Comparing Plasma Donor-derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study.

BACKGROUND: Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study (ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study (ClinicalTrials.gov No. NCT04239703). METHODS: We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states. RESULTS: Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA ) but also with genes induced by injury and expressed in macrophages (eg, SERPINA1 and HMOX1 ). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts. CONCLUSIONS: In this first analysis of Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in clinical management of heart transplant recipients.

Challenges with the current United Network for Organ Sharing heart allocation system.

PURPOSE OF REVIEW: The revised United States heart organ allocation system was launched in October 2018. In this review, we summarize this United Network for Organ Sharing (UNOS) policy and describe intended and unintended consequences. RECENT FINDINGS: Although early studies published after the change suggested postheart transplant survival declined at 6 months and 1 year, recent publications with longer follow-up time have confirmed comparable posttransplant survival in adjusted models and several patient cohorts. Moreover, the new allocation decreased overall waitlist time from 112 to 39 days ( P  < 0.001). Mean ischemic time increased because of greater distances traveled to acquire donor hearts under broader sharing. Despite the intention to decrease exception requests by expanding the number of priority tiers to provide more granular risk stratification, ∼30% of patients remain waitlisted under exception status. Left-ventricular assist device (LVAD) implants are declining and the number of LVAD patients on the transplant list has decreased dramatically after the allocation system change. SUMMARY: As the next allocation system is developed, it is imperative to curtail the use of temporary mechanical support as a strategy solely for listing purposes, identify attributes that more clearly stratify the severity of illness, provide greater oversight of exception requests, and address concerns regarding patients with durable LVADs.

Left Ventricular Assist Devices: A Primer For the General Cardiologist.

Durable implantable left ventricular assist devices (LVADs) have been shown to improve survival and quality of life for patients with stage D heart failure. Even though LVADs remain underused overall, the number of patients with heart failure supported with LVADs is steadily increasing. Therefore, general cardiologists will increasingly encounter these patients. In this review, we provide an overview of the field of durable LVADs. We discuss which patients should be referred for consideration of advanced heart failure therapies. We summarize the basic principles of LVAD care, including medical and surgical considerations. We also discuss the common complications associated with LVAD therapy, including bleeding, infections, thrombotic issues, and neurologic events. Our goal is to provide a primer for the general cardiologist in the recognition of patients who could benefit from LVADs and in the principles of managing patients with LVAD. Our hope is to "demystify" LVADs for the general cardiologist.

Balancing the tug of war: intraoperative and postoperative management of multiorgan transplantation.

PURPOSE OF REVIEW: Multiorgan heart transplants (MOHT) have steadily increased and account for approximately 4% of all heart transplants performed. Although long-term outcomes of MOHT are similar to heart transplant alone, perioperative management remains an issue with nearly double the rate of prolonged hospitalization. Better understanding of hemodynamic environments encountered and appropriate therapeutic targets can help improve perioperative management. RECENT FINDINGS: Accurate and precise hemodynamic monitoring allows for early identification of complications and prompt assessment of therapeutic interventions. This can be achieved with a multimodal approach using traditional monitoring tools, such a pulmonary artery catheter and arterial line in conjunction with transesophageal echocardiography. Specific targets for optimizing graft perfusion are determined by phase of surgery and organ combination. In some circumstances, the surgical sequence of transplant can help mitigate or avoid certain detrimental hemodynamic environments. SUMMARY: With better understanding of the array of hemodynamic environments that can develop during MOHT, we can work to standardize hemodynamic targets and therapeutic interventions to optimize graft perfusion. Effectively navigating this perioperative course with multimodal monitoring including transesophageal echocardiography can mitigate impact of complications and reduce prolonged hospitalization associated with MOHT.

SGLT2 inhibitors: a new pillar of the heart failure regimen.

Initially intended as an adjunct treatment for type 2 diabetes mellitus (T2DM), SGLT2-inhibitors (SGLT2i) have transformed into an unexpected pillar of the heart failure (HF) regimen. The past several years have witnessed a meteoric rise of this drug class, starting with the serendipitous results of trials assessing the safety of the glucose-lowering therapy in a broad range of cardiovascular patients and culminating with the demonstration of a reduction in hospitalizations for heart failure and cardiovascular mortality in dedicated heart failure populations. The heart failure benefits of SGLT2i are independent of a patient's glycemic status, but the salient mechanisms of cardioprotection remain a subject of robust debate and ongoing research. Cardiologists as well as physicians of other disciplines should become familiar with the main indications, benefits, and clinical consideration of implementation. In this review, we will discuss the advance of SGLT2i in heart failure, ranging from the results of large randomized clinical trials to potential mechanisms of action.

The dominant left ventricular assist device: lessons from an era.

The production and distribution of the HeartWare ventricular assist device has come to an abrupt end, but with this end comes the opportunity to reflect upon lessons learned from its lifespan. Running counter to the standard of evidence-based practice, the era of the HeartWare ventricular assist device was marred with fragmented data in relation to its primary counterpart, the HeartMate III. This created an incomplete understanding of devices, limited individualized patient care, and effectively positioned providers to make inferences regarding device superiority. We briefly review pertinent literature on this topic among the most commonly implanted durable devices from the era, detail the inherent limitations of this data, and argue the necessity of randomized clinical trials among novel devices towards the optimization of patient care.

Considerations and experience driving expansion of combined heart-liver transplantation.

PURPOSE OF REVIEW: Heart transplantation concomitant with a liver transplant may be warranted when end-stage heart failure results in irreversible liver failure. Previously reported outcomes have been excellent yet the specific immunoprotective role of the liver allograft is not known. We review the current literature about the immunologic benefit for combined heart and liver transplantation (CHLT). RECENT FINDINGS: The total number of combined heart and liver transplants continues to increase and accounts for approximately 25 cases per year. Familial amyloid polyneuropathy with cardiac cirrhosis is the most common indication for CHLT while adult congenital heart disease (CHD) with associated cirrhosis is increasing in frequency. The majority of recent registry data suggest a statistically equivalent to modestly improved survival advantage for CHLT compared with isolated heart transplantation. Direct mechanisms accounting for this survival advantage are not proven, but combined heart and liver transplants experience lower rates of acute cardiac rejection and cardiac allograft vasculopathy (CAV). SUMMARY: Combined heart and liver transplants remain a small percentage of the total heart transplants worldwide, but the majority of recent literature confirms the safety and viability of this option for patients with end-stage heart and liver disease. Equivalent to modestly improved survival outcomes, lower rates of acute cardiac rejection and CAV warrant further investigation into the liver allograft's immunoprotective effect on the transplanted heart. The key mechanisms of tolerogenicity have important implications for surgical technique and immunosuppression requirements. Future directions include development of criteria for heart-liver transplant candidacy and identification of equitable allocation protocols.

Community-Acquired Acute Kidney Injury as a Risk Factor of de novo Heart Failure Hospitalization.

OBJECTIVES: Because patients with hospital-acquired acute kidney injury (AKI) are at risk for subsequent development of heart failure (HF) and little is known about the relation between community-acquired AKI (CA-AKI) and HF, we sought to determine if CA-AKI is a risk factor for incident HF hospitalization. METHODS: We utilized Baylor Scott & White Health databases at the primary care and inpatient hospitalization levels to identify adults without a prior history of HF who had 2 or more serum creatinine measurements within 13 months in the primary care setting. We defined CA-AKI as a serum creatinine increase ≥0.3 mg/dL or ≥1.5 times the baseline for consecutive values within a 13-month period. We created a flag for de novo HF hospitalization at 90, 180, and 365 days following CA-AKI evaluation. RESULTS: In the analyses, 210,895 unique adults were included, of whom 5,358 (2.5%) had CA-AKI. Those with CA-AKI had higher rates of comorbidities, higher rate of males (48 vs. 42%, p < 0.001), and were older (61.5 [50.3, 73.1] vs. 54.1 [42.8, 64.7] years, p < 0.001) than those who did not have CA-AKI. In total, 607 (0.3%), 833 (0.4%), and 1,089 (0.5%) individuals had an incident HF hospitalization in the 90, 180, and 365 days following the CA-AKI evaluation, respectively. After adjusting for demographic and clinical characteristics, patients with CA-AKI had >2 times the risk of de novo HF hospitalization compared with patients who did not have CA-AKI (90 days: 2.35 [1.83-3.02], p < 0.001; 180 days: 2.52 [2.04-3.13], p < 0.001; 365 days: 2.16 [1.77-2.64], p < 0.001). These multivariable models yielded strong predictive abilities, with the areas under the receiver-operating characteristic curve >0.90. CONCLUSION: After controlling for baseline and clinical characteristics, patients with CA-AKI were at approximately twofold the risk of de novo HF hospitalization (within 90, 180, and 365 days) compared with those who did not have CA-AKI. Hence, detecting CA-AKI may provide an opportunity for early intervention at the primary care level to possibly delay HF development.

Donor predicted heart mass as predictor of primary graft dysfunction.

BACKGROUND: Concern over the hazards associated with undersized donor hearts has impeded the utilization of otherwise viable allografts for transplantation. Previous studies have indicated predicted heart mass (PHM) may provide better size matching in cardiac transplantation than total body weight (TBW). We investigated whether size-matching donor hearts by PHM is a better predictor of primary graft dysfunction (PGD) than matching by TBW. METHODS: Records of consecutive adult cardiac transplants performed between 2012 and 2016 at a single-center academic hospital were reviewed. We compared patients implanted with hearts undersized by ≥30% with those implanted with donor hearts matched for size (within 30%), and performed the analysis both for undersizing by PHM and for undersizing by TBW. The primary outcome was moderate/severe PGD within 24 hours, according to the 2014 International Society for Heart and Lung Transplantation consensus. Secondary outcome was 1-year survival. RESULTS: Of 253 patients, 21 (8%) and 30 (12%) received hearts undersized by TBW and PHM, respectively. The overall rate of moderate/severe PGD was 13% (33 patients). PGD was associated with undersizing if performed by PHM (p = 0.007), but not if performed by TBW (p = 0.49). One-year survival was not different between groups (log-rank, p > 0.8). Multivariate analysis confirmed that undersizing donor hearts by PHM, but not by TBW, was predictive of moderate/severe PGD (OR 3.3, 95% CI 1.3 to 8.6). CONCLUSIONS: Undersized donor hearts by ≥30% by PHM may increase rates of PGD after transplantation, confirming that PHM provides more clinically appropriate size matching than TBW. Better size matching may ultimately allow for expanding the donor pool.

Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have a 2-3-fold increased risk of myocardial infarction. Recent work suggests that plasma high density lipoproteins (HDL) from patients with RA are more proinflammatory than HDL from controls. We examined the effects of atorvastatin 80 mg daily on the inflammatory properties of HDL and clinical disease activity in RA. METHODS: Twenty subjects with active RA (mean Disease Activity Score 5.13 +/- 0.92) without dyslipidemia and no history of coronary artery disease were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable antirheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/proinflammatory properties of HDL were determined by a cell-free assay (CFA) that measures lipid oxidation products. RESULTS: After 12 weeks, subjects completing the A protocol had a mean reduction in CFA values of 14.8 +/- 21.7%, while subjects completing P protocol had a mean increase in CFA values of 7.1 +/- 13.2% (p = 0.026). There was a trend for a decrease in highly sensitive C-reactive protein (hs-CRP) over 12 weeks in the A group compared to an increase in hs-CRP in the P group (p > 0.05), but changes in measures of clinical disease activity and plasma cytokine/intercellular adhesion molecule-1 levels were not significantly different in the A and P groups. CONCLUSION: In patients with active RA, HDL was rendered more antiinflammatory by high-dose atorvastatin compared to placebo. Functional characterization of HDL may warrant further investigation as a method of cardiovascular risk assessment in RA patients without traditional coronary risk factors. (ClinicalTrials.gov number NCT00356473).