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Purpose of Review Transthyretin amyloidosis is an increasingly recognized cause of restrictive cardiomyopathy related to amyloid fibril deposition in cardiac tissues. As treatment therapies have emerged for transthyretin amyloidosis (ATTR), so has interest in using biomarkers to identify disease prior to advanced presentation. Recent Findings Lower levels of transthyretin and retinol binding protein-4 have been demonstrated in patients with pathogenic mutations of transthyretin either with or without clinical disease. Levels associate with the severity of mutations as well as response to treatment with transthyretin stabilizers or small interfering RNA molecules which silence transthyretin production. Transthyretin stability is the rate limiting step of amyloid fibril formation and directly measuring transthyretin kinetic stability has the potential to identify patients as risk as well as therapeutic response to treatment regardless of pathogenic or wild-type genetics. In addition, non-antibody protein-based peptide probes have been developed that directedly measure misfolded transthyretin oligomers due to transthyretin breakdown. Although promising, both TTR kinetic and protein peptide probes remain in early stages of clinical investigation. Summary Transthyretin, retinol binding protein-4, transthyretin kinetic stability, and protein-based peptide probes have potential as biomarkers to facilitate an earlier ATTR diagnosis for patients with pathogenic transthyretin mutations.

Aims Patients with obesity and ischaemic heart failure may counter‐intuitively have better outcomes compared with patients with normal body weight due to an ‘obesity paradox’. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). Methods and results We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P‐interaction = 0.90). There was a non‐significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85–1.00, P = 0.051]. Increasing body size (per 5 kg/m2) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45–4.26, P < 0.001) and infectious mediastinitis (odds ratio 2.09, 95% CI 1.10–3.97, P = 0.024) at 30 days but not other 30 day safety outcomes. Conclusions The benefit of CABG vs. medical therapy for ischaemic heart failure was consistent regardless of BMI or WHO obesity class for death or secondary clinical outcomes. However, higher BMI was associated with some short‐term post‐CABG complications.

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.

Data regarding cardiogenic shock (CS) from safety-net hospitals serving socioeconomically-disadvantaged patients are limited. In addition, little is known regarding long-term outcomes and management of heart failure-related CS (HF-CS), a population potentially especially vulnerable to adverse social determinants of health (SDOH). A single-center retrospective cohort study of patients with Stage C, D, or E CS at a public safety-net hospital between 2017 and 2023 was performed. Management and outcomes were compared between patients with HF-CS and myocardial infarction-CS (AMI-CS). The primary outcome was survival through 2 years. The cohort included 378 patients (median age 57y, 44% Black race, 35% Hispanic ethnicity, 81% HF-CS, 19% AMI-CS); 23% received mechanical circulatory support. Thirty-day mortality was lower among patients with HF-CS than AMI-CS (16% vs 28%; HR 0.50 [95% CI 0.30 to 0.84], p = 0.01]). In contrast, mortality from 31 days through 2 years was higher after HF-CS (45% vs 22%, HR 1.94 [1.11 to 3.38], p = 0.02). At long-term follow-up, 53% of survivors were on beta blockers and 32% on no guideline-directed medical therapies. Eighteen patients (5%) received transplant or left ventricular assist device, all of whom had HF-CS and survived through available follow up (median 2.3y [0.9 to 4.0]). In conclusion, in a large safety-net hospital serving a diverse population with adverse SDOH, HF-CS was much more common than AMI-CS, with lower short-term but higher long-term mortality in HF-CS. Use of advanced therapies was low, with favorable survival among patients who received these. These results highlight the importance of expanding access to specialized heart failure care for socially vulnerable patients with CS.

Background Coronary artery bypass grafting (CABG) has demonstrated long‐term mortality benefits in patients with HFREF and obstructive coronary artery disease (CAD), but whether phenotypic heterogeneity influences the benefits of CABG is unknown. We applied clustering analysis to STICHES (Surgical Treatment for Ischemic Heart Failure Extension Study) to identify phenogroups with different long‐term risk profiles and investigate differences in CABG benefits between phenogroups. Methods and Results STICHES was a randomized controlled trial evaluating the effect of CABG in addition to medical therapy versus medical therapy alone. We split the STICHES participants into derivation (n = 753) and validation (n = 459) cohorts. We phenomapped the derivation cohort using penalized model‐based clustering. We fit multivariable Cox models to investigate long‐term differences in all‐cause mortality, cardiovascular (CV) mortality, and a composite of all‐cause mortality/CV hospitalization between phenogroups and whether phenogroup assignment modified the effects of CABG on these outcomes. Findings were internally validated on the validation cohort. Four phenogroups were identified in the derivation cohort. The highest‐risk group was at a twofold greater risk of death (HR: 2.0, 95% CI: 1.4–2.9, p < 0.001) and CV death (HR: 2.0, 95% CI: 1.3–3.1, p = 0.002), and a 1.5‐fold greater risk for death/CV hospitalization (HR: 1.5, 95% CI: 1.1–2.1, p = 0.016). Phenogroup assignment did not modify the effects of CABG on the outcomes (p > 0.05 for all). Similar results were obtained in the validation cohort. Conclusions The beneficial effects of CABG on all‐cause mortality, CV mortality, and a composite of all‐cause mortality and CV hospitalization persist despite phenotypic heterogeneity in HFREF and CAD. a) Kaplan‐Meier curve for all‐cause mortality in the derivation cohort stratified by clustering‐derived phenogroups. P‐value in the lower left of a) is the result of the log‐rank test. b) Hazard ratios for all‐cause mortality as obtained by multivariable Cox proportional‐hazards modeling in the derivation cohort stratified by clustering‐derived phenogroups. Similar results were obtained in the validation cohort. Note that the P‐value reported for the interaction effect between treatment assignment and phenogroup assignment is the result of the likelihood‐ratio test for the addition of an interaction term between phenogroup assignment and treatment assignment to the Cox proportional‐hazards model.

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. Summary 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.

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. Summary 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.