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Aims: Two key echocardiographic parameters that are currently used to diagnose heart failure (HF) with preserved ejection fraction (HFpEF) are left atrial volume index (LAVi) and left ventricular mass index (LVMi). We investigated whether patients' characteristics, biomarkers, and co-morbidities are associated with these parameters and whether the relationships differ between patients with HFpEF or HF with reduced ejection fraction (HFrEF). Methods: We consecutively enrolled 831 outpatients with typical signs and symptoms of HF and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels and categorized patients based upon left ventricular ejection fraction (LVEF): LVEF < 40% (HFrEF), LVEF between 40% and 50% (HF with mid-range ejection fraction), and LVEF ≥ 50% (HFpEF). The study includes consecutively enrolled HF patients from an HF outpatient clinic at a tertiary medical centre in the Netherlands. All patients underwent baseline characterization, laboratory measurements, and echocardiography. Results: Four hundred sixty-nine patients had HFrEF, 189 HF with mid-range ejection fraction, and 173 HFpEF. The patients with HFrEF were rather male [HFrEF: 323 (69%); HFpEF: 80 (46%); P < 0.001], and the age was comparable (HFrEF 67 ± 13; HFpEF 70 ± 14; P = 0.069). In HFpEF, more patients had hypertension [190 (40.5%); 114 (65.9%); P < 0.001], higher body mass indices (27 ± 8; 30 ± 7; P < 0.001), and atrial fibrillation [194 (41.4); 86 (49.7); P = 0.029]. The correlation analyses showed that in HFrEF patients, LAVi was significantly associated with age (β 0.293; P < 0.001), male gender (β 0.104; P = 0.042), body mass index (β −0160; P = 0.002), diastolic blood pressure (β −0.136; P < 0.001), New York Heart Association (β 0.174; P = 0.001), atrial fibrillation (β 0.381; P < 0.001), galectin 3 (β 0.230; P < 0.001), NT-proBNP (β 0.183; P < 0.001), estimated glomerular filtration rate (β −0.205; P < 0.001), LVEF (β −0.173; P = 0.001), and LVMi (β 0.337; P < 0.001). In HFpEF patients, only age (β 0.326; P < 0.001), atrial fibrillation (β 0.386; P < 0.001), NT-proBNP (β 0.176; P = 0.036), and LVMi (β 0.213; P = 0.013) were associated with LAVi. Conclusions: Although LVMi and LAVi are hallmark parameters to diagnose HFpEF, they only correlate with a few characteristics of HF and mainly with atrial fibrillation. In contrast, in HFrEF patients, LAVi relates strongly to several other HF parameters. These findings underscore the complexity in visualizing the pathophysiology of HFpEF and question the relation between cardiac structural remodeling and the impact of co-morbidities.

Background: Accurate measurement of kidney function in patients with neuromuscular disorders is challenging. Cystatin C, a marker not influenced by skeletal muscle degradation, might be of clinical value in these patients.Methods: We consecutively enrolled 39 patients with neuromuscular disorders. We investigated the association of the eGFR, based on plasma creatinine and Cystatin C, with clinical and biochemical variables associated with kidney function, namely age and galectin-3.Results: Creatinine-based eGFR was 242 (±80) and Cystatin C-based eGFR was 110 (±23) mL/min/1.73 m2. Cystatin C-based eGFR was associated with age (β −0.63 p < 0.0001) and galectin-3 levels (β −0.43 p < 0.01), while creatinine-based eGFR was not (β −0.22 p = 0.20; β −0.28 p = 0.10). Sensitivity analyses in Duchenne and Becker patients revealed the same results: Cystatin C-based eGFR was associated with age (β −0.61 p < 0.01) and galectin-3 levels (β −0.43 p = 0.05), while creatinine-based eGFR was not (β −0.32 p = 0.13; β −0.34 p = 0.14).Conclusions: These data indicate that estimation of renal function in patients with neuromuscular disorders cannot reliably be achieved with creatinine, while Cystatin C appears a reasonable alternative. Since a large proportion of patients with neuromuscular disorders develops heart failure, and requires heart failure medication, adequate monitoring of renal function is warranted.

Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage–dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4–Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. Significance: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4–Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies. See related commentary by Young and Bluestone, p. 537. This article is highlighted in the In This Issue feature, p. 521

Background Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis. Purpose The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury. Methods We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I. Results Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p Conclusions Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

Cardio-Oncology has blossomed as a new field in cardiovascular medicine, in large part due to new therapies, which may have cardiovascular sequelae. Despite this, anthracyclines still serve as cornerstone therapy for most pediatric cancers, several solid tumors and hematological malignancies. Cardiotoxicity is the main limiting concern with anthracyclines, and this is particularly an issue in patients in extremes of age (both young and old patients). Pediatric hearts are susceptible for cardiotoxicity, while in older patients, concomitant risk factors may contribute to lower threshold for cardiotoxic effects. With increasing patient survival, a significant increase in elderly cancer patients and long-term cardiotoxicity effects of anthracyclines, a better mechanistic understanding of age-dependent processes—that define cardiotoxicity—is needed. This review sheds light on how age affects underlying molecular pathways of anthracycline-associated cardiotoxicity and aims to provide preventive strategies that can be used in clinical practice.

BackgroundNearly half of all U.S. oncology patients meet FDA eligibility criteria to receive treatment with an immune checkpoint inhibitor (ICI). With increasing use of ICIs, preventing, diagnosing and treating immune-related adverse events (irAEs) are urgent clinical challenges. Myocarditis is an uncommon irAE, affecting < 1% of ICI-treated patients, but is highly fatal, with a mortality rate of nearly 50%. Genetically altered Pdcd1-/-Ctla4± mice die prematurely and specifically due to myocarditis. This model recapitulates the clinical and pathological features of ICI-myocarditis, including abundant cardiac infiltrating CD8+ T cells. The potential autoantigen(s) involved in ICI-myocarditis are unknown for both human disease and our murine model.MethodsWe used Pdcd1-/-Ctla4± mice on the C57BL6 background as a model of ICI-myocarditis. Single cell RNA and T cell receptor (TCR) sequencing was performed on sorted CD45+ cardiac immune cells from four affected Pdcd1-/-Ctla4± mice compared to six healthy wild type mice. The most three clonal TCRs (TCR-A, B, C), derived from two independent Pdcd1-/-Ctla4± mice, were reconstructed using stiTChR and transduced into reporter T cell lines for antigen discovery. Alpha-myosin was selected as a candidate autoantigen due to lack of presentation in the thymus. Reporter TCR-A, B, and C cells were screened using a library of overlapping 20 amino acid peptides derived from alpha-myosin in co-culture with bone marrow derived dendritic cells.ResultsTreatment with anti-CD8, but not anti-CD4, depleting antibodies rescues survival of Pdcd1-/-Ctla4± mice. Furthermore, adoptive transfer of splenocytes from Pdcd1-/-Ctla4± mice with myocarditis to Rag1-/- recipient mice was sufficient to induce fatal myocarditis. Single cell RNA/TCR sequencing on the cardiac immune infiltrate of Pdcd1-/-Ctla4± mice identified highly activated, clonal CD8+ T cells as the dominant cell population. The TCR-A cell line, the most clonal TCR identified in single cell TCR sequencing, activates NFAT, NFkB, and AP-1 reporters in response to the alpha-myosin epitope VIQYFASI. The TCR-B and TCR-C cell lines activate their reporters in response to the alpha myosin peptide DALLVIQWNIRAFMGVKNWP, indicating that alpha-myosin is an autoantigen in this mouse model of ICI-myocarditis.ConclusionsClonal, activated CD8+ T cells are critical for the development of ICI-myocarditis. Alpha-myosin is an autoantigen recognized by the most clonal cardiac CD8+ T cells. Efforts are currently underway to determine whether human TCRs derived from ICI-myocarditis samples recognize similar antigens. These studies are the first to identify a candidate autoantigen in ICI-myocarditis and may yield new insights into irAE pathogenesis.Ethics ApprovalAll animal experiments were in accordance with the VUMC Institutional Animal Care and Use Committee (IACUC), protocol # M2000067

Introduction: Heart failure (HF) remains a major public health problem worldwide, affecting approximately 23 million patients, and is predominantly a disease of the elderly population. Elderly patients mostly suffer from HF with preserved ejection fraction (HFpEF), which often presents with multiple co-morbidities and they require multiple medical treatments. This, together with the heterogeneous phenotype of HFpEF, makes it a difficult syndrome to diagnose and treat.Areas covered: Although HF is most abundant in the elderly, this group is still underrepresented in clinical trials, which results in the lack of evidence-based medical regimens. The current review has focused on new potential therapies for this poorly studied population. The focus will be on several classes of drugs currently recommended or might be expected soon. These will include sacubitril/valsartan (former LCZ696), Omecamtiv mecarbil, Vericiguat, Ivabradine, mineralocorticoid receptor antagonists (MRAs) and potassium binders.Expert opinion: We discuss promising new treatments and hypothesize that personalized approaches will be needed to treat elderly patients optimally. Medical doctors should not only focus on HF therapy, but comorbidities and polypharmacy should also influence therapeutic decision making. Furthermore, the importance of quality of life as a management endpoint should not be underestimated in the frail elderly.