- Regenerative Potential of Neonatal Porcine Hearts. [Journal Article]
- CircCirculation 2018 Jul 20
- Background -Rodent hearts can regenerate myocardium lost to apical resection or myocardial infarction for up to 7 days after birth, but whether a similar window for myocardial regeneration also exis...
Background -Rodent hearts can regenerate myocardium lost to apical resection or myocardial infarction for up to 7 days after birth, but whether a similar window for myocardial regeneration also exists in large mammals is unknown. Methods -Acute myocardial infarction (AMI) was surgically induced in neonatal pigs on postnatal days 1, 2, 3, 7, and 14 (i.e., the P1, P2, P3, P7, and P14 groups, respectively). Cardiac systolic function was evaluated before AMI and at 30 days post AMI via transthoracic echocardiography. Cardiomyocyte cell cycle activity was assessed via immunostaining for proliferation and mitosis markers, infarct size was evaluated histologically, and telomerase activity was measured by quantitative PCR. Results -Systolic function at day 30 post- AMI was largely restored in P1 animals and partially restored in P2 animals, but significantly impaired when AMI was induced on postnatal day 3 or later. Hearts of P1 animals showed little evidence of scar formation or wall thinning on day 30 after AMI, with increased measures of cell-cycle activity seen six days after AMI (i.e. postnatal day 7) compared to postnatal day 7 in noninfarcted hearts. Conclusions -The neonatal porcine heart is capable of regeneration following AMI during the first 2 days of life. This phenomenon is associated with induction of cardiomyocyte proliferation, and is lost when cardiomyocytes exit cell cycle shortly after birth.
- Early Regenerative Capacity in the Porcine Heart. [Journal Article]
- CircCirculation 2018 Jul 20
- Background -The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) prolife...
Background -The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown if hearts of young large mammals can regenerate. Methods -We examined the regenerative capacity of the pig heart in neonatal animals (ages: 2, 3 or 14 days postnatal) after myocardial infarction (MI) or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry and Western blotting were performed to study cell proliferation, sarcomere dynamics and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. Results -After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls and did not recover function. Genome wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day old animals that was absent in 2-day old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the MI showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Conclusions -Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.
- Preoperative Predictors of Death and Sustained Ventricular Tachycardia After Pulmonary Valve Replacement in Patients with Repaired Tetralogy of Fallot Enrolled in the INDICATOR Cohort. [Journal Article]
- CircCirculation 2018 Jul 20
- Background -Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot (rTOF) before pulmonary valve replacement (PVR). However, pre-PVR predictors...
Background -Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot (rTOF) before pulmonary valve replacement (PVR). However, pre-PVR predictors for post-PVR sustained ventricular tachycardia (VT) and death have not been identified. Methods -Patients with rTOF enrolled in the INDICATOR cohort-a 4-center international cohort study- who had a comprehensive preoperative evaluation and subsequently underwent PVR were included. Pre-procedural clinical, electrocardiogram, cardiovascular magnetic resonance (CMR), and postoperative outcome data were analyzed. Cox proportional hazards multivariable regression analysis was used to evaluate factors associated with time from pre-PVR CMR until the primary outcome-death, aborted sudden cardiac death, or sustained VT. Results -Of the 452 eligible patients (median age at PVR 25.8 years), 36 (8%) reached the primary outcome (27 deaths, 2 resuscitated death, and 7 sustained VT) at a median time after PVR of 6.5 years. Cox proportional hazards regression identified pre-PVR right ventricular (RV) ejection fraction < 40% (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.18 to 4.85; P = 0.02), RV mass-to-volume ratio ≥ 0.45 g/mL (HR 4.08; 95%, CI 1.57 to 10.6; P = 0.004), and age at PVR ≥ 28 years (HR 3.10; 95% CI 1.42 to 6.78; P = 0.005) as outcome predictors. In a subgroup analysis of 230 patients with Doppler data, predicted RV systolic pressure ≥40 mm Hg was associated with the primary outcome (HR 3.42; 95% CI 1.09 to 10.7; P = 0.04). Preoperative predictors of a composite secondary outcome-postoperative arrhythmias and heart failure-included older age at PVR, pre-PVR atrial tachyarrhythmias, and a higher left ventricular end-systolic volume index. Conclusions -In this observational investigation of patients with rTOF, an older age at PVR and pre-PVR RV hypertrophy and dysfunction were predictive of shorter time to postoperative death and sustained VT. These findings may inform the timing of PVR if confirmed by prospective clinical trials.
- Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition: A Translational Study in the Dog and Rabbit. [Journal Article]
- CircCirculation 2018 Jul 20
- Background -Phosphodiesterase type-1 (PDE1) hydrolyzes cyclic AMP and cGMP and is constitutively expressed in the heart, though cardiac effects from its acute inhibition in vivo are largely unknown....
Background -Phosphodiesterase type-1 (PDE1) hydrolyzes cyclic AMP and cGMP and is constitutively expressed in the heart, though cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly express PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs and rabbits, in normal and failing hearts, and explored its regulatory pathways. Methods -Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously ± dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of beta-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left-ventricular myocytes. Results -In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to beta-adrenergic receptor (β-AR) agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbit, β-AR-blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-AR agonism (isoproterenol) or PDE3 inhibition (cilostamide, CIL) increased both. Unlike CIL, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only CIL increased calcium transients. Conclusions -PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via beta-AR receptors or PDE3 modulation. ITI-214, which has completed Phase I trials, may provide a novel therapy for HF.
- Ventricular Arrhythmias Underlie Sudden Death in Rats With Heart Failure and Preserved Ejection Fraction. [Journal Article]
- CACirc Arrhythm Electrophysiol 2018; 11(8):e006452
- CONCLUSIONS: In this rat model with phenotypically verified HFpEF, sudden death was common and generally associated with VA. Further clinical studies are warranted to determine whether these insights translate to sudden death in HFpEF patients.
- QTc Interval and Risk of Cardiac Events in Adults With Anorexia Nervosa: A Long-Term Follow-Up Study. [Journal Article]
- CACirc Arrhythm Electrophysiol 2018; 11(8):e005995
- CONCLUSIONS: Overall, there was no difference in mean QTc interval or risk of prolonged QTc between AN patients and healthy controls. However, AN patients had a notably increased all-cause mortality, as well as an increased risk of cardiac events, which was not related to the baseline QTc interval.
- Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction - The Randomized SHOCK-COOL Trial. [Journal Article]
- CircCirculation 2018 Jul 19
- Background -Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock following acute myocardial infarction. The objective of this study was to inves-tigate ...
Background -Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock following acute myocardial infarction. The objective of this study was to inves-tigate hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. Methods -Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary in-tervention without classical indication for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 h or control. The primary endpoint was cardiac power index at 24 h; secondary endpoints included other hemodynamic parameters as well as serial measurements of arterial lactate. Results -No relevant differences were observed for the primary endpoint cardiac power index at 24 h (mild therapeutic hypothermia vs. control: 0.41 [interquartile range 0.31-0.52] vs. 0.36 [inter-quartile range 0.31-0.48] W/m2; p=0.50, median difference -0.025 [95% confidence interval -0.12 to 0.06 W/m2]). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8 and 10 hours were significantly higher in patients in the MTH group with a slower decline (p for interaction 0.03). There were no differences in 30-day mortality: (60 vs. 50%, hazard ratio 1.27 [95% confidence interval 0.55-2.94]; p=0.55). Conclusions -In this randomized trial mild therapeutic hypothermia failed to show a substantial beneficial effect in patients with cardiogenic shock after acute myocardial infarction on cardiac power index at 24 h. Clinical Trial Registration -URL: www.clinicaltrials.gov Unique Identifier: NCT01890317.
- Cardiomyopathy and Preeclampsia: Shared Genetics? [Journal Article]
- CircCirculation 2018 Jul 18
- Background -Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations cau...
Background -Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations causing idiopathic CM were recently implicated in peripartum CM. We sought to determine whether CM gene mutations are also a contributory factor in PE. Methods -Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of PE completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing (WES) was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with CM. Missense variants were deemed "damaging missense" if so classified by any of 7 standard function prediction algorithms. Variants were defined as "loss-of-function" if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from two control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium (ExAC). PE was not excluded in control groups. Results -Of 181 subjects with confirmed PE, 96% were Caucasian. 72% had ≥1 preterm PE delivery <37 weeks. Among PE subjects, WES demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 CM genes considered. The prevalence of these loss-of-function variants was significantly higher in PE subjects (5.5%) compared to the local control (2.5%) population (p=0.014). 68% of women with PE carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum CM, most mutations (55%) were found in the TTN gene. 73% of PE subjects had TTN mutations in PE cohort versus 48% in local controls (p=1.36E-11). Conclusions -Women who develop PE are more likely to carry protein-altering mutations in genes associated with CM, particularly in TTN. Mutations promoting CM are prevalent in PE, idiopathic CM, and peripartum CM, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
- Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence - Prospective Data from the Women's Health Study. [Journal Article]
- CircCirculation 2018 Jul 18
- Background -Despite strong and consistent prospective associations of elevated low-density lipoprotein-cholesterol (LDL-C) concentration with incident coronary and cerebrovascular disease (CCVD), da...
Background -Despite strong and consistent prospective associations of elevated low-density lipoprotein-cholesterol (LDL-C) concentration with incident coronary and cerebrovascular disease (CCVD), data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle concentration (LDL-P), rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein-cholesterol (HDL-C) may be the primary lipid driver of PAD risk. Methods -The study population was a prospective cohort study of 27,888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations as well as nuclear magnetic resonance (NMR) spectroscopy-derived lipoprotein measures were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization. Results -In age-adjusted analyses, while LDL-C was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very low-density lipoprotein particle subclasses (VLDL-P), increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle concentration (HDL-P) (all P for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (HRadj 2.03; 95% CI, 1.14 to 3.59), small LDL-P [HRadj 2.17 (1.10 to 4.27)], very large VLDL-P (HRadj 1.68 (1.06 to 2.66)], medium VLDL-P (HRadj 1.98 (1.15 to 3.41)], and TC:HDL-C [HRadj, 3.11 (1.67 to 5.81)]. HDL was inversely associated with risk; HRadj for extreme tertiles of HDL-C and HDL-P were 0.30 (P-trend <0.0001) and 0.29 (P-trend <0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident CCVD. Finally, the addition of LDL-P and HDL-P to TC:HDL-C measures identified women at heightened PAD risk. Conclusions -In this prospective study, NMR-derived measures of LDL particle concentration, but not LDL-C, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and NMR-derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to CCVD. Clinical Trial Registration -URL: http://clinicaltrials.gov Unique Identifier: NCT00000479.
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- Temporal Trends in Contemporary Use of Ventricular Assist Devices by Race and Ethnicity. [Journal Article]
- CHCirc Heart Fail 2018; 11(8):e005008
- CONCLUSIONS: From 2012 to 2015, VAD implantation rates increased among African-Americans but not other racial/ethnic groups. The greatest increase in rate was observed among middle-aged African-American men, suggesting a decline in racial disparities. Further investigation is warranted to reduce disparities among women and older racial/ethnic minorities.