Clonal Hematopoiesis of Indeterminate Potential and Long-term Outcomes in Heart Transplantation.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) mutations, an aging trait, has been associated with progression of cardiovascular disease and development of malignancy. Uncertainty prevails regarding a robust association between CHIP and heart transplantation outcomes. OBJECTIVES: To determine prevalence of CHIP mutations in heart transplantation and their association with long-term outcomes including cardiac allograft vasculopathy (CAV), graft failure, malignancy, and all-cause mortality. METHODS: We conducted a mixed retrospective-prospective observational study of heart transplant recipients with targeted sequencing for CHIP mutations (Variant allele frequency (VAF) of ≥2%). The primary composite outcome was first occurrence of CAV grade ≥2, graft failure, malignancy, cardiac re-transplantation, or all-cause death. Secondary outcomes were the individual components of the composite primary outcome. Sensitivity analyses with base-case and extreme scenarios were performed. RESULTS: Among 95 HT recipients, 30 had CHIP mutations (31.6%). DNMT3A mutations were most common (44.7%) followed by PPM1D (13.2%), SF3B1 (10.5%), TET2 (7.9%) and TP53 (7.9%). The only significant independent predictor of CHIP was age at enrollment or age at transplantation. After multivariable adjustment, CHIP was not associated with the primary outcome which occurred in 44 (46.3%) patients (HR=0.487; 95%CI:0.197-1.204; p=0.119), malignancy alone or death. CONCLUSION: We demonstrated no association between CHIP mutations and post-transplant outcomes including CAV, graft failure, malignancy, and all-cause mortality. In line with previously published data, our analysis provides additional evidence on the lack of clinical value of using CHIP mutations as a biomarker for surveillance in outcomes after heart transplantation.

Cardiomyopathy in First-Degree Relatives of Patients Presenting With Acute Myocarditis: Prevalence and Prognostic Significance.

BACKGROUND: Acute myocarditis has been genetically linked to dilated cardiomyopathy (DCM), but the clinical significance remains uncertain. We investigated the prevalence and long-term prognosis of DCM and heart failure (HF) among unselected patients hospitalized with acute myocarditis and their first-degree relatives compared with an age- and sex-matched cohort. METHODS: This was an observational study utilizing the Danish nationwide registries, where all patients with a first-time myocarditis diagnosis from 1995 to 2018 were identified and matched (on birth year and sex) with 10 controls from the general population. RESULTS: Totally 3176 patients with acute myocarditis and 31 760 controls were included (median age, 49.8 [Q1-Q3, 32.5-70.2] years; 35.6% female). At baseline, patients with myocarditis had a higher prevalence of DCM (7 [0.2%] versus 8 [0.0%]) and HF (336 [10.6%] versus 695 [2.2%]) than controls; P<0.0001 for both. Patients with myocarditis more often had siblings with DCM (12 [0.4%] versus 17 [0.05%]) or HF (36 [1.1%] versus 89 [0.3%]); P<0.0001, odds ratios 7.09 (3.38-14.85) and 2.92 (1.25-6.80), respectively, whereas parental DCM and HF did not differ among patients with myocarditis and controls. Patients with myocarditis had greater 20-year incidence of DCM, HF, and all-cause mortality (0.5% [0.3%-0.9%], 15% [13%-17%], and 47% [44%-50%]) compared with controls (0.06% [0.03%-0.11%], 6.8% [6.4%-7.3%], and 34% [33%-35%]; P<0.0001). Having a first-degree relative with DCM or HF was associated with increased long-term mortality among the patients with myocarditis (hazard ratio, 1.40 [1.11-1.77]) but not among the controls (hazard ratio, 0.90 [0.81-1.01]; Pdifference=0.0008). CONCLUSIONS: Acute myocarditis aggregates with DCM within families, where it carries a worsened prognosis. A differential association between parents and siblings (with sibling preponderance) could suggest that additional environmental factors are important for myocarditis development even in predisposed individuals.

Inflammation in heart failure: pathophysiology and therapeutic strategies.

A role for inflammation in the development and progression of heart failure (HF) has been proposed for decades. Multiple studies have demonstrated the potential involvement of several groups of cytokines and chemokines in acute and chronic HF, though targeting these pathways in early therapeutic trials have produced mixed results. These studies served to highlight the complexity and nuances of how pro-inflammatory pathways contribute to the pathogenesis of HF. More recent investigations have highlighted how inflammation may play distinct roles based on HF syndrome phenotypes, findings that may guide the development of novel therapies. In this review, we propose a contemporary update on the role of inflammation mediated by the innate and adaptive immune systems with HF, highlighting differences that exist across the ejection fraction spectrum. This will specifically be looked at through the lens of established and novel biomarkers of inflammation. Subsequently, we review how improvements in inflammatory pathways may mediate clinical benefits of existing guideline-directed medical therapies for HF, as well as future therapies in the pipeline targeting HF and inflammation.

Contemporary Left Ventricular Assist Device Therapy as a Bridge or Alternative to Transplantation.

Left ventricular assist devices (LVADs), which were introduced as a bridge to heart transplantation, are now an established alternative to heart transplantation (HT) for patients with advanced heart failure. These devices have undergone significant technological advancements over the years, and contemporary LVADs prolong life substantially in patients dependent on inotropic therapy or in those with severe ambulatory advanced heart failure with a median survival that exceeds 5 y, and most patients benefit from a doubling in functional capacity, even among those intended as destination therapy because of ineligibility for transplantation. Other intended goals for LVAD implantation consist of (1) bridge to remission or recovery and (2) bridge to transplant or candidacy for transplant. In the former situation, few selected patients underwent LVAD implantation, facilitating myocardial remission to recovery that allowed explantation. Among those bridged to transplantation, survival in the intended goal was excellent, with 80% success at 5 y (with a 50% rate of transplantation). In this review, we provide a brief historical background on the evolution of LVADs and discuss outcomes with contemporary pumps, immunological and infection-related impact of such devices, impact of bridging in HT, and use of devices for facilitating myocardial recovery and remission. Furthermore, we discuss implications of HT allocation policies, with a specific focus within the United States, and outline future perspectives and novel device in development.

Outcomes of untreated subclinical antibody-mediated rejection after heart transplantation.

Subclinical antibody-mediated rejection (AMR) is represented by histopathological and/or immunopathological manifestations in the absence of significant cardiac allograft dysfunction. Treatment remains uncertain as there is a lack of data on asymptomatic heart transplant (HT) recipients (HTR) with a positive cardiac biopsy. We sought to determine the impact of untreated subclinical biopsy-proven AMR, regardless of circulating donor-specific antigen (DSA) expression, when diagnosed on surveillance biopsies in the first year after HT. This retrospective case control study evaluated 260 HTR between May 2004 and February 2021. These comprised 231 controls and 29 patients with untreated subclinical AMR. The mortality event rate was higher in controls (2.63 events per 100 person-years) compared to the scAMR Group (1.71 events per 100 person-years), a difference that did not reach statistical significance (hazard ratio 0.66, CI: 0.18-2.36). The combined event rate of cardiac allograft vasculopathy (CAV), graft dysfunction, or mortality was higher in the subclinical AMR group (5.60 events per 100 person-years) than in controls (3.89 events per 100 person-years) but did not reach statistical significance (hazard ratio 1.63, CI: 0.07-40.09). Our results suggest that subclinical AMR diagnosed in the first year after HT on surveillance biopsy is not associated with decreased survival. This may sway the management of subclinical AMR towards a more conservative approach in transplant-capable institutions that currently prioritize treatment, though prospective, randomized studies of such a management strategy are required.

Cardiac Xenotransplantation: Challenges, Evolution, and Advances.

The increased need for heart transplantation in patients with advanced heart failure has introduced demand for a greater supply of donor hearts. Progress in cross-species experimental models has led to promise for ushering in the clinical use of xenotransplantation (XTx) as a potential solution to the organ shortage worldwide. In this review, the authors first highlight the historical advances that led to the first pig-to-human heart transplantation, a landmark moment in the field of advanced heart failure. The authors discuss immunologic, infectious, and physiological challenges for implementation of XTx, as well as innovations in the science of genetic manipulation that allowed clinical translation of this therapy. The authors consider ongoing barriers that affect ongoing translation of this technology into clinical care in the current era. Finally, the authors propose a framework for advancing clinical application of XTx.

Cancer Screening in Solid Organ Transplant Recipients: A Focus on Screening Liver, Lung, and Kidney Recipients for Cancers Related to the Transplanted Organ.

Over the last few decades, the life expectancy of solid organ transplant recipients (SOTRs) has improved significantly. With SOTRs living longer, more recipients are dying from cancer. There is a reported 2- to 3-fold increased risk of cancer-specific mortality in SOTRs compared with the general population. Cancer in an SOTR can be de novo, recurrent, or donor-derived. Cancer screening in this population is crucial, as early detection and treatment may improve outcomes. In the absence of randomized controlled trials dedicated to SOTRs, clinicians rely on clinical practice guidelines from regional and national transplant societies; however, these may vary considerably across jurisdictions and transplanted organ. At present, no widely accepted consensus exists for cancer screening protocols in SOTRs, particularly with regard to screening for malignancy related to transplanted organ. Some SOTRs may be at higher risk of malignancies within the allograft. This is particularly the case in lung and liver recipients, though less common in kidney recipients who are at increased risk of developing renal cell cancer in their native kidneys. This increased risk has not been uniformly incorporated into screening recommendations for SOTRs. In this review, we summarize the cancer screening recommendations for SOTRs from various transplant organizations based on transplanted organ. This review also discusses the complexity and controversies surrounding screening of cancer in the allograft and future avenues to improve cancer detection in this context. More studies specific to SOTRs are required to form generalizable and evidence-based cancer screening guidelines, particularly with respect to cancer screening in the allograft.

Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.

Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.

A Rare Case of Coronary Artery Dilatation and Giant Pseudoaneurysm.

Coronary artery fistula are anomalous connections with coronary vessels or cardiac chambers, potentially resulting in coronary dilatation and pseudoaneurysm formation. We present the case of a 68-year-old woman referred to our institution for a voluminous coronary pseudoaneurysm secondary to coronary artery fistula presenting as a nearly completely obstructive left atrial mass. (Level of Difficulty: Intermediate.).

Heart Failure With Midrange Ejection Fraction-What Is It, If Anything?

The patient cohort with left ventricular ejection fractions (LVEFs) of 41%-49%, which has been defined as heart failure with midrange ejection fraction (HFmrEF), represent a significant proportion of the heart failure (HF) population. Despite the clear cutoffs established by different society guidelines, confusion remains regarding the exact significance of midrange LVEF within the HF syndrome. Patients with LVEF 41%-49% represent a heterogeneous group of patients sharing pathophysiologic mechanisms, biomarker profiles, comorbidities, and clinical characteristics with patients with preserved and reduced LVEF. In this clinical review, we discuss the underlying pathophysiologic mechanisms that culminate in the clinical syndrome of HF and contribute to the disparities observed between HFpEF, HFrEF, and HFmrEF. We highlight differences and similarities in clinical characteristics and imaging features between HFpEF and HFrEF in an effort to disentangle the heterogeneous group of patients with midrange LVEF, but ultimately we conclude that LVEF should be seen as simply one important element of a continuum throughout the HF syndrome, and that although is useful, it is an oversimplification, because HF syndrome is more of a continuum. The underlying pathophysiology, etiology, and comorbidities of patients presenting with HF is becoming ever more important as the limitations of a classification solely based on LVEF are being better recognised, and as patient-specific personalisation of care is becoming ever more important.

Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection / Argumentando a favor do uso combinado de inibidores de SGLT2 e agonistas do receptor GLP1 para proteção cardiorrenal

ABSTRACT Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

RESUMO Inibidores do cotransporter-2 de glicose sódica (SGLT2) e agonistas do receptor peptídeo-1 do tipo glucagon (GLP-1RA) foram inicialmente aprovados para melhorar o controle glicêmico no tratamento da diabetes tipo 2. Os ensaios clínicos também demonstraram efeitos benéficos em relação aos parâmetros cardiovasculares e renais. Além de melhorar o controle glicêmico, essas terapias promovem perda de peso e redução da pressão arterial quando usadas individualmente, e de forma aditiva quando usadas em conjunto. Consequentemente, tirar proveito de mecanismos de ação complementares com o uso combinado dessas duas classes de agentes para melhorar ainda mais os resultados cardiorrenais é conceitualmente atraente, mas ainda precisa ser explorado em detalhes em ensaios clínicos. Nesta revisão, discutimos os mecanismos propostos para proteção renal, benefícios clínicos e eventos adversos associados ao uso individual e combinado de inibidores de SGLT2 e GLP-1RA. O tratamento do diabetes tipo 2 mudou significativamente nos últimos anos, passando do controle exclusivamente glicêmico para o tratamento simultâneo de comorbidades associadas em uma população de pacientes com risco significativo de doença cardiovascular e progressão da doença renal crônica. É nessa perspectiva que procuramos delinear a justificativa para o uso sequencial e/ou combinado de inibidores de SGLT2 e GLP-1RA em pacientes com diabetes tipo 2.

Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection.

Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

Current Review of Implantable Cardioverter Defibrillator Use in Patients With Left Ventricular Assist Device.

PURPOSE OF REVIEW: While use of implantable cardioverter defibrillator (ICD) in patients with heart failure (HF) and reduced ejection fraction is recommended, their role in patients with left ventricular assist device (LVAD) remains controversial, especially with continuous flow (CF) devices. RECENT FINDINGS: Ventricular arrhythmias (VA) in LVAD patients are frequent and associated with worse outcomes, especially postoperatively. Data on the role of ICDs in LVAD patients are scarce, based on case reports or small retrospective series. While the majority of LVAD patients currently have an ICD, it seems that some might not derive any benefit, with additional risks in terms of inappropriate shocks, psychological distress, and infections. Some CF-LVAD patients are at high risk of VA and hemodynamic collapse; under those circumstances, an ICD might provide benefits. A randomized-controlled trial of routine ICD implantation in CF-LVAD would be needed to clarify their impact on survival in low risk patients.

Statin Use and Risk of Vascular Events Among Cancer Patients After Radiotherapy to the Thorax, Head, and Neck.

Background This study aimed to explore whether statins reduce radiation-induced vascular complications in cancer patients postradiotherapy to the thorax, head, and neck. Methods and Results We conducted a retrospective cohort study within a provincial linked database of 5718 cardiac patients with thorax and head or neck cancer having undergone radiotherapy between 2000 and 2011. One thousand five hundred fifty-two patients were identified as nonstatin users and 4166 as statin users. The primary outcome of interest was the composite of cerebrovascular (transient ischemic attack, and fatal or nonfatal stroke) or cardiovascular events (fatal or nonfatal myocardial infarction). Time-dependent Cox proportional hazard analyses were performed. The crude event rate was 10.31% for nonusers and 9.03% for statin users (hazard ratio of 0.92 [95% CI 0.76-1.10, P=0.3451]), over a mean time to event/censoring of 534±687 days for nonusers and 594±706 days for the statin users. After adjusting for age, sex, prior history of stroke/transient ischemic attack or myocardial infarction, diabetes mellitus, dyslipidemia, atrial fibrillation, chronic kidney disease, heart failure, and hypertension, statin use postradiotherapy was associated with a nonsignificant 15% relative risk reduction, but a strong trend toward reducing the primary outcome (hazard ratio=0.85 95% CI 0.69-1.04, P=0.0811). The use of statins was associated with a significant reduction of 32% for the outcome of stroke alone (hazard ratio=0.68, 95% CI 0.48-0.98, P=0.0368). Conclusions Statin use post radiation therapy was associated with a significant reduction in stroke, with a trend toward significantly reducing cardiovascular and cerebrovascular events.