Circulating transthyretin and retinol binding protein 4 levels among middle-age V122I TTR carriers in the general population.

BACKGROUND: Hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has a long latency phase before clinical onset, creating a need to identify subclinical disease. We hypothesized circulating transthyretin (TTR) and retinol binding protein 4 (RBP4) levels would be associated with TTR carrier status and correlated with possible evidence of subclinical ATTRv-CA. METHODS: TTR and RBP4 were measured in blood samples from V122I TTR carriers and age-, sex- and race-matched non-carrier controls (1:2 matching) among Dallas Heart Study participants (phases 1 (DHS-1) and 2 (DHS-2)). Multivariable linear regression models determined factors associated with TTR and RBP4. RESULTS: There were 40 V122I TTR carriers in DHS-1 and 54 V122I TTR carriers in DHS-2. In DHS-1 and DHS-2, TTR was lower in V122I TTR carriers (p < .001 for both), and RBP4 in DHS-2 was lower in V122I TTR carriers than non-carriers (p = .002). Among V122I TTR carriers, TTR was negatively correlated with markers of kidney function, and limb lead voltage (p < .05 for both) and TTR and RBP4 were correlated with atrial volume in DHS-2 (p < .05). CONCLUSIONS: V122I TTR carrier status is independently associated with lower TTR and RBP4 in comparison with non-carriers. These findings support the hypothesis that TTR and RBP4 may correlate with evidence of subclinical ATTRv-CA.

Natriuretic Peptides and Cardiac Troponins: Markers of Disease Progression and Risk in Light Chain Cardiac Amyloidosis.

PURPOSE OF REVIEW: Light chain (AL) amyloidosis can cause an infiltrative cardiomyopathy that can result in symptomatic heart failure. The vague, nonspecific onset of signs and symptoms may lead to a delay in diagnosis and treatment leading to poor outcomes. Cardiac biomarkers, such as troponins and natriuretic peptides, play a pivotal role in diagnosis, determining prognosis, and assessing treatment response in patients with AL amyloidosis. Because of the evolving landscape for both diagnosis and treatment of AL cardiac amyloidosis, we review the critical role these and other biomarkers play in the clinical management of this disease. RECENT FINDINGS: A number of conventional cardiac and noncardiac serum biomarkers are commonly used in AL cardiac amyloidosis and may be surrogates for cardiac involvement and inform prognosis. These include typical heart failure biomarkers such as levels of circulating natriuretic peptides as well as cardiac troponins. Other noncardiac biomarkers frequently measured in AL cardiac amyloidosis included difference between the involved and uninvolved free light chains (dFLC) and markers of endothelial cell activation and damage such as von Willebrand factor antigen and matrix metalloproteinases. AL amyloidosis can lead to cardiac involvement which has been associated with poor outcomes, especially if not identified and treated early. Natriuretic peptides and cardiac troponins are cornerstones for the diagnosis and management of AL cardiac amyloidosis. Their levels may represent cardiac stress, injury, and possibly degree of cardiac involvement, and they play a key role in AL amyloidosis disease staging.

Donation after circulatory determination of death in heart transplant: impact on current and future allocation policy.

PURPOSE OF REVIEW: Historically, the selection criteria for heart transplant candidates has prioritized posttransplant survival while contemporary allocation policy is focused on improving waitlist survival. Donor scarcity has continued to be the major influence on transplant allocation policy. This review will address the opportunity of donation after circulatory determination of death (DCDD) and potential impact on future policy revisions. RECENT FINDINGS: In 2018, changes to U.S. heart allocation policy led to several intended and unintended consequences. Beneficial changes include reduced waitlist mortality and broader geographic sharing. Additional impacts include scarcer pathways to transplant for patients with a durable left ventricular assist device, increased reliance on status exceptions, and expanded use of temporary mechanical support. DCDD is anticipated to increase national heart transplant volumes by ∼30% and will impact waitlist management. Centers that offer DCDD procurement will have reduced waitlist times, reduced waitlist mortality, and higher transplant volumes. SUMMARY: While DCDD will provide more transplant opportunities, donor organ scarcity will persist and influence allocation policies. Differential patient selection, waitlist strategy, and outcome expectations may indicate that allocation is adjusted based on the procurement options at individual centers. Future policy, which will consider posttransplant outcomes, may reflect that different procurement strategies may yield different outcomes.

Hemodynamic Gain Index and Exercise Capacity in Heart Failure With Preserved Ejection Fraction.

Decreased exercise capacity portends a poor prognosis in heart failure with preserved ejection fraction (HFpEF). The hemodynamic gain index (HGI) is an integrated marker of hemodynamic reserve measured during exercise stress testing and is associated with survival. The goal of this study was to establish the association of HGI with exercise capacity, serum biomarkers, and echocardiography features in subjects with HFpEF. In 209 subjects with HFpEF enrolled in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial who underwent cardiopulmonary exercise testing, we calculated the HGI ([peak heart rate [HR] × peak systolic blood pressure [SBP]-[HR at rest × SBP at rest])/(HR at rest × SBP at rest) and tested associations with outcomes of interest. The median (interquartile range) HGI was 0.94 (0.5 to 1.3) beats per min/mm Hg. In multivariable-adjusted linear regression, higher HGI was associated with greater peak oxygen consumption (VO2), VO2 at anaerobic threshold, peak minute ventilation, and 6-minute walk distance (all p <0.001). Higher HGI was associated with lower serum high-sensitivity troponin I, pro-collagen III, N-terminal pro-B-type natriuretic peptide, and creatinine (all p <0.05) and with longer deceleration time, lower E/A ratio, and lower left atrial volume index by echocardiography (all p <0.05). In conclusion, higher HGI in stable HFpEF was associated with greater exercise capacity, a biomarker profile indicating less myocardial injury and fibrosis and less kidney dysfunction, and with less severe diastolic dysfunction. These results suggest that HGI, an easily calculated metric from routine exercise testing, is a marker of functional capacity and disease severity in HFpEF and may serve as a surrogate for VO2 parameters for use in treadmill testing without gas exchange capability.

Update on Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis.

PURPOSE OF REVIEW: Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy and an increasingly recognized cause of morbidity and mortality. There remains substantial delay between initial symptoms and diagnosis. With the recent emergence of various targeted therapies proven to reduce morbidity and mortality, there is an imperative to diagnose subclinical disease. Biomarkers may be well-suited for this role. RECENT FINDINGS: Conventional markers of heart failure, such as natriuretic peptides and cardiac troponins, and estimated glomerular filtration rate are associated with risk in ATTR-CM. Circulating transthyretin (TTR) levels parallel TTR kinetic stability, correlate with disease severity, and may serve as indirect markers of ATTR-CM disease activity and response to targeted treatment. There is also growing evidence for the correlation of TTR to retinol-binding protein 4, a biomarker which independently associates with this disease. The rate-limiting step for ATTR pathogenesis is dissociation of the TTR homotetramer, which may be quantified using subunit exchange to allow for early risk assessment, prognostication, and assessment of treatment response. The protein species that result from the dissociation and misfolding of TTR are known as nonnative transthyretin (NNTTR). NNTTR is quantifiable via peptide probes and is a specific biomarker whose reduction is positively correlated with improvement in neuropathic ATTR amyloidosis. Neurofilament light chain (NfL) is released into the blood after axonal damage and correlates with neuropathic ATTR amyloidosis, but its clinical use in ATTR-CM is uncertain. Conventional markers of heart failure, transthyretin, retinol-binding protein 4, transthyretin kinetic stability, nonnative transthyretin, peptide probes, and neurofilament light chain have potential as biomarkers to enable early, subclinical diagnosis in patients with transthyretin cardiac amyloidosis.

Biomarker-Based Assessment for Infectious Risk Before and After Heart Transplantation.

PURPOSE OF REVIEW: Survival outcomes for heart transplant recipients have improved in recent decades, but infection remains a significant cause of morbidity and mortality. In this review, we discuss several biological markers, or biomarkers, that may be used to monitor immunologic status in this patient population. RECENT FINDINGS: While modest, data on the utility of immune biomarkers in heart transplant recipients suggest correlation between low level of immune response and increased infection risk. More novel assays, such as the detection of circulating levels of pathogen cell-free DNA in plasma and the use of Torque teno virus load as a surrogate for net state of immunosuppression, have potential to be additional important biomarkers. Biomarker approaches to individualize immunosuppression therapy among heart transplant recipients is a promising area of medicine. However, additional studies are needed to inform the optimal protocol in which to incorporate these biomarkers into clinical practice.

New-Onset Atrial Fibrillation in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Registry.

BACKGROUND: New-onset atrial fibrillation (AF) in patients hospitalized with COVID-19 has been reported and associated with poor clinical outcomes. We aimed to understand the incidence of and outcomes associated with new-onset AF in a diverse and representative US cohort of patients hospitalized with COVID-19. METHODS: We used data from the American Heart Association COVID-19 Cardiovascular Disease Registry. Patients were stratified by the presence versus absence of new-onset AF. The primary and secondary outcomes were in-hospital mortality and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, stroke, cardiogenic shock, and heart failure). The association of new-onset AF and the primary and secondary outcomes was evaluated using Cox proportional-hazards models for the primary time to event analyses. RESULTS: Of the first 30 999 patients from 120 institutions across the United States hospitalized with COVID-19, 27 851 had no history of AF. One thousand five hundred seventeen (5.4%) developed new-onset AF during their index hospitalization. New-onset AF was associated with higher rates of death (45.2% versus 11.9%) and MACE (23.8% versus 6.5%). The unadjusted hazard ratio for mortality was 1.99 (95% CI, 1.81-2.18) and for MACE was 2.23 (95% CI, 1.98-2.53) for patients with versus without new-onset AF. After adjusting for demographics, clinical comorbidities, and severity of disease, the associations with death (hazard ratio, 1.10 [95% CI, 0.99-1.23]) fully attenuated and MACE (hazard ratio, 1.31 [95% CI, 1.14-1.50]) partially attenuated. CONCLUSIONS: New-onset AF was common (5.4%) among patients hospitalized with COVID-19. Almost half of patients with new-onset AF died during their index hospitalization. After multivariable adjustment for comorbidities and disease severity, new-onset AF was not statistically significantly associated with death, suggesting that new-onset AF in these patients may primarily be a marker of other adverse clinical factors rather than an independent driver of mortality. Causality between the MACE composites and AF needs to be further evaluated.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

The Cost of Return to Play Protocols in Collegiate Athletes Recovering from Coronavirus Disease 2019.

INTRODUCTION/PURPOSE: SARS-CoV-2 infection (COVID-19) can result in myocarditis. Protocols were developed to allow competitive athletes to safely return to play (RTP) after a COVID-19 infection, but the financial impact of these protocols is unknown. Our objective was to determine the differential cost of post-COVID-19 RTP protocols for competitive collegiate athletes. METHODS: This multicenter retrospective cohort study of clinical evaluation of 295 athletes after COVID-19 infection was performed at four institutions with three RTP protocols. Costs were calculated using adjusted Center for Medicare and Medicaid Services pricing. All athletes underwent electrocardiogram and clinical evaluation. A tiered approach performed cardiac imaging and biomarker analysis for major symptoms. A universal transthoracic echocardiogram (TTE) approach performed TTE and biomarkers for all athletes. A universal exercise stress echocardiogram (ESE) approach performed ESE and biomarkers for all athletes. RESULTS: The cost per athlete was $632.51 ± 651.80 ($44,908 total) in tiered group (n = 71), $1,072.30 ± 517.93 ($87,928 total) in the universal TTE group (n = 82), and $1357.38 ± 757.05 ($192,748 total) in the universal ESE group (n = 142) (P < 0.001). Extrapolated national costs for collegiate athletes would be $39 to 64 million higher for universal imaging approaches versus a tiered approach. Only seven athletes had probable/possible myocarditis with no significant difference between approaches. CONCLUSIONS: Cardiac screening in collegiate athletes after COVID-19 infection resulted in significant cost to the health care system. A tiered-based approach was more economical, and a universal exercise echocardiogram group detected slightly more myocardial abnormalities by cardiac magnetic resonance imaging. The clinical consequences of these approaches are unknown.

Phenomapping a Novel Classification System for Patients With Destination Therapy Left Ventricular Assist Devices.

Patients with continuous flow destination therapy (DT) left ventricular assist devices (LVAD) comprise a heterogeneous population. We hypothesized that phenotypic clustering of individuals with DT LVADs by their implantation characteristics will be associated with different long-term risk profiles. We analyzed 5,999 patients with continuous flow DT LVADs in Interagency Registry for Mechanically Assisted Circulatory Support using 18 continuous variable baseline characteristics. We Z-transformed the variables and applied a Gaussian finite mixture model to perform unsupervised clustering resulting in identification of 4 phenogroups. Survival analyses considered the competing risk for cumulative incidence of transplant or the composite end point of death or heart transplant where appropriate. Phenogroup 1 (n = 1,163, 19%) was older (71 years) and primarily white (81%). Phenogroups 2 (n = 648, 11%) and 3 (n = 3,671, 61%) were of intermediate age (70 and 62 years), weight (85 and 87 kg), and ventricular size. Phenogroup 4 (n = 517, 9%) was younger (40 years), heavier (108 kg), and more racially diverse. The cumulative incidence of death, heart transplant, bleeding, LVAD malfunction, and LVAD thrombosis differed among phenogroups. The highest incidence of death and the lowest rate of heart transplant was seen in phenogroup 1 (p <0.001). For adverse outcomes, phenogroup 4 had the lowest incidence of bleeding, whereas LVAD device thrombosis and malfunction were lowest in phenogroup 1 (p <0.001 for all). Finally, the incidence of stroke, infection, and renal dysfunction were not statistically different. In conclusion, the present unsupervised machine learning analysis identified 4 phenogroups with different rates of adverse outcomes and these findings underscore the influence of phenotypic heterogeneity on post-LVAD implantation outcomes.