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Cardiovascular diseases have multifactorial causes. Classical cardiovascular risk factors, such as arterial hypertension, smoking, hyperlipidemia, and diabetes associate with the development of vascular stenoses and coronary heart disease. Further comorbidities and its impact on cardiovascular metabolism have gotten more attention recently. Thus, also cancer biology may affect the heart, apart from cardiotoxic side effects of chemotherapies. Cancer is a systemic disease which primarily leads to metabolic alterations within the tumor. An emerging number of preclinical and clinical studies focuses on the interaction between cancer and a maladaptive crosstalk to the heart. Cachexia and sarcopenia can have dramatic consequences for many organ functions, including cardiac wasting and heart failure. These complications significantly increase mortality and morbidity of heart failure and cancer patients. There are concurrent metabolic changes in fatty acid oxidation (FAO) and glucose utilization in heart failure as well as in cancer, involving central molecular regulators, such as PGC-1α. Further, specific inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-β), non-inflammatory cytokines (myostatin, SerpinA3, Ataxin-10) and circulating metabolites (D2-HG) may mediate a direct and maladaptive crosstalk of both diseases. Additionally, cancer therapies, such as anthracyclines and angiogenesis inhibitors target common metabolic mechanisms in cardiomyocytes and malignant cells. This review focuses on cardiovascular, cancerous, and cancer therapy-associated alterations on the systemic and cardiac metabolic state.

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-021-00880-w.

Summary. Deep vein thromboses lead to post thrombotic syndrome in up to 50% of patients, which entails significant morbidity and socioeconomic costs. Endovascular treatment of iliofemoral deep vein thrombosis aims to reduce the development and the severity of post thrombotic syndrome. This case series of four cases demonstrates that acute and chronic thrombotic stenoses or occlusions can be safely managed by ultrasound guided endovascular treatment minimizing the number of interventions, bleeding risk and radiation exposure.

Aims Our aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18F‐FDG positron emission tomography–computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism. Methods and results In a retrospective cohort study, we analysed cardiac and skeletal muscle 18F‐FDG uptake in onco‐positron emission tomography–computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and non‐lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18F‐FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step‐down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non‐Hodgkin's lymphoma (n = 57), and non‐lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval—CI], P

Simple Summary Immune checkpoint inhibitors are revolutionizing cancer treatment, but lead to the occurrence of immune related adverse events including ICI-associated myocarditis (ICIM). To date, transcriptional alterations of this rare phenomenon with a high mortality rate are not characterized. 19 ICIM patients at the University Hospitals Heidelberg and Kiel showed diverse clinical presentations. Comparative transcriptomics was able to distinguish ICIM patients from patients with dilated cardiomyopathy or virus-induced myocarditis in the upregulation of 3784 genes. The RNA-based analyses and immunohistology revealed a potential role of an inflammasome-regulating protein, GBP5, as a potential pathomechanism in cardiomyocytes. These alterations may help to diagnose ICIM and potentially enable to identify patients at risk in an early stage. Abstract Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway ‘response to interferon-gamma’, we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM.

Aims Cardio‐oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients. Methods and results In this cohort study, we evaluated 930 patients that were admitted to the cardio‐oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N‐terminal pro brain‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity cardiac troponin T levels (hs‐cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT‐proBNP did not significantly correlate with all‐cause mortality (ACM) (logistic regression LVEF

Introduction: Checkpoint inhibitors (ICIs) have gained importance in recent years regarding the treatment of a variety of oncologic diseases. The possibilities of diagnosing cardiac adverse autoimmune effects of ICIs are still limited. We aimed to implement FAPI PET/CT imaging in detecting ICI-induced myocarditis. Methods: In a retrospective study, FAPI PET/CT scans of 26 patients who received ICIs from 01/2017 to 10/2019 were analyzed. We compared tracer enrichment in the heart of patients without any signs of a cardiac disease (n=23) to three patients with suspected ICI-induced myocarditis. To exclude any significant coronary heart disease, cardiac catherization was performed. Myocardial biopsies were examined, especially in regard to the infiltration of immune cells. Results: Three patients showed clinical manifestations of an ICI syndrome including myocarditis with elevated levels of hsTnT (175 pg/ml, 1771 pg/ml, 157 pg/ml). Further cardiological assessments revealed ECG abnormalities, lymphocyte infiltration of the myocardium in the biopsies or wall motion abnormalities in echocardiography. These patients’ FAPI PET/CTs showed a locally defined cardiac enrichment of the marker which was absent in patients receiving ICIs without any signs of immunological adverse effects and cardiac impairment (n=23) (Median SUV myocarditis patients: 1.79 (IQR: 1.65, 1.85), median SUV non-myocarditis patients: 1.15 (IQR: 0.955, 1.52)). Conclusions: Myocardial biopsy, the current gold standard of the diagnosis of ICI-induced myocarditis, is susceptible to sampling errors and results arrive within a few days. We provide first evidence that FAPI PET/CT is able to diagnose ICI-induced myocarditis and can demonstrate locally enhanced manifestation of ICI-induced myocarditis on time.

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing clinical use leads to higher rates of adverse immune related events (irAEs). One of those irAEs is the ICI-induced myocarditis (ICIM) - a rare phenomenon with an estimated mortality rate of up to 50%. We aimed to characterize the molecular changes of ICIM which are not yet understood completely. Methods: Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11) and virus-induced myocarditis (VIM, n=5). Results: Clinical analysis of 19 patients with ICIM showed an inconsistent presentation, e.g. an elevation of cardiac biomarkers (hsTnT, NT-proBNP, CK), a drop in leftventricular ejection fraction or late gadolinium enhancement in cMRI. We found 3784 (FDR Conclusion: Taken together, we were able to identify CD8 and CD8-associated genes as specifically regulated transcripts in ICIM. Moreover, based on the variable clinical phenotype, we propose that analysis of CD8 and CD8-dependent genes will be important to identify ICIM patients and to potentially sub-differentiate different phenotypes.

Aims Heart failure is characterized by structural and metabolic cardiac remodelling. The aim of the present study is to expand our understanding of the complex metabolic alterations in the transition from pathological hypertrophy to heart failure and exploit the results from a translational perspective. Methods and results Mice were subjected to transverse aortic constriction (TAC) or sham surgery and sacrificed 2 weeks, 4 weeks, or 6 weeks after the procedure. Samples from plasma, liver, skeletal muscle, and heart were collected and analysed using metabolomics. Cardiac samples were also analysed by transcriptional profiling. Progressive alterations of key cardiac metabolic pathways and gene expression patterns indicated impaired mitochondrial function and a metabolic switch during transition to heart failure. Similar to the heart, liver, and skeletal muscle revealed significant metabolic alterations such as depletion of essential fatty acids and glycerolipids in late stages of heart failure. Circulating metabolites, particularly fatty acids, reflected cardiac metabolic defects, and deteriorating heart function. For example, inverse correlation was found between plasma and the heart levels of triacylglycerol (C18:1, C18:2, C18:3), and sphingomyelin (d18:1, C23:0) already at an early stage of heart failure. Interestingly, combining metabolic and transcriptional data from cardiac tissue revealed that decreased carnitine shuttling and transportation preceded mitochondrial dysfunction. We, thus, studied the therapeutic potential of OCTN2 (Organic Cation/Carnitine Transporter 2), an important factor for carnitine transportation. Cardiac overexpression of OCTN2 using an adeno-associated viral vector significantly improved ejection fraction and reduced interstitial fibrosis in mice subjected to TAC. Conclusion Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in heart failure, which can be used for identification of novel biomarkers and potential therapeutic targets.

Background This article about the emerging field of cardio-oncology highlights typical side effects of oncological therapies in the cardiovascular system, cardiovascular complications of malignancies itself, and potential preventive or therapeutic modalities. Methods We performed a selective literature search in PubMed until September 2016. Results Cardiovascular events in cancer patients can be frequently attributed to oncological therapies or to the underlying malignancy itself. Furthermore, many patients with cancer have pre-existing cardiovascular diseases that can be aggravated by the malignancy or its therapy. Cardiovascular abnormalities in oncological patients comprise a broad spectrum from alterations in electrophysiological, laboratory or imaging tests to the occurrence of thromboembolic, ischemic or rhythmological events and the impairment of left ventricular function or manifest heart failure. Discussion A close interdisciplinary collaboration between oncologists and cardiologists/angiologists as well as an increased awareness of potential cardiovascular complications could improve clinical care of cancer patients and provides a basis for an improved understanding of underlying mechanisms of cardiovascular morbidity.

Aims Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. Methods and results Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography. Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. Conclusion This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Multiple myeloma is a malignant disease, caused by an uncontrolled clonal proliferation of a specific group of white blood cells, the plasma cells. Clinical manifestations include bone pain due to osteolysis, hypercalcemia, anemia, and renal insufficiency. Proteasome inhibitors have substantially improved survival of patients suffering from multiple myeloma, providing an efficient treatment option mainly for relapsed and refractory multiple myeloma. Although constituting one substance class, bortezomib, carfilzomib, and ixazomib differ greatly regarding their non-hematologic side effects. This article reviews the clinical and preclinical data on approved proteasome inhibitors in an attempt to decipher the underlying pathomechanisms related to cardiovascular adverse events seen in clinical trials.

Supplemental Digital Content is available in the text., Background: FAP (fibroblast activation protein) plays an important role in cardiac wound healing and remodeling. Although initially developed as a theranostic ligand for metastasized cancer, FAPI (FAP inhibitor) tracers have recently been used to study cardiac remodeling following myocardial infarction in small-animal models. The aim of the study was to evaluate the activity of FAP via FAPI–positron emission tomography–computed tomography scans in human hearts. Methods: FAPI–positron emission tomography–computed tomography scans of 229 patients of 2 consecutive cohorts (modeling cohort: n=185; confirmatory cohort: n=44) suffering from metastasized cancer were analyzed applying the American Heart Association 17-segment model of the left ventricle. Logistic regression models were created using data from the modeling cohort. Multivariate regression models were established using Akaike information criterion in a step-down approach. Results: Fourteen percent of patients had preexisting coronary artery disease (n=31), 33% arterial hypertension (n=75), and 12% diabetes mellitus type II (n=28). Forty-three percent had been treated with platin derivatives (n=100), 14% with anthracyclines (n=32), and 10% had a history of prior radiation to the chest (n=23). High left ventricular FAPI signals correlated with the presence of cardiovascular risk factors (odds ratio [OR], 4.3, P=0.0029), a focal myocardial signal pattern (OR, 3.9, P=0.0068), diabetes mellitus type II (OR, 4.1, P=0.046), and beta-blocker use (OR, 3.8, P=0.049) in univariate regression models. In a multivariate analysis, increased signal intensity was significantly higher in patients with cardiovascular risk factors (overweight [OR, 2.6, P=0.023], diabetes mellitus type II [OR, 2.9, P=0.041], certain chemotherapies [platinum derivatives; OR, 3.0, P=0.034], and a history of radiation to the chest [OR, 3.5, P=0.024]). A focal enrichment pattern was more frequently observed in patients with known cardiovascular risk factors (P

The downregulation of β-adrenergic receptors (β-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 β-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to β-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.

International audience; 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 desminsyncoilin 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.

It is still a controversial issue whether different classes of antihypertensive drugs are equally effective in the regression of cardiac hypertrophy and associated complications. The present study compared the effects of prolonged treatment with the Ca2+-channel blocker amlodipine and the ACE inhibitor enalapril, respectively, in TGR(mREN2)27 rats (TGR), an animal model of renin-dependent hypertension. TGR were divided into three groups and received either amlodipine, enalapril or drinking water without addition, Sprague-Dawley rats (SPRD) served as normotensive control group. Cardiovascular parameters were monitored by radiotelemetry, and drug doses were titrated until 24-h blood pressure was reduced to approximately 140/90 mmHg in both active treatment groups. After 8 weeks of treatment left ventricular (LV) hypertrophy was completely reversed in both treatment groups despite a tenfold increase in plasma angiotensin II in amlodipine-treated TGR. In untreated TGR LV catecholamines were depleted, and beta1-adrenergic stimulation of adenylyl cyclase was blunted. Treatment of TGR with enalapril prevented both the depletion of tissue catecholamines and the desensitisation of LV beta1-adrenoceptors. Amlodipine had no effect on cardiac adrenergic signal transduction. Basal activity of LV soluble guanylyl cyclase was not different between TGR and SPRD, but its sensitivity to stimulation by nitric oxide was slightly reduced in TGR. Treatment had no effect on basal and stimulated guanylyl cyclase activity. The present study in an animal model of renin-dependent hypertension suggests that blood pressure reduction per se is sufficient for a regression of cardiac hypertrophy. However, beta-adrenergic desensitisation was prevented only in the enalapril-treated group, supporting a blood pressure-independent contribution of the renin-angiotensin system to the regulation of beta-adrenergic signal transduction.

Background: Desmin is a type III intermediate filament which plays a central role in maintaining the structural integrity of cardiac and skeletal muscle cells. Mutations in the desmin coding gene are associated with a heterogeneous phenotype involving cardiomyopathies, cardiac conduction disease and myopathy. Desminopathies are most commonly diagnosed in adults in their mid 30s and show a progressive course, with cardiac involvement as the most important factor limiting prognosis. As of today, only symptomatic treatment is available for patients. Similar to patients with distinct defects in the desmin gene, knockout mice develop dilative cardiomyopathy compared to wildtype littermates. Aim of our study was to determine whether an adeno-associated-viral vector (AAV) mediated gene transfer of the intact desmin cDNA can either prevent or slow-down the development of cardiomyopathy in desmin-deficient (des-KO) mice. Methods: murine desmin cDNA under the control of the TNNT2 promoter was packaged into AAV serotype 9 capsids and were intravenously injected into adult des-KO mice. AAV9-luciferase vectors were used as controls. Left ventricular function was monitored using echocardiography before vector application and 3 months, 6 months and 9 months after treatment. After left heart catheterisation to assess pressure-volume (PV)-loops mice were sacrificed after 10 months for histological and molecular analyses. Results: AAV9-mediated transfer of the desmin cDNA resulted in an efficient reconstitution of desmin with intact intercalated discs. Echocardiographic analyzes revealed a fractional shortening of 38 + 4% (n=10) in desmin deficient mice treated with desmin cDNA compared to 28 + 4% (n=9) in AAV9-luciferase control-treated mice (1-way ANOVA, p < 0.05). PV-loops showed significant improvement in cardiac contractility with increased dp/dtmax in AAV9-desmin-treated mice 7742 + 539 mmHg/sec (n=7) compared to luciferase-treated mice 5901 + 466 mmHg/sec (n=9) suggesting an amelioration of the cardiomyopathy phenotype in AAV9-desmin-treated mice. Conclusion: Our study establishes an approach to specifically treat desmin-related cardiomyopathy by targeting gene expression into the myocardium through systemic application of AAV vectors.