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One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Among patients with heart failure and a reduced ejection fraction, those who received the cardiac myosin activator omecamtiv mecarbil had a lower incidence of a composite of heart-failure events or cardiovascular death at a median of 22 months than those who received placebo.

Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation.

Allogenic induced pluripotent stem cell-derived cardiomyocytes transplanted directly into infarcted cynomolgus monkey hearts show electrical coupling with host cardiomyocytes improve cardiac contractile function after mild immunosuppression. Stem cells rescue heart attack in a primate model Yuji Shiba et al . report that, using mild immunosuppression, allogenic iPSC-derived cardiomyocytes transplanted directly into infarcted non-human primate hearts can engraft and survive. The engrafted cells electrically couple with host cardiomyocytes and improve cardiac contractile function. Arrhythmias, seen in a previous study of embryonic stem cell-derived cardiomyocyte transplantation into non-human primate hearts, were also seen here, cautioning that further research to control post-transplant arrhythmias is needed before this stem cell therapy can be translated to the clinic. Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy 1 , few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey ( Macaca fascicularis ), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes as assessed by use of the fluorescent calcium indicator G-CaMP7.09. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to vehicle-treated controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

•T3 replacement therapy was safe.•T3 replacement therapy improved regional contractile dysfunction.•T3 replacement therapy has a potential cardioprotective benefit. The aim of the study was to investigate whether TH replacement therapy is safe and impact infarct size, left ventricular (LV) volumes and function in patients with acute myocardial infarction (AMI) and low T3 syndrome (LT3S). Thirty-seven AMI/LT3S patients were randomly treated or untreated with liothyronine (T3) therapy (maximum dosage 15 mcg/m2/die) in addition to standardized treatment (T3-treated group, n = 19; untreated group, n = 18). TH and thyroxine (TSH) during hospital stay and at 1-month and 6 months were evaluated. At discharge and at 6 months LV volumes, ejection fraction, wall motion score index (WMSI) and infarct extent were measured by cardiac MR. T3-treated patients had a significant increase in fT3 (p = 0.003 and p <0.001) at discharge and 1-month. These patients had no signs or symptoms of hyperthyroidism or arrhythmias. At follow-up, there was a significant reduction in WMSI in both groups (T3-treated group: Δ = −0.12, p = 0.001; untreated group: Δ = −0.04, p = 0.04) and the difference value (discharge/follow-up) was significantly higher in T3-treated group than in untreated group (mean difference between groups = 0.08, 95% confidence interval [CI]: 0.01 to 0.15, p = 0.05). Also, stroke volume increased significantly in the T3-treated group (Δ = 3.4, 95% CI: 0.8 to 6, p <0.01) at follow-up. In conclusion, this is the first pilot experience in which T3 replacement therapy resulted safe and able to improve regional dysfunction in patients with STEMI/LT3S.

Abstract Rationale Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility. Objectives To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV–arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP). Methods We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure–volume loop analysis. Measurements and Main Results Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate. Conclusions In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Human iPS cell (iPSC)-derived cardiomyocytes (CMs) hold promise for drug discovery for heart diseases and cardiac toxicity tests. To utilize human iPSC-derived CMs, the establishment of three-dimensional (3D) heart tissues from iPSC-derived CMs and other heart cells, and a sensitive bioassay system to depict physiological heart function are anticipated. We have developed a heart-on-a-chip microdevice (HMD) as a novel system consisting of dynamic culture-based 3D cardiac microtissues derived from human iPSCs and microelectromechanical system (MEMS)-based microfluidic chips. The HMDs could visualize the kinetics of cardiac microtissue pulsations by monitoring particle displacement, which enabled us to quantify the physiological parameters, including fluidic output, pressure, and force. The HMDs demonstrated a strong correlation between particle displacement and the frequency of external electrical stimulation. The transition patterns were validated by a previously reported versatile video-based system to evaluate contractile function. The patterns are also consistent with oscillations of intracellular calcium ion concentration of CMs, which is a fundamental biological component of CM contraction. The HMDs showed a pharmacological response to isoproterenol, a β-adrenoceptor agonist, that resulted in a strong correlation between beating rate and particle displacement. Thus, we have validated the basic performance of HMDs as a resource for human iPSC-based pharmacological investigations.

Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m 2 doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m 2 dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: −0·82, 95% CI −1·31 to −0·33; end-systolic dimension: 0·57, 0·21–0·93) but not for those who also received dexrazoxane (−0·41, −0·88 to 0·06; 0·15, −0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46–0·48) and thickness-to-dimension ratio (0·66, 0·64–0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24–2·11), but not in boys (−0·10, −0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44–1·85), but not in boys (0·19, −0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3–12·1), event-free survival was 77% (95% CI 67–84) for children in the doxorubicin-alone group, and 76% (67–84) for children in the doxorubicin plus dexrazoxane group (p=0·99). Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

The RNA-binding protein QKI belongs to the hnRNP K-homology domain protein family, a well-known regulator of pre-mRNA alternative splicing and is associated with several neurodevelopmental disorders. Qki is found highly expressed in developing and adult hearts. By employing the human embryonic stem cell (hESC) to cardiomyocyte differentiation system and generating QKI-deficient hESCs (hESCs- QKI del ) using CRISPR/Cas9 gene editing technology, we analyze the physiological role of QKI in cardiomyocyte differentiation, maturation, and contractile function. hESCs- QKI del largely maintain normal pluripotency and normal differentiation potential for the generation of early cardiogenic progenitors, but they fail to transition into functional cardiomyocytes. In this work, by using a series of transcriptomic, cell and biochemical analyses, and the Qki-deficient mouse model, we demonstrate that QKI is indispensable to cardiac sarcomerogenesis and cardiac function through its regulation of alternative splicing in genes involved in Z-disc formation and contractile physiology, suggesting that QKI is associated with the pathogenesis of certain forms of cardiomyopathies. RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.