Objectives We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle ...anomalies enrolled in the Single Ventricle Reconstruction trial. Methods Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality. Results Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations. Conclusions Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization.
Abstract
Aims
To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium.
Methods and results
Hand1 is expressed within the cardiomyocytes ...of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5–13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure.
Conclusion
Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development.
Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor. Transcatheter mitral-valve repair may improve their clinical outcomes.
At ...78 sites in the United States and Canada, we enrolled 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. Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up. The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 88.0%.
Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval CI, 0.40 to 0.70; P<0.001). The rate of freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001).
Among 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, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079 .).
Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological ...activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.
Summary Background Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, ...patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. Methods We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. Findings In the placebo group, patients with the highest heart rates (≥87 beats per min bpm, n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio HR 2·34, 95% CI 1·84–2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352). Interpretation Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. Funding Servier, France.
Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in ...mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.
Aims
Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as ...conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2-5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen-inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop.
Methods and results
Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na+ channel pore-forming α-subunit (Nav1.5-α), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection.
Conclusion
Nkx2-5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes.
Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS ...complex, which suggests the potential usefulness of CRT in such patients.
We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure.
On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval CI, 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02).
In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).
The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients ...with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes
. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer
. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.
PDF
