Pharmacogenomics in Heart Failure: Where Are We Now and How Can We Reach Clinical Application?

Heart failure is becoming increasingly prevalent in the United States and is a significant cause of morbidity and mortality. Several therapies are currently available to treat this chronic illness; however, clinical response to these treatment options exhibit significant interpatient variation. It is now clearly understood that genetics is a key contributor to diversity in therapeutic response, and evidence that genetic polymorphisms alter the pharmacokinetics, pharmacodynamics, and clinical response of heart failure drugs continues to accumulate. This suggests that pharmacogenomics has the potential to help clinicians improve the management of heart failure by choosing the safest and most effective medications and doses. Unfortunately, despite much supportive data, pharmacogenetic optimization of heart failure treatment regimens is not yet a reality. In order to attenuate the rising burden of heart failure, particularly in the context of the recent paucity of new effective interventions, there is an urgent need to extend pharmacogenetic knowledge and leverage these associations in order to enhance the effectiveness of existing heart failure therapies. The present review focuses on the current state of pharmacogenomics in heart failure and provides a glimpse of the aforementioned future needs

Factors influencing patient willingness to participate in genetic research after a myocardial infarction

Abstract Background Achieving 'personalized medicine' requires enrolling representative cohorts into genetic studies, but patient self-selection may introduce bias. We sought to identify characteristics associated with genetic consent in a myocardial infarction (MI) registry. Methods We assessed correlates of participation in the genetic sub-study of TRIUMPH, a prospective MI registry (n = 4,340) from 24 US hospitals between April 2005 and December 2008. Factors examined included extensive socio-demographics factors, clinical variables, and study site. Predictors of consent were identified using hierarchical modified Poisson regression, adjusting for study site. Variation in consent rates across hospitals were quantified by the median rate ratio (MRR). Results Most subjects consented to donation of their genetic material (n = 3,484; 80%). Participation rates varied greatly between sites, from 40% to 100%. After adjustment for confounding factors, the MRR for hospital was 1.22 (95% confidence interval (CI) 1.11 to 1.29). The only patient-level factors associated with consent were race (RR 0.93 for African Americans versus whites, 95% CI 0.88 to 0.99) and body mass index (RR 1.03 for BMI ≥ 25, 95% CI 1.01 to 1.06). Conclusion Among patients with an MI there were notable differences in genetic consent by study site, but little association with patient-level factors. This suggests that variation in the way information is presented during recruitment, or other site factors, strongly influence patients' decision to participate in genetic studies.Peer Reviewe

Right Ventricular Failure Following Left Ventricular Assist Device Implant: An Intermacs Analysis

Purpose: Right heart failure (RHF) management following LVAD include inotropes, right ventricular mechanical support and heart transplant. We analyzed the outcomes of severe RHF following implant of a fully magnetically levitated or hybrid magnetic centrifugal durable LVAD. Methods: In this INTERMACS analysis we identified patients who developed severe RHF following LVAD from 2013 until 2020 as bridge to recovery or transplant. Patients were categorized in three groups based on RHF treatment strategy: inotrope support (group 1), temporary mechanical support (group 2), and durable centrifugal RVAD (group 3). Kaplan Meier and Cox-regression survival analysis between groups was undertaken. Logistic regression analysis for new onset dialysis was conducted. Results: 2509 patients developed severe RHF after LVAD. 2199 (87.6%) patients were managed with inotropes (group 1), 233 (9.3%) with temporary RVAD (group 2) and 77 (3.1%) with durable RVAD (group 3). Group 1 had fewer patients with INTERMACS profile 1 and 2 (21.6%, p\u3c0.001). One year survival was 84.6%, 59.3%, and 63.8% in groups 1,2, and 3 (mortality HR=2.4 and 3.3 for groups 2 and 3 vs. group 1, p\u3c0.05). One year survival to transplant was 27%, 36.5%, and 53.6% in groups 1, 2, and 3, respectively (p\u3c0.05). Group 2 had higher incidence of new onset dialysis (42.6%, p=0.049). Conclusion: Survival with RHF following LVAD implant varies based on treatment strategy; inotrope support is associated with increased survival. Patients with durable RVAD are more likely to survive to transplant. Patient selection studies for durable RVAD with contraindications for transplant are necessary

VALIDATION OF POLYGENIC SCORE FOR BETA-BLOCKER SURVIVAL BENEFIT IN HEART FAILURE USING THE UNITED KINGDOM BIOBANK

Background: A novel polygenic response predictor (PRP) for beta blocker (BB) survival benefit in heart failure (HF) was recently described which separated European ancestry BB responders from non-responders using a score derived from 44 genetic loci. We tested whether this would replicate in the United Kingdom Biobank (UKB) dataset. Methods: UKB data pull identified patients with a HF diagnosis, genetic data and prescription data. Ejection fraction (EF) data was not available. BB exposure was quantified using BB dose and prescription frequency. The PRP was calculated using the genetic loci, weights, and cutoff value from the original description. Cox models were constructed of time to all-cause mortality adjusted for clinical risk (MAGGIC score), BB propensity score, BB exposure and BB exposure*PRP interaction. Results: Among 7502 HF patients included, 34% were women, 54% had coronary disease, 33% atrial fibrillation, 51% baseline BB usage, and 22% (n=1651) were PRP-predicted responders. Patients in the PRP responder group had strong survival benefit associated with BB exposure (HR=0.55, p=0.016), while PRP non-responders showed little BB effect (HR=0.92, p=0.466) and this difference was significant (p-interaction =0.051). Survival curves by PRP group and dichotomized BB exposure (high vs. low) are shown in the figure. Conclusion: The polygenic BB response predictor replicated in HF patients from the UKB regardless of EF. This innovative genomic medicine tool requires testing in a clinical trial

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction

BACKGROUND: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS). Methods: Patients meeting Framingham criteria for HF with EF\u3c50% were enrolled (n=1017) and plasma underwent SOMAscan® profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and N-Terminal pro-B-Type Natriuretic Peptide (NTproBNP), then was tested in the validation cohort. Risk stratification improvement was evaluated by C-statistic, integrated discrimination index (IDI), continuous net reclassification index (NRI), and median improvement in risk score (MIRS) for 1-year and 3-year mortality. Results: Participants\u27 mean age was 68 years, 48% identified as African American, 35% were female and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio (HR) =2.27 [95% Confidence interval (95%CI) 1.84-2.82], p=6.3x10(-14)), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (p=2.2x10(-6)), and it remained significant after adjustment for clinical score and NTproBNP (HR=1.37, 95%CI 1.05-1.79, p=0.021). The HFrEF-PRS improved metrics of risk stratification (C-statistic change=0.009, p=0.612; IDI=0.041, p=0.010; NRI=0.391, p=0.078; MIRS=0.039, p=0.016) and associated with cardiovascular death and HF phenotypes (e.g. 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. Conclusions: A plasma multi-protein score improved risk stratification in HFrEF patients and identified novel candidates

Novel Trial Design: CHIEF-HF

BACKGROUND: The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms. METHODS: One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (\u3e40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire. RESULTS: The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSIONS: CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial

Race and beta-blocker survival benefit in patients with heart failure: an investigation of self-reported race and proportion of African genetic ancestry

BACKGROUND: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry. METHODS AND RESULTS: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (P\u3e0.1 for all). CONCLUSIONS: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry