Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial ...paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.
Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in ...COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown.
ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days.
Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was -16.8% (interquartile range, -45.7 to 36.8;
=0.41) with rNAPc2 treatment and -11.2% (-36.0 to 34.4;
=0.91) with heparin (
=0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% -14.9 to 145.2;
=0.02) than the rNAPc2 group (median, 25.9% -49.1 to 136.4;
=0.14;
=0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, -32.7% -44.7 to 4.3;
=0.007 and heparin median, -16.8% -36.0 to 0.5;
=0.008,
=0.34).
rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8.
URL: https://www.
gov; Unique identifier: NCT04655586.
Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of ...heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline.
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death ("death") until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55-4.10; P<0.001) and a doubling (or more) of risk with left ventricular mass at the mean value or lower (P for interaction=0.05).
RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline.
The factors that determine the risk for sudden death or implantable cardioverter defibrillator therapy in patients receiving cardiac resynchronization therapy (CRT) therapies are largely unknown.
We ...hypothesized that clinical measures of heart failure severity and the presence of comorbid conditions would predict the risk of malignant arrhythmias in the 1520 patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Outcomes in the CRT group after implantable cardioverter defibrillator therapy were also evaluated. The CRT-defibrillator device reduced the risk of sudden death by 56% compared with drug therapy (17 of 595 2.9% versus 18 of 308 5.8%, P<0.02). CRT therapy was not associated with sudden death risk reduction (48 of 617 7.8%). Other factors associated with reduced sudden death risk were left ventricular ejection fraction >20% (HR, 0.55 95% CI, 0.35 to 0.87; P=0.01), QRS duration >160 ms (HR, 0.63 95% CI, 0.40 to 0.997; P=0.05), and female gender (HR, 0.56 95% CI, 0.34 to 0.94; P=0.003). The risk for sudden death was increased by advanced New York Heart Association class IV heart failure (HR, 2.62 95% CI, 1.61 to 4.26; P<0.011) and renal dysfunction (HR, 1.69 95% CI, 1.06 to 2.69; P=0.03). An appropriate shock was experienced in 88 (15%) of the 595 CTR-D patients. In the CRT-defibrillator patients, female gender (HR, 0.54 95 % CI, 0.31 to 0.94; P=0.03) and use of neurohormonal antagonists were associated with reduced risk. Class IV heart failure status increased risk. Appropriate implantable cardioverter defibrillator therapy was positively associated with risk of death or all-cause hospitalization (HR, 1.57; P<0.002), pump failure death or hospitalization (HR, 2.35; P<0.001), and sudden death (HR, 2.99; P=0.03), but not total mortality (HR, 1.3; P=0.28).
In CRT candidates, sudden cardiac death risk is associated with higher New York Heart Association class and renal dysfunction. In CRT-defibrillator recipients, reduction in the risk of an appropriate shock is associated with medical therapy with neurohormonal antagonists, female gender, and New York Heart Association functional class III versus IV clinical status. Shock therapy was associated with worse outcome.
Antiadrenergic treatment is currently an emerging and very promising approach to the treatment of chronic heart failure. Although the adrenergic nervous system can be pharmacologically inhibited at ...multiple levels, it is the use of receptor-blocking agents that has generated the most interest and provided the most data for the “proof of concept” of this approach. In part because antiadrenergic treatment of chronic heart failure has developed in an atmosphere in which it was initially considered to be contraindicated (i.e., before Phase III clinical trials could be initiated), a large body of hypothesis-driven basic and clinical investigation was required to define the overall rationale and demonstrate feasibility. This article will review these data and propose a single primary mechanism of action to explain most of the clinical benefits of these agents.
In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, 1520 patients with advanced heart failure were assigned in a 1:2:2 ratio to optimal pharmacological ...therapy or optimal pharmacological therapy plus cardiac resynchronization therapy (CRT-P) or CRT with defibrillator (CRT-D). Use of CRT-P and CRT-D was associated with a significant reduction in combined risk of death or all-cause hospitalizations. Because mortality also was significantly reduced (optimal pharmacological therapy versus CRT-D only), an assessment of the true reduction in hospitalization rates must consider the competing risk of death and varying follow-up times.
To overcome the challenges of comparing treatment groups, we used a nonparametric test of right-censored recurrent events that accounts for multiple hospital admissions, differential follow-up time between treatment groups, and death as a competing risk. An end-point committee adjudicated and classified all hospitalizations. Compared with optimal pharmacological therapy, CRT-P and CRT-D were associated with a 21% and 25% reduction in all-cause, 34% and 37% reduction in cardiac, and 44% and 41% reduction in heart failure hospital admissions per patient-year of follow-up, respectively. Similar reductions were seen in hospitalization days per patient-year. The reduction in hospitalization rate for heart failure in the CRT groups appeared within days of randomization and remained sustained. Noncardiac hospitalization rates were not different between groups.
Use of CRT with or without a defibrillator in advanced heart failure patients was associated with marked reductions in all-cause, cardiac, and heart failure hospitalization rates in an analysis that accounted for the competing risk of mortality and unequal follow-up time.
The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration. In this study, cardiolipin molecular species and cytochrome oxidase (COx) activity were studied in ...interfibrillar (IF) and subsarcolemmal (SSL) cardiac mitochondria from Spontaneously Hypertensive Heart Failure (SHHF) and Sprague-Dawley (SD) rats throughout their natural life span. Fisher Brown Norway (FBN) and young aortic-constricted SHHF rats were also studied to investigate cardiolipin alterations in aging versus pathology. Additionally, cardiolipin was analyzed in human hearts explanted from patients with dilated cardiomyopathy. A loss of tetralinoleoyl cardiolipin (L4CL), the predominant species in the healthy mammalian heart, occurred during the natural or accelerated development of heart failure in SHHF rats and humans. L4CL decreases correlated with reduced COx activity (no decrease in protein levels) in SHHF cardiac mitochondria, but with no change in citrate synthase (a matrix enzyme) activity. The fraction of cardiac cardiolipin containing L4CL became much lower with age in SHHF than in SD or FBN mitochondria. In summary, a progressive loss of cardiac L4CL, possibly attributable to decreased remodeling, occurs in response to chronic cardiac overload, but not aging alone, in both IF and SSL mitochondria. This may contribute to mitochondrial respiratory dysfunction during the pathogenesis of heart failure.
Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no ...previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for
Arg389Gly and Ser49Gly,
Gln27Glu and Gly16Arg, and
Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (
<0.05) reduced association with incident VF, and none was associated with increased VF risk except for
Gly389 homozygotes in the subset of patients not receiving β-blockers.
Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the
322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both
Gly49 carriers (OR, 0.67 0.56-0.80) and
Del carriers (OR, 0.57 0.45- 0.71) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles
Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and β-arrestin interactions leading to cardioprotective biased signaling, and
Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.
Abnormalities in Ca
homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca
homeostasis in cardiomyocytes. Alternative splicing of a single
gene ...produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by
exons 1 to 8. In humans, mutations in the
gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive.
We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for
, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the
gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on
knockout mice to assess the role of
in cardiac arrhythmogenesis, as assessed by ECG. Ca
transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which
regulates cardiac function and triadin levels in the heart.
We report that
maintains cardiac function, at least in part, by regulating alternative splicing of the
gene. Knockout of
in mice downregulates cardiac triadin, impairs Ca
handling, and causes premature death.
knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in
knockout cardiomyocytes is sufficient to restore Ca
handling. Last,
colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to
precursor mRNA.
These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.
Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
We hypothesized that sex hormones would be associated with RV morphology in a large ...cohort free of cardiovascular disease.
Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Higher estradiol levels were associated with higher RVEF (β per 1 lnnmol/L, 0.88; 95% confidence interval CI, 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 lnnmol/L, -0.87; 95% CI, -1.67 to -0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 lnnmol/L, 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 lnnmol/L, 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 lnnmol/L, 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
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