A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.

The ability to fight or flee from a threat relies on an acute adrenergic surge that augments cardiac output, which is dependent on increased cardiac contractility and heart rate. This cardiac response depends on ß-adrenergic-initiated reversal of the small RGK G protein Rad-mediated inhibition of voltage-gated calcium channels (CaV) acting through the Cavß subunit. Here, we investigate how Rad couples phosphorylation to augmented Ca2+ influx and increased cardiac contraction. We show that reversal required phosphorylation of Ser272 and Ser300 within Rad's polybasic, hydrophobic C-terminal domain (CTD). Phosphorylation of Ser25 and Ser38 in Rad's N-terminal domain (NTD) alone was ineffective. Phosphorylation of Ser272 and Ser300 or the addition of 4 Asp residues to the CTD reduced Rad's association with the negatively charged, cytoplasmic plasmalemmal surface and with CaVß, even in the absence of CaVα, measured here by FRET. Addition of a posttranslationally prenylated CAAX motif to Rad's C-terminus, which constitutively tethers Rad to the membrane, prevented the physiological and biochemical effects of both phosphorylation and Asp substitution. Thus, dissociation of Rad from the sarcolemma, and consequently from CaVß, is sufficient for sympathetic upregulation of Ca2+ currents.

A Genetically Encoded Actuator Selectively Boosts L-type Calcium Channels in Diverse Physiological Settings.

L-type Ca 2+ channels (Ca V 1.2/1.3) convey influx of calcium ions (Ca 2+ ) that orchestrate a bevy of biological responses including muscle contraction and gene transcription. Deficits in Ca V 1 function play a vital role in cardiac and neurodevelopmental disorders. Yet conventional pharmacological approaches to upregulate Ca V 1 are limited, as excessive Ca 2+ influx leads to cytotoxicity. Here, we develop a genetically encoded enhancer of Ca V 1.2/1.3 channels (GeeC) to manipulate Ca 2+ entry in distinct physiological settings. Specifically, we functionalized a nanobody that targets the Ca V macromolecular complex by attaching a minimal effector domain from a Ca V enhancer-leucine rich repeat containing protein 10 (Lrrc10). In cardiomyocytes, GeeC evoked a 3-fold increase in L-type current amplitude. In neurons, GeeC augmented excitation-transcription (E-T) coupling. In all, GeeC represents a powerful strategy to boost Ca V 1.2/1.3 function in distinct physiological settings and, in so doing, lays the groundwork to illuminate new insights on neuronal and cardiac physiology and disease.

5-Year Outcomes After Bioresorbable Coronary Scaffolds Implanted With Improved Technique.

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were designed to improve late event-free survival compared with metallic drug-eluting stents. However, initial trials demonstrated worse early outcomes with BVS, in part due to suboptimal technique. In the large-scale, blinded ABSORB IV trial, polymeric everolimus-eluting BVS implanted with improved technique demonstrated noninferior 1-year outcomes compared with cobalt chromium everolimus-eluting stents (CoCr-EES). OBJECTIVES: This study sought to evaluate the long-term outcomes from the ABSORB IV trial. METHODS: We randomized 2,604 patients at 147 sites with stable or acute coronary syndromes to BVS with improved technique vs CoCr-EES. Patients, clinical assessors, and event adjudicators were blinded to randomization. Five-year follow-up was completed. RESULTS: Target lesion failure at 5 years occurred in 216 (17.5%) patients assigned to BVS and 180 (14.5%) patients assigned to CoCr-EES (P = 0.03). Device thrombosis within 5 years occurred in 21 (1.7%) BVS and 13 (1.1%) CoCr-EES patients (P = 0.15). Event rates were slightly greater with BVS than CoCr-EES through 3-year follow-up and were similar between 3 and 5 years. Angina, also centrally adjudicated, recurred within 5 years in 659 patients (cumulative rate 53.0%) assigned to BVS and 674 (53.3%) patients assigned to CoCr-EES (P = 0.63). CONCLUSIONS: In this large-scale, blinded randomized trial, despite the improved implantation technique, the absolute 5-year rate of target lesion failure was 3% greater after BVS compared with CoCr-EES. The risk period for increased events was limited to 3 years, the time point of complete scaffold bioresorption; event rates were similar thereafter. Angina recurrence after intervention was frequent during 5-year follow-up but was comparable with both devices.(Absorb IV Randomized Controlled Trial; NCT02173379).

Five-Year Follow-up after Transcatheter Repair of Secondary Mitral Regurgitation.

BACKGROUND: Data from a 5-year follow-up of outcomes after transcatheter edge-to-edge repair of severe mitral regurgitation, as compared with outcomes after maximal doses of guideline-directed medical therapy alone, in patients with heart failure are now available. METHODS: We randomly assigned patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy to undergo transcatheter edge-to-edge repair plus receive medical therapy (device group) or to receive medical therapy alone (control group) at 78 sites in the United States and Canada. The primary effectiveness end point was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk of death or hospitalization for heart failure, and safety, among other outcomes, were assessed through 5 years. RESULTS: Of the 614 patients enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of hospitalization for heart failure through 5 years was 33.1% per year in the device group and 57.2% per year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.41 to 0.68). All-cause mortality through 5 years was 57.3% in the device group and 67.2% in the control group (hazard ratio, 0.72; 95% CI, 0.58 to 0.89). Death or hospitalization for heart failure within 5 years occurred in 73.6% of the patients in the device group and in 91.5% of those in the control group (hazard ratio, 0.53; 95% CI, 0.44 to 0.64). Device-specific safety events within 5 years occurred in 4 of 293 treated patients (1.4%), with all the events occurring within 30 days after the procedure. CONCLUSIONS: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite guideline-directed medical therapy, transcatheter edge-to-edge repair of the mitral valve was safe and led to a lower rate of hospitalization for heart failure and lower all-cause mortality through 5 years of follow-up than medical therapy alone. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.).

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery.

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.

Sympathetic Nervous System Regulation of Cardiac Calcium Channels.

Calcium influx through voltage-gated calcium channels, Cav1.2, in cardiomyocytes initiates excitation-contraction coupling in the heart. The force and rate of cardiac contraction are modulated by the sympathetic nervous system, mediated substantially by changes in intracellular calcium. Norepinephrine released from sympathetic neurons innervating the heart and epinephrine secreted by the adrenal chromaffin cells bind to ß-adrenergic receptors on the sarcolemma of cardiomyocytes initiating a signaling cascade that generates cAMP and activates protein kinase A, the targets of which control calcium influx. For decades, the mechanisms by which PKA regulated calcium channels in the heart were not known. Recently, these mechanisms have been elucidated. In this chapter, we will review the history of the field and the studies that led to the identification of the evolutionarily conserved process.

Effect of mechanical unloading on genome-wide DNA methylation profile of the failing human heart.

Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about the epigenetic regulation of the noncoding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 patients with HF at LVAD implantation, 8 patients at LVAD explantation, and 7 nonfailing (NF) donors using a high-density bead array platform identified 2,079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in nonischemic cardiomyopathy (NICM). LVAD support resulted in normalization of 3.2% of HF-associated DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FBXO16, EFCAB13, and AKAP13) or hypermethylated and downregulated (TBX3) in HF. A potentially novel cardiac-specific super-enhancer long noncoding RNA (lncRNA) (LINC00881) is hypermethylated and downregulated in human HF. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown reduces peak calcium amplitude in the beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These data suggest that HF-associated changes in myocardial DNA methylation within coding and noncoding genomes are minimally reversible with mechanical unloading. Epigenetic reprogramming strategies may be necessary to achieve sustained clinical recovery from heart failure.

Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response.

Fight-or-flight responses involve ß-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for ß-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of ß-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel ß-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.

Bleeding and Ischemic Outcomes With Ticagrelor Monotherapy According to Body Mass Index.

BACKGROUND: There is a paucity of data regarding the safety and efficacy of different antiplatelet regimens according to standardized body mass index (BMI) categories. OBJECTIVES: The aim of this study was to investigate bleeding and ischemic outcomes according to BMI in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial. METHODS: The TWILIGHT trial randomized high-risk patients to ticagrelor plus aspirin or ticagrelor plus placebo at 3 months after percutaneous coronary intervention. In this secondary analysis, patients were stratified by standard BMI categories, as recommended by the European Society of Cardiology Working Group on Thrombosis (normal weight [BMI 18.5-24.99 kg/m2], overweight [BMI 25-29.99 kg/m2], and obese [BMI ≥30 kg/m2]) and by median BMI, as prespecified in the protocol. RESULTS: Among 7,038 patients randomized and with available BMI, 1,807 (25.7%) were normal weight, 2,927 (41.6%) were overweight, and 2,304 (32.7%) were obese. In normal-weight, overweight, and obese patients, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced the primary endpoint of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding (normal weight: HR: 0.48 [95% CI: 0.32-0.73]; overweight: HR: 0.57 [95% CI: 0.41-0.78]; obese: HR: 0.63 [95% CI: 0.44-0.91]; P for interaction = 0.627), without any increase in the composite ischemic endpoint of all-cause death, myocardial infarction, or stroke (normal weight: HR: 1.36 [95% CI: 0.84-2.19]; overweight: HR: 0.92 [95% CI: 0.63-1.35]; obese: HR: 0.84 [95% CI: 0.56-1.25]; P for interaction = 0.290). These findings were consistent with the prespecified analysis by median BMI. CONCLUSIONS: Among high-risk patients undergoing percutaneous coronary intervention, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced bleeding events without any increase in ischemic risk across different BMI categories.

Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.

Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of NaV1.5 inactivation results in a small persistent Na influx known as late Na current (I Na,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic I Na,L in an isoform-specific manner. This scheme suggests a complex orchestration of I Na,L in cardiomyocytes that may contribute to variable disease expressivity of NaV1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I Na,L with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I Na,L in pathophysiology and outline potential therapeutic avenues.

Polymer-Based Versus Polymer-Free Stents in High Bleeding Risk Patients: Final 2-Year Results From Onyx ONE.

BACKGROUND: Resolute Onyx polymer-based zotarolimus-eluting stents (ZES) were noninferior in safety and effectiveness to BioFreedom polymer-free biolimus A9-coated stents (DCS) in high-bleeding-risk (HBR) patients treated with 1-month dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) at 1 year. OBJECTIVES: This study reports the final 2-year results of the randomized Onyx ONE trial. METHODS: The Onyx ONE (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy (DAPT) for High-Bleeding Risk Patients) trial randomly assigned HBR patients to treatment with ZES or DCS. Following 1-month DAPT, event-free patients received SAPT (either aspirin or a P2Y12 inhibitor at physician discretion). The primary safety endpoint, a composite of cardiac death, myocardial infarction, or stent thrombosis at 1 year, was determined at 1 year. Rates of primary and secondary endpoints were calculated after final follow-up at 2 years. RESULTS: A total of 1,003 patients were randomly allocated to ZES and 993 patients to DCS. Follow-up was complete in 980 (97.7%) ZES patients and 962 (96.9%) DCS patients at 2 years. The primary safety endpoint occurred in 208 (21.2%) patients in the ZES group and 199 (20.7%) patients in the DCS group (risk difference: 0.5%; 95% CI: -3.1% to 4.2%; P = 0.78) at 2 years without significant differences in individual components of the composite endpoint. The secondary effectiveness endpoint occurred in 217 (22.1%) patients in the ZES group and 202 (21.0%) patients in the DCS group (risk difference: 1.1%; 95% CI: -2.5% to 4.8%; P = 0.54). CONCLUSIONS: Among patients at HBR treated with 1-month DAPT followed by SAPT, the Resolute Onyx polymer-based ZES had similar 2-year outcomes for the primary safety and secondary effectiveness endpoint compared with the BioFreedom polymer-free DCS. (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy [DAPT] for High-Bleeding Risk Patients [Onyx ONE]; NCT03344653).

Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.

Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C - encoding the CaV1.2 L-type voltage-gated Ca2+ channel - and increased Ca2+ signaling are associated with CAVD, whether increased Ca2+ influx through the druggable CaV1.2 causes CAVD is unknown. We confirmed the association between increased CaV1.2 expression and CAVD in surgically removed aortic valves from patients. We extended our studies with a transgenic mouse model that mimics increased CaV1.2 expression within aortic valve interstitial cells (VICs). In young mice maintained on normal chow, we observed dystrophic valve lesions that mimic changes found in presymptomatic CAVD and showed activation of chondrogenic and osteogenic transcriptional regulators within these valve lesions. Chronic administration of verapamil, a CaV1.2 antagonist used clinically, slowed the progression of lesion development in vivo. Exploiting VIC cultures, we demonstrated that increased Ca2+ influx through CaV1.2 drives signaling programs that lead to myofibroblast activation of VICs and upregulation of genes associated with aortic valve calcification. Our data support a causal role for Ca2+ influx through CaV1.2 in CAVD and suggest that early treatment with Ca2+ channel blockers is an effective therapeutic strategy.

Detecting Cardiovascular Protein-Protein Interactions by Proximity Proteomics.

Rapidly changing and transient protein-protein interactions regulate dynamic cellular processes in the cardiovascular system. Traditional methods, including affinity purification and mass spectrometry, have revealed many macromolecular complexes in cardiomyocytes and the vasculature. Yet these methods often fail to identify in vivo or transient protein-protein interactions. To capture these interactions in living cells and animals with subsequent mass spectrometry identification, enzyme-catalyzed proximity labeling techniques have been developed in the past decade. Although the application of this methodology to cardiovascular research is still in its infancy, the field is developing rapidly, and the promise is substantial. In this review, we outline important concepts and discuss how proximity proteomics has been applied to study physiological and pathophysiological processes relevant to the cardiovascular system.

Adrenergic Regulation of Calcium Channels in the Heart.

Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart.

Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current-induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.

Use of Proximity Labeling in Cardiovascular Research.

Protein-protein interactions are of paramount importance in regulating normal cardiac physiology. Methodologies to elucidate these interactions in vivo have been limited. Recently, proximity-dependent biotinylation, with the use of BioID, TurboID, and ascorbate peroxidase, has been developed to uncover cellular neighborhoods and novel protein-protein interactions. These cutting-edge techniques have enabled the identification of subcellular localizations of specific proteins and the neighbors or interacting proteins within these subcellular regions. In contrast to classic methods such as affinity purification and subcellular fractionation, these techniques add covalently bound tags in living cells, such that spatial relationships and interaction networks are not disrupted. Recently, these methodologies have been used to identify novel protein-protein interactions relevant to the cardiovascular system. In this review, we discuss the development and current use of proximity biotin-labeling for cardiovascular research.

Probing ion channel neighborhoods using proximity proteomics.

Protein-protein interactions are critically important for cellular functions, including regulation of ion channels. Ion channels are typically part of large macromolecular complexes that impact their function. These complexes have traditionally been elucidated via standard biochemical techniques including immunoprecipitation, pull-down assays and mass spectrometry. Recently, several methods have been developed to provide a more complete depiction of the microenvironment or "neighborhood" of proteins of interest. These new methods, which fall broadly under the category of proximity-dependent labeling techniques, aim to overcome the limitations imposed by antibody-based techniques and mass spectrometry. In this chapter, we describe the use of proximity labeling to elucidate the cardiac CaV1.2 macromolecular complex under basal conditions and after ß-adrenergic stimulation. Using these methodologies, we have identified the mechanism underlying adrenergic stimulation of the Ca2+ current in the heart.

3-Year Outcomes of Transcatheter Mitral Valve Repair in Patients With Heart Failure.

BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) resulted in fewer heart failure hospitalizations (HFHs) and lower mortality at 24 months in patients with heart failure (HF) with mitral regurgitation (MR) secondary to left ventricular dysfunction compared with guideline-directed medical therapy (GDMT) alone. OBJECTIVES: This study determined if these benefits persisted to 36 months and if control subjects who were allowed to cross over at 24 months derived similar benefit. METHODS: This study randomized 614 patients with HF with moderate-to-severe or severe secondary MR, who remained symptomatic despite maximally tolerated GDMT, to TMVr plus GDMT versus GDMT alone. The primary effectiveness endpoint was all HFHs through 24-month follow-up. Patients have now been followed for 36 months. RESULTS: The annualized rates of HFHs per patient-year were 35.5% with TMVr and 68.8% with GDMT alone (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.37 to 0.63; p < 0.001; number needed to treat (NNT) = 3.0; 95% CI: 2.4 to 4.0). Mortality occurred in 42.8% of the device group versus 55.5% of control group (HR: 0.67; 95% CI: 0.52 to 0.85; p = 0.001; NNT = 7.9; 95% CI: 4.6 to 26.1). Patients who underwent TMVr also had sustained 3-year improvements in MR severity, quality-of-life measures, and functional capacity. Among 58 patients assigned to GDMT alone who crossed over and were treated with TMVr, the subsequent composite rate of mortality or HFH was reduced compared with those who continued on GDMT alone (adjusted HR: 0.43; 95% CI: 0.24 to 0.78; p = 0.006). CONCLUSIONS: Among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite GDMT, TMVr was safe, provided a durable reduction in MR, reduced the rate of HFH, and improved survival, quality of life, and functional capacity compared with GDMT alone through 36 months. Surviving patients who crossed over to device treatment had a prognosis comparable to those originally assigned to transcatheter therapy. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]; NCT01626079).