Max Planck Institute for Heart and Lung Research

Madani M.M., Wiedenroth C.B., Jenkins D.P., Fadel E., de Perrot M.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a consequence of unresolved organized thromboembolic obstruction of the pulmonary arteries, which can cause pulmonary hypertension (PH) and right heart failure (RVF). Due to its subtle signs, it is challenging to determine its exact incidence and prevalence. Furthermore, CTEPH may also present without any prior venous thromboembolic (VTE) history, contributing to underdiagnosis and undertreatment. Diagnosis requires a high degree of suspicion and is ruled out by a normal V/Q scintigraphy. Additional imaging by CT and/or conventional angiography, as well as right heart catheterization are required to confirm CTEPH and formulate treatment plans. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for eligible patients and can be potentially curative. PTE has a low mortality rate of 1-2% at expert centers and offers excellent long-term survival. Furthermore, recent advances in the techniques allow distal endarterectomy with comparable outcomes. There are alternative treatment options available for those who may not be operable or have prohibitive risks, providing some benefit. However, CTEPH is a progressive disease with low long-term survival rates if left untreated. Given excellent short and long-term outcomes of surgery, as well as the benefits seen with other treatment modalities in non-candidate patients, it is crucial that precapillary PH and CTEPH are ruled out in any patient with dyspnea of unexplained etiology. These patients should be referred to expert centers where accurate operability assessment, and appropriate treatment strategies can be offered by a multidisciplinary team.

Candreva A., Gotschy A., Stehli J., Bissig L., Lodi Rizzini M., Chiastra C., Gallo D., Morbiducci U., Klingenberg R., Heg D., Matter C.M., Ruschitzka F., Manka R., Stähli B.E.

Background Coronary microvascular dysfunction has been associated with adverse cardiovascular events following acute myocardial infarction. This study evaluates the role of the angiography‐derived index of microcirculatory resistance (angio‐IMR) in predicting myocardial damage in patients with ST‐segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI). Methods and Results In this post hoc analysis of the CLEVER‐ACS (Controlled‐Level Everolimus in Acute Coronary Syndromes) trial, the associations between post‐PCI angio‐IMR of infarct‐related coronary arteries (IRAs) and infarct size, microvascular obstruction, and left ventricular ejection fraction at 30 days as assessed by cardiac magnetic resonance were investigated. High post‐PCI angio‐IMR was defined as ≥40 mm Hg*s . In non‐IRAs, angio‐IMR was measured before IRA‐PCI. A total of 52 IRAs and 94 non‐IRAs of 52 patients were analyzed. Post‐PCI angio‐IMR was 41.5 (interquartile range [IQR], 28.5–55.7) mm Hg*s  in IRAs and pre‐PCI angio‐IMR was 43.7 (IQR, 31.7–54.0) mm Hg*s in non‐IRAs ( P =0.70). Patients with high post‐PCI angio‐IMR (52%) exhibited a larger myocardial infarct size (36.0 [IQR, 23.0–52.5] g versus 14.5 [IQR, 6.50–26.5] g, P <0.001) and a lower left ventricular ejection fraction (46.5% [IQR, 39.5%–49.5%] versus 55.0% [IQR, 48.0%–61.4%], P =0.002) at 30 days as compared with those with low post‐PCI angio‐IMR values. Post‐PCI angio‐IMR positively correlated with myocardial infarct size (r=0.45, P =0.001) and extent of microvascular obstruction (r=0.40, P =0.004) at 30 days. Post‐PCI angio‐IMR predicted myocardial infarct size (area under the curve, 0.78 [IQR, 0.65–0.92]; P =0.001) and extent of microvascular obstruction (area under the curve, 0.74 [IQR, 0.60–0.89]; P =0.009) at 30 days. Conclusions In patients with ST‐segment–elevation myocardial infarction, post‐PCI angio‐IMR was identified as independent predictor of myocardial infarct size and extent of microvascular obstruction. Registration URL: https:// clinicaltrials.gov ; Unique Identifier: NCT01529554.

Cho H., Lai C., Bonnavion R., Alnouri M.W., Wang S., Roquid K.A., Kawase H., Campos D., Chen M., Weinstein L.S., Martínez A., Looso M., Sanda M., Offermanns S.

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B–mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide–synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.

Hernandez-Olmos V., Heering J., Ildefeld N., Ehrler J.H., Kaps A., Rajkumar R., Marinescu B., Kaiser A., Macinkovic I., Elewa M.A., Alnouri M.W., Elson L., Schubert-Zsilavecz M., Kallenborn-Gerhardt W., Schmidtko A., et. al.

Ley L., Wiedenroth C.B., Guth S., Gold C., Yogeswaran A., Ghofrani H.A., Bandorski D.

Background: Pulmonary hypertension (PH) can cause characteristic electrocardiographic (ECG) changes due to right ventricular hypertrophy and/or strain. The aims of the present study were to explore the diagnostic accuracy of ECG parameters for the diagnosis of PH, applying the recently adjusted mean pulmonary artery pressure (mPAP) threshold of >20 mmHg, and to determine the role of “R V1, V2 + S I, aVL − S V1”. Methods: Between July 2012 and November 2023, 100 patients without PH, with pulmonary arterial hypertension, or with chronic thromboembolic pulmonary hypertension were retrospectively enrolled. Results: The sensitivity and specificity of the ECG parameters for the diagnosis of PH varied from 3 to 98% and from 3 to 100% (means: 39% and 87%). After optimising the parameters’ cut-offs, the mean sensitivity (39% to 66%) increased significantly but the mean specificity (87% to 74%) slightly decreased. “R V1, V2 + S I, aVL − S V1” was able to predict an mPAP >20 mmHg (OR: 34.33; p < 0.001) and a pulmonary vascular resistance >5 WU (OR: 17.14, p < 0.001) but could not predict all-cause mortality. Conclusions: Even with improved cut-offs, ECG parameters alone are not able to reliably diagnose or exclude PH because of their low sensitivity. However, they still might be helpful to reveal a suspicion of PH, especially in early diagnostic stages, e.g., in primary care with general practitioners or non-specialised cardiologists and pulmonologists. “R V1, V2 + S I, aVL − S V1” was able to predict the diagnosis of (severe) PH but could not predict all-cause mortality. Nevertheless, it can still be useful in risk stratification.

Liu X., Gu L., Hao C., Xu W., Leng F., Zhang P., Li W.

Structural variants (SVs) over 50 base pairs play a significant role in phenotypic diversity and are associated with various diseases, but their analysis is complex and resource-intensive. Numerous computational tools have been developed for SV prioritization, yet their effectiveness in biomedicine remains unclear. Here we benchmarked eight widely used SV prioritization tools, categorized into knowledge-driven (AnnotSV, ClassifyCNV) and data-driven (CADD-SV, dbCNV, StrVCTVRE, SVScore, TADA, XCNV) groups in accordance with the ACMG guidelines. We assessed their accuracy, robustness, and usability across diverse genomic contexts, biological mechanisms and computational efficiency using seven carefully curated independent datasets. Our results revealed that both groups of methods exhibit comparable effectiveness in predicting SV pathogenicity, although performance varies among tools, emphasizing the importance of selecting the appropriate tool based on specific research purposes. Furthermore, we pinpointed the potential improvement of expanding these tools for future applications. Our benchmarking framework provides a crucial evaluation method for SV analysis tools, offering practical guidance for biomedical research and facilitating the advancement of better genomic research tools.

Sohns C., Moersdorf M., Marrouche N.F., Bergau L., Costard-Jaeckle A., Crijns H.J., Fox H., Hindricks G., Dagres N., Sossalla S., Schramm R., Fink T., El Hamriti M., Sciacca V., Didenko M., et. al.

Wang Z., Mehra A., Wang Q., Gupta S., Ribeiro da Silva A., Juan T., Günther S., Looso M., Detleffsen J., Stainier D.Y., Marín-Juez R.

ABSTRACT VEGFA administration has been explored as a pro-angiogenic therapy for cardiovascular diseases including heart failure for several years, but with little success. Here, we investigate a different approach to augment VEGFA bioavailability: by deleting the VEGFA decoy receptor VEGFR1 (also known as FLT1), one can achieve more physiological VEGFA concentrations. We find that after cryoinjury, zebrafish flt1 mutant hearts display enhanced coronary revascularization and endocardial expansion, increased cardiomyocyte dedifferentiation and proliferation, and decreased scarring. Suppressing Vegfa signaling in flt1 mutants abrogates these beneficial effects of flt1 deletion. Transcriptomic analyses of cryoinjured flt1 mutant hearts reveal enhanced endothelial MAPK/ERK signaling and downregulation of the transcription factor gene egr3. Using newly generated genetic tools, we observe egr3 upregulation in the regenerating endocardium, and find that Egr3 promotes myofibroblast differentiation. These data indicate that with enhanced Vegfa bioavailability, the endocardium limits myofibroblast differentiation via egr3 downregulation, thereby providing a more permissive microenvironment for cardiomyocyte replenishment after injury.

Yogarajah J., Hutter J., Kahle P., Beaujean P., Tomic M., Hain A., Sossalla S., Kuniss M., Neumann T.

Background and Aims: Various pulsed field ablation (PFA) systems are currently being developed. Recently, a novel CE-approved circular array PFA catheter (PulseSelect™ PFA System, Medtronic, Minneapolis, MN, USA) was introduced. Data on this commercially available system are sparse. The aim was to elucidate real-world data assessing the feasibility, safety, and acute efficacy of pulmonary vein isolation (PVI) and ablation beyond PVI with this novel ablation system. Methods: Consecutive patients with paroxysmal and persistent atrial fibrillation (AF) undergoing first-time ablation with the circular PFA catheter were enrolled in this study. In patients with persistent AF and left atrial (LA) enlargement (LA area > 20 cm2), additional left atrial roof ablation (LARA) was performed. Those with concomitant typical atrial flutter received adjunctive cavo-tricuspid isthmus (CTI) ablation. Results: A total of 100 AF patients were included (29% female, 50% persistent AF). Of these, 33 patients (33%) underwent adjunctive LARA, 1 patient (1%) received posterior wall isolation, and 6 patients (6%) required additional CTI ablation. The skin-to-skin procedural time averaged 66.3 ± 13.8 min, while the fluoroscopy time and dose area product were 13.7 ± 4.7 min and 6.8 ± 4.9 Gycm2, respectively. Acute PVI was achieved in 100% of pulmonary veins. A bidirectional conduction block of the LARA and CTI lines was confirmed in all patients, and no major adverse events were reported. Conclusions: These real-world data demonstrate the feasibility, safety, and acute efficacy of PVI and ablation beyond PVI using a novel circular array PFA catheter in patients with atrial fibrillation and flutter. The system can easily be integrated with standard PVI workflows. Further and larger studies are warranted to assess the clinical long-term effectiveness and safety of this PFA system.

Sohns C., Fink T., Crijns H.J., Costard‐Jaeckle A., Marrouche N.F., Sossalla S., Schramm R., El Hamriti M., Moersdorf M., Didenko M., Braun M., Sciacca V., Konietschke F., Rudolph V., Gummert J., et. al.

AimsTimely referrals for transplantation and left ventricular assist device (LVAD) play a key role in favourable outcomes in patients with advanced heart failure (HF). Cardiovascular mortality, driven by sudden cardiac death, is the main reason for dying while waiting for heart transplantation (HTx). The purpose of the Preventive Catheter Ablation for ventricular arrhythmiaS in patients with end‐sTage heart faiLure rEferred for heart transplantation eValuaTion (CASTLE‐VT) trial is to test the hypothesis that prophylactic catheter ablation of arrhythmogenic ventricular scar tissue will reduce mortality, need for LVAD implantation, and urgent HTx in patients with end‐stage HF related to ischaemic cardiomyopathy (ICM).MethodsCASTLE‐VT is a randomized evaluation of prophylactic ablative treatment of arrhythmogenic ventricular scar in patients referred for HTx evaluation and diagnosed with ICM. Ablation will be performed with the use of a substrate‐based approach in which the myocardial scar is mapped and ablated while the heart remains predominantly in sinus rhythm. The primary endpoint is the composite of all‐cause mortality, worsening of HF requiring prioritized transplantation or LVAD implantation. The main secondary study endpoints are all‐cause mortality, cardiovascular mortality, incidence of implantable cardioverter‐defibrillator (ICD) therapy, hospitalizations, quality of life, time to first ICD therapy, number of device‐detected ventricular tachycardia/ventricular fibrillation episodes, left ventricular function, and exercise tolerance. CASTLE‐VT will randomize 160 patients with a follow‐up period of 2 years.ConclusionCASTLE‐VT will determine whether prophylactic catheter ablation of arrhythmogenic ventricular scar tissue reduces mortality in patients with end‐stage HF who are referred for HTx evaluation.

Sharma S., Artner T., Preissner K.T., Lang I.M.

Cardiovascular diseases (CVD) and their complications continue to be the leading cause of mortality globally. With recent advancements in molecular analytics, individualized treatments are gradually applied to the diagnosis and treatment of CVD. In the field of diagnostics, liquid biopsy combined with modern analytical technologies is the most popular natural source to identify disease biomarkers, as has been successfully demonstrated in the cancer field. While it is not easy to obtain any diseased tissue for different types of CVD such as atherosclerosis, deep vein thrombosis or stroke, liquid biopsies provide a simple and non-invasive alternative to surgical tissue specimens to obtain dynamic molecular information reflecting disease states. The release of cell-free ribonucleic acids (cfRNA) from stressed/damaged/dying and/or necrotic cells is a common physiological phenomenon. CfRNAs are a heterogeneous population of various types of extracellular RNA found in body fluids (blood, urine, saliva, cerebrospinal fluid) or in association with vascular/atherosclerotic tissue, offering insights into disease pathology on a diagnostic front. In particular, cf-ribosomal RNA has been shown to act as a damaging molecule in several cardio-vascular disease conditions. Moreover, such pathophysiological functions of cfRNA in CVD have been successfully antagonized by the administration of RNases. In this review, we discuss the origin, structure, types, and potential utilization of cfRNA in the diagnosis of CVD. Together with the analysis of established CVD biomarkers, the profiling of cfRNA in body fluids may thereby provide a promising approach for early disease detection and monitoring.

Sciacca V., Sohns C., Crijns H.J., Marrouche N.F., Schramm R., Moersdorf M., Fink T., Bergau L., Hindricks G., Dagres N., Sossalla S., Costard‐Jaeckle A., Fox H., El Hamriti M., Konietschke F., et. al.

AbstractAimsThe CASTLE‐HTx trial showed the benefit of atrial fibrillation (AF) ablation compared to medical therapy in decreasing mortality, need for left ventricular assist device implantation or heart transplantation (HTx) in patients with end‐stage heart failure (HF). Herein we describe the effects of catheter ablation on AF burden, arrhythmia recurrences, and ventricular function in end‐stage HF.Methods and resultsThe CASTLE‐HTx protocol randomized 194 patients in end‐stage HF with AF to catheter ablation and medical therapy or medical therapy alone. AF burden, left ventricular ejection fraction (LVEF), and type of AF were assessed at baseline and at each follow‐up visit. Overall, 97 patients received ablation; 66 patients (68%) underwent pulmonary vein isolation (PVI) and 31 patients (32%) were treated with PVI and additional ablation. Electroanatomic mapping showed the extent of left atrial low voltage (cardiomyopathy) >10% in 31 (31.9%) patients. At 12 months post‐ablation, persistent AF was present in 31/89 patients (34.8%), which was significantly less frequent compared to baseline (p = 0.0001). Median AF burden reduction was 36.3 (interquartile range 13.6–63.3) percentage points at 12 months and LVEF improved from 29.2 ± 6.2% to 39.1 ± 8.3% (p < 0.001) following ablation. AF burden reduction <50% was significantly associated with LVEF improvement ≥5% at 12 months after ablation (p = 0.017).ConclusionAtrial fibrillation ablation in end‐stage HF leads to a substantial decrease in AF burden, a regression from persistent to paroxysmal AF and notably improved LVEF. Favourable ablation outcomes were observed in patients regardless of the presence or absence of signs indicating left atrial cardiomyopathy.

Leonardo C., Ermenegildo D.R., Christof K., Amir J., Pedro M., Pascal D., Christelle M., Olivier P., Andrea G., Kwangdeok L., Wenjiao L., Haran B., Johannes S., Bernard T., Christopher R., et. al.

Abstract Background and Aims Cardiac resynchronization therapy (CRT) via biventricular (BIV) pacing is indicated in patients with heart failure (HF), reduced ejection fraction and prolonged QRS duration. Quadripolar leads and MultiPoint Pacing (MPP) allow multiple left ventricle (LV) sites pacing. We aimed to assess clinical benefit of MPP in patients who do not respond to standard BIV pacing. Methods Overall 3724 patients were treated with standard BIV pacing. After 6 months, 1639 patients were considered as CRT non-responders (echo-measured relative reduction in LV end-systolic volume (LVESV) &lt; 15%) and randomized to MPP or BIV. Results We analysed 593 randomized patients (291 MPP, 302 BIV), who had BIV pacing &gt;97% of time before randomization and complete 12-months clinical and echocardiographic data. The endpoint, composed by freedom from cardiac death and HF hospitalizations, and by LVESV relative reduction ≥15% between randomization and 12 months, occurred more frequently in MPP (96/291 (33.0%)) vs. BIV (71/302 (23.5%), p = 0.0103), also confirmed at multivariate analysis (hazard ratio = 1.55, 95% confidence interval = 1.02-2.34, p = 0.0402 vs. BIV). HF hospitalizations occurred less frequently in MPP (14/291 (4.81%)) vs. BIV (29/302 (9.60%), incidence rate ratio = 50%, p = 0.0245). Selecting patients with large (&gt;30 ms) dispersion of interventricular electrical delay among the 4 LV lead dipoles, reverse remodeling was more frequent in MPP (18/51 (35.3%)) vs. BIV (11/62 (17.7%), p = 0.0335). Conclusion In patients who do not respond to standard CRT, despite high BIV pacing percentage, MPP is associated with lower occurrence of HF hospitalizations and higher probability of reverse LV remodeling, compared with BIV pacing.

Maroli G., Schänzer A., Günther S., Garcia-Gonzalez C., Rupp S., Schlierbach H., Chen Y., Graumann J., Wietelmann A., Kim J., Braun T.

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment.

Bellec M., Chen R., Dhayni J., Trullo A., Avinens D., Karaki H., Mazzarda F., Lenden H., Favard C., Lehmann R., Bertrand E., Lagha M., Dufourt J.

Live imaging of translation based on tag recognition by a single-chain antibody is a powerful technique to assess translation regulation in living cells. However, this approach is challenging and requires optimization in terms of expression level and detection sensitivity of the system, especially in a multicellular organism. Here, we improved existing fluorescent tools and developed new ones to image and quantify nascent translation in the livingDrosophilaembryo and in mammalian cells. We tested and characterized five different green fluorescent protein variants fused to the single-chain fragment variable (scFv) and uncovered photobleaching, aggregation, and intensity disparities. Using different strengths of germline and somatic drivers, we determined that the availability of the scFv is critical in order to detect translation throughout development. We introduced a new translation imaging method based on a nanobody/tag system named ALFA-array, allowing the sensitive and simultaneous detection of the translation of several distinct mRNA species. Finally, we developed a largely improved RNA imaging system based on an MCP-tdStaygold fusion.