolic pump function and severe mitral valve regurgitation. Inotropic treatment and MitraClip® (Abbott Vascular, Santa Clara, CA, USA) implantation resulted in enhancement of hemodynamics. The rising prevalence of methamphetamine abuse should give reason to raise awareness for the diagnostic work-up and patient history particularly in cases of unexplained cardiomyopathy in young patients.

AAV-9 mediated phosphatase-1 inhibitor-1 overexpression improves cardiac contractility in unchallenged mice but is deleterious in pressure-overload.

The downregulation of ß-adrenergic receptors (ß-AR) and decreased cAMP-dependent protein kinase activity in failing hearts results in decreased phosphorylation and inactivation of phosphatase-inhibitor-1 (I-1), a distal amplifier element of ß-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to ß-AR desensitization; therefore its modulation is a promising approach in heart failure treatment. Aim of our study was to assess the effects of adeno-associated virus serotype 9 (AAV9) - mediated cardiac-specific expression of constitutively active inhibitor-1 (I-1c) and to investigate whether I-1c is able to attenuate the development of heart failure in mice subjected to transverse aortic constriction (TAC). 6-8 week old C57BL/6 N wild-type mice were subjected to banding of the transverse aorta (TAC). Two days later 2.8 × 1012 AAV-9 vector particles harbouring I-1c cDNA under transcriptional control of a human troponin T-promoter (AAV9/I-1c) were intravenously injected into the tail vein of these mice (n=12). AAV9 containing a Renilla luciferase reporter (AAV9/hRluc) was used as a control vector (n=12). Echocardiographic analyses were performed weekly to evaluate cardiac morphology and function. 4 weeks after TAC pressure- volume measurements were performed and animals were sacrificed for histological and molecular analyses. Both groups exhibited progressive contractile dysfunction and myocardial remodeling. Surprisingly, echocardiographic assessment and histological analyses showed significantly increased left ventricular hypertrophy in AAV9/I-1c treated mice compared to AAV9/hRluc treated controls as well as reduced contractility. Pressure-volume loops revealed significantly impaired contractility after AAV9/I-1c treatment. At the molecular level, hearts of AAV9/I-1c treated TAC mice showed a hyperphosphorylation of the SR Ca2+-ATPase inhibitor phospholamban. In contrast, expression of AAV9/I-1c in unchallenged animals resulted in selective enhancement of phospholamban phosphorylation and augmented cardiac contractility. Our data suggest that AAV9-mediated cardiac-specific overexpression of I-1c, previously associated with enhanced calcium cycling, improves cardiac contractile function in unchallenged animals but failed to protect against cardiac remodeling induced by hemodynamic stress questioning the use of I-1c as a potential strategy to treat heart failure in conditions with increased afterload.

[Essential cardiac biomarkers in the differential diagnosis of acute chest pain : An update]. / Essenzielle kardiale Biomarker in der Differenzialdiagnose des akuten Thoraxschmerzes : Ein Update.

Cardiac biomarkers are an integral part of the diagnostic work-up and risk stratification of patients with chest pain. Cardiac troponins are highly sensitive diagnostic biomarkers in patients with acute coronary syndrome and have prognostic value in a multitude of acute and chronic diseases. In patients with suspected pulmonary embolism (PE) D­dimer can be used together with the Wells score for exclusion of PE. In patients with confirmed PE, B­type natriuretic peptide (BNP), N­terminal pro-BNP (NT-proBNP) and heart-type fatty acid binding protein (h-FABP) can be used for risk stratification. Although normal D­dimer levels largely decrease the possibility of acute aortic dissection, clinicians should not rely on D­dimer alone to exclude the diagnosis of acute aortic syndrome. This continuing medical education article provides an overview of the most important biomarkers recommended in current guidelines for differential diagnoses of patients with chest pain with a focus on cardiac troponins in acute coronary syndrome.

Precision medicine for cardiovascular disease : Learning lessons from cardiomyopathies.

Evidence-based medicine has considerably advanced the treatment of highly prevalent cardiovascular diseases. Its implementation was driven by multicenter interventional trials in treatment and placebo cohorts, propelling numerous biomedical innovations toward standard of care. While a uniform treatment can be effective in such disease cohorts ("one size fits all"), it neglects the genetic and phenotypic individuality of a single patient and his or her disease. Accordingly, a recent observation was made that several newer "mega" trials, demanding considerable resources for their execution, showed statistically significant differences in outcome, however, with small overall efficacies that render implementation in the clinics unlikely. To overcome this concerning development, new methods for individualized treatment of cardiovascular disease are required. Rarer conditions, such as distinct cardiomyopathies, may deliver the blueprint for a paradigm shift: deep and precise phenotyping of individual patients by a multimodal approach and development of targeted treatments for smaller groups ("one treatment for many") or even for single patients ("one treatment of some").

Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease.

AIMS: Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments. METHODS AND RESULTS: Deep RNA sequencing of cardiomyocyte development and ß-adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes. CONCLUSION: CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets.

Strengths and limitations of coronary angiography with turbo high-pitch third-generation dual-source CT.

AIM: To define practical limitations of diagnostic image quality for recently introduced turbo high-pitch scan mode (THP) in third-generation dual-source computed tomography (CT). MATERIALS AND METHODS: Two hundred and twenty-nine consecutive patients undergoing CT coronary angiography were included in this retrospective single-centre analysis. A contrast-enhanced volume dataset was acquired in THP. Image quality of coronary segments was classified as diagnostic or non-diagnostic by three blinded readers. Segments were stated as non-diagnostic if at least one of three readers could neither exclude nor confirm significant stenoses. Multivariable logistic regression was used to assess relationships between number of non-diagnostic segments and common influencing factors. RESULTS: Median effective radiation dose was 0.6 (interquartile range [IQR], 0.4-0.8) mSv overall and 0.3 (IQR, 0.3-0.4) mSv in the 70 kV subgroup of this middle aged, predominantly pre-obese cohort (age: 61 [IQR, 52-67] years; body mass index [BMI]: 26 [IQR, 23-29] kg/m2) with a low-moderate median Agatston score (AS) 0 (IQR, 0-70). Diagnostic image quality was found in 98.1% of 3,678 coronary segments. AS was independently associated with diagnostic image quality (B=0.34; p=0.02), whereas heart rate, BMI, and presence of arrhythmia were not. The portion of diagnostic coronary segments decreased slightly in obese patients with heart rates >65 beats/min and dropped significantly in patients with an AS >600 (p=0.003). CONCLUSION: THP enables CT coronary angiography with minimal radiation exposure and is most appropriate in non-obese patients with stable sinus rhythm ≤65 beats/min and a calcium score ≤600.

Precision medicine approach to genetic cardiomyopathy.

Precision medicine aims to achieve improved survival by strategies that recognize the genetic and phenotypic individuality of patients and stratify treatment accordingly. Genetic cardiomyopathies represent an ideal disease group to fully embark on this concept: they are in total frequent diseases with a marked morbidity and mortality and there is ample knowledge about their predisposing genetic factors and associated functional mechanisms. The current review highlights the genetic etiology and gives examples of the diverse treatment strategies that are envisaged in the future.

AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice.

Mutations of the human desmin (DES) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice. Our approach leads to a partial reconstitution of desmin protein expression and the de novo formation of the extrasarcomeric desmin-syncoilin network in cardiomyocytes of treated animals. This finding was accompanied by reduced fibrosis and heart weights and improved systolic left-ventricular function when compared with control vector-treated DES-KO mice. Since the re-expression of desmin protein in cardiomyocytes of DES-KO mice restores the extrasarcomeric desmin-syncoilin cytoskeleton, attenuates the degree of cardiac hypertrophy and fibrosis, and improves contractile function, AAV-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression.

[Does coronary CT change the cardiologist's clinical practice?]. / Verändert die Koronar-CT den klinischen Alltag des Kardiologen?

Technological advances in computed tomography (CT) resulted in an expansion of (the spectrum of) indications and numbers of examination in cardiology. Thus, CT found it's way into cardiological clinical practice as well as in current guidelines. This article describes the state of the technology, current developments, and the clinical significance of cardiac CT. Determination of indications, conduct, and assessment of coronary CT affect the core content of cardiological expertise. On the basis of the expected further increase in coronary CT examinations, cardiologists need to be familiar with this modality. Hence, the curriculum "Cardiac CT" for the additional qualification of cardiologists has been introduced. The conduct and interpretation of cardiac CT require the expertise of cardiologists and radiologists to ensure its diagnostic value and patient safety in the best possible way. Therefore, structures for cooperation between the two disciplines need to be established in outpatient and in inpatient care.

Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno-associated viral vectors.

Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.

Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.

Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.

Comprehensive bio-imaging using myocardial perfusion reserve index during cardiac magnetic resonance imaging and high-sensitive troponin T for the prediction of outcomes in heart transplant recipients.

We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high-sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1±4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization ("hard cardiac events") and revascularization procedures were prospectively collected. During a follow-up duration of 4.2±1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate=14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate=0%). In conclusion, comprehensive "bio-imaging" using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk-stratification in HT recipients.

[Essential cardiac biomarkers in myocardial infarction and heart failure]. / Essenzielle kardiale Biomarker bei Myokardinfarkt und Herzinsuffizienz.

With the discovery of novel biomarkers in cardiovascular diseases, over the past decades considerable improvements in diagnosis, risk stratification and patient care could be achieved; however, despite extensive research, only few biomarkers have met the requirements of significantly improving diagnostic or prognostic approaches. Among the most established markers are cardiac troponins and natriuretic peptides, which are recommended in current guidelines for myocardial infarction or heart failure and are routinely used in clinical practice. Cardiac troponins T and I are the preferred biomarkers of choice for definition of myocardial infarction and proved to be prognostically relevant not only in acute coronary syndrome but also in non-cardiac diseases. The natriuretic peptides B-type natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) aid in diagnosis, risk stratification and monitoring of heart failure. In recent years several new promising markers have been proposed which might add incremental clinical information, most notably copeptin and growth differentiation factor (GDF) 15; however, larger studies are still required before recommendations for routine clinical use can be made.

Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of relaxin.

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation.