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BACKGROUND: Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel–mediated neurogenic inflammatory cascade underlies ventricular remodeling–related mechanotransduction. METHODS: By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)–specific Piezo1 knockdown rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody–mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. RESULTS: Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron–specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron–specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. CONCLUSIONS: Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. Results: Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m2 and 63.8 ± 14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m2) (P=0.74). Median baseline (IQR) NT-proBNP was 51 pg/mL (20, 105 pg/mL) and 55 pg/mL (21, 132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=0.70) for systolic blood pressure, diastolic blood pressure and NT-proBNP, respectively. No clinically meaningful between group differences in LV volumes (diastolic and systolic indexed to baseline BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041. [ABSTRACT FROM AUTHOR]

Background: Differences in adverse cardiac remodeling between patients who have bicuspid (BAV) and tricuspid aortic valve (TAV) with severe isolated aortic stenosis (AS) and its prognostic impact after surgical aortic valve replacement remains unclear. We sought to investigate differences in preoperative diastolic and systolic function in patients with BAV and TAV who have severe isolated AS and the incidence of postoperative heart failure hospitalization and mortality. Methods: Two hundred seventy-one patients with BAV (n=152) or TAV (n=119) and severe isolated AS without coronary artery disease or other valvular heart disease, scheduled for surgical aortic valve replacement, were prospectively included. Comprehensive preoperative echocardiographic assessment of left ventricular (LV) diastolic and systolic function was performed. The heart failure events were registered during a mean prospective follow-up of 1260 days versus 1441 days for patients with BAV or TAV, respectively. Results: Patients with BAV had a more pronounced LV hypertrophy with significantly higher indexed LV mass ([LVMi] 134 g/m2 versus 104 g/m2, P <0.001), higher prevalence of LV diastolic dysfunction (72% versus 44%, P <0.001), reduced LV ejection fraction (55% versus 60%, P <0.001), significantly impaired global longitudinal strain (P <0.001), significantly higher NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P =0.007), and a higher prevalence of preoperative levosimendan treatment (P <0.001) than patients with TAV. LVMi was associated with diastolic dysfunction in both patients with BAV and TAV. There was a significant interaction between aortic valve morphology and LVMi on LV ejection fraction, which indicated a pronounced association between LVMi and LV ejection fraction for patients with BAV and lack of association between LVMi and LV ejection fraction for patients with TAV. Postoperatively, the patients with BAV required significantly more inotropic support (P <0.001). The patients with BAV had a higher cumulative incidence of postoperative heart failure admissions compared with patients with TAV (28.2% versus 10.6% at 6 years after aortic valve replacement, log-rank P =0.004). Survival was not different between patients with BAV and TAV (log-rank P =0.165). Conclusions: Although they were significantly younger, patients with BAV who had isolated severe AS had worse preoperative LV function and an increased risk of postoperative heart failure hospitalization compared with patients who had TAV. Our findings suggest that patients who have BAV with AS might benefit from closer surveillance and possibly earlier intervention. [ABSTRACT FROM AUTHOR]

Despite declines in heart failure morbidity and mortality with current therapies, rehospitalization rates remain distressingly high, substantially affecting individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. Because these events are highly interrelated, targeting a single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling. [ABSTRACT FROM AUTHOR]

Background--Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed. Methods and Results--Herein we report that glycogen synthase kinase-3β (GSK-3β) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a profibrotic myoibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3β. Mechanistically, GSK-3β inhibits profibrotic transforming growth factor-β1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling. Conclusions--These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes.Methods: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses.Results: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR.Conclusions: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: In patients with significant (moderate and severe) tricuspid regurgitation (TR), the decision to intervene is influenced by right ventricular (RV) size and function. RV remodeling in significant secondary TR has been underexplored. The aim of this study was to characterize RV remodeling in patients with significant secondary TR and to investigate its prognostic implications.Methods: RV remodeling was characterized by transthoracic echocardiography in 1292 patients with significant secondary TR (median age 71 [62-78]; 50% male). Four patterns of RV remodeling were defined according to the presence of RV dilation (tricuspid annulus≥40 mm) and RV systolic dysfunction (tricuspid annulus systolic excursion plane<17 mm): pattern 1, normal RV size and systolic function; pattern 2, dilated RV with preserved systolic function; pattern 3, normal RV size with systolic dysfunction; and pattern 4, dilated RV systolic dysfunction. The primary end point was all-cause mortality and the event rates were compared across the 4 patterns of RV remodeling.Results: A total of 183 (14%) patients showed pattern 1 RV remodeling; 256 (20%) showed pattern 2; 304 (24%) presented with pattern 3; and 549 (43%) had pattern 4 RV remodeling. Patients with pattern 4 RV remodeling were more frequently male; more often had coronary artery disease, worse renal function, and impaired left ventricular ejection fraction; and were more often symptomatic. Only 98 (8%) patients underwent tricuspid valve annuloplasty during follow-up. During a median follow-up of 34 (interquartile range, 0-60) months, 510 (40%) patients died. The 5-year survival rate was significantly worse in patients presenting with patterns 3 and 4 RV remodeling in comparison with pattern 1 (52% and 49% versus 70%; P=0.002 and P<0.001, respectively), and were independently associated with poor outcome on multivariable analysis.Conclusions: In patients with significant secondary TR, patients with RV systolic dysfunction have worse clinical outcome regardless of the presence of RV dilation. [ABSTRACT FROM AUTHOR]

Background-Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering. Methods and Results-Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n = 7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.3 with chordal cutting alone, 2.0±0.4 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r2=0.82, P<0.01). Conclusions-Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up [ABSTRACT FROM AUTHOR]

The article discusses therapeutic strategies that target cellular pathways governing left ventricular remodeling in the two major types of heart failure (HF). It looks at several advances in understanding of mechanisms underlying pathological ventricular remodeling. It also discusses several antiremodeling therapies, including inhibitors of the renin-angiotensin-aldosteron axis and lipid-lowering drugs.

Background: Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP.Methods: Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia).Results: Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, P<0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], P=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], P=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, P<0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], P=0.002) were associated with poor outcome.Conclusions: LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP. [ABSTRACT FROM AUTHOR]

Background--Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications. Methods and Results--We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. Conclusions--SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease. [ABSTRACT FROM AUTHOR]

Background: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI.Methods: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction.Results: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism.Conclusions: These data suggest that IDO could constitute a new therapeutic target during acute MI. [ABSTRACT FROM AUTHOR]

Background--We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR). Methods and Results--MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR + sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR + sildenafil versus 7.4±0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3+0.4 versus 10.5±0.2 versus 11.7+0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR + sildenafil group than in the MR group (70.2+2.2% for sham versus 67.0+4.2% for MR+sildenafil versus 58.9+2.5% for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR + sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR + sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR + sildenafil group. Conclusions--Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil. [ABSTRACT FROM AUTHOR]

Background--Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction associated with left ventricular (LV) dilatation and dysfunction, which doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response, with initial compensatory rise in prohypertrophic and antiapoptotic signals, followed by their exhaustion. We have shown that early MR repair 30 days after myocardial infarction is associated with LV reverse remodeling. It is not known whether MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesized that late repair will not result in LV reverse remodeling. Methods and Results--Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical myocardial infarction and implantation of an LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) versus sham (no repair). LV remodeling was assessed by 3-dimensional echocardiography, dP/dt, preload-recruitable stroke work, and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation, and reduced ejection fraction (all P<0.01 versus baseline, P=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6±5% versus 27±16% for late repair versus sham, P<0.01) but was not associated with changes in LV volumes (end-diastolic volume 106±15 versus 110±22 mL; end-systolic volume 35±6 versus 36±6 mL) or increases in preload-recruitable stroke work (41±7 versus 39±13 mL mm Hg) or dP/dt (803±210 versus 732±194 mm Hg/s) at 135 days (all P=NS). Activated Akt, central in the hypertrophic process, and signal transducer and activator of transcription 3 (STAT3), a critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups. Conclusions--Late correction of moderate volume overload after myocardial infarction did not improve LV volume or contractility. Upregulation of prohypertrophic intracellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a window of opportunity to repair ischemic MR after which no beneficial effect on LV is observed, despite successful repair. [ABSTRACT FROM AUTHOR]

Introduction: The heart undergoes extensive structural changes following myocardial infarction (MI). Beyond the loss of myocytes and influx of immune cells, significant changes to the composition of the extracellular matrix (ECM) occur. Coincident with these changes, production of hyaluronan (HA) increases after MI. HA production is regulated by hyaluronan synthases (HAS), which form HA, and hyaluronidases (HYAL), which cleave HA. Yet, neither changes in expression of HAS and HYAL genes nor specific biological actions HA in ventricular remodeling have been elucidated. Hypothesis: Because post-MI elevations in HA coincide with immune cell infiltration, we sought to elucidate the impact of HA composition [i.e., low molecular weight (LMW) and high molecular weight (HMW) HA] on macrophage function, and to characterize the impact of macrophage polarization on HA metabolism. Methods: Wild-type mice were subjected to MI. Cardiac tissue was harvested and analyzed for expression of HA metabolizing enzymes. To determine the sufficiency of HA in prompting an immunophenotype, naïve bone marrow-derived macrophages were exposed to LMW and HMW HA. To characterize the role of macrophage polarization per se on HA metabolism, macrophages were polarized to pro-inflammatory and reparative phenotypes. We also characterized the impact of HA on macrophage polarization by polarizing macrophages with or without HA. Results: MI reduced ejection fraction and fractional shortening (n=5, p<0.05). MI augmented expression of hyaluronan synthase 2 (HAS2; 10-fold, n=5, p<0.05) and hyaluronidases (2 to 4-fold, n=5, p<0.05). Exposing naïve macrophages to HMW HA provoked a pro-inflammatory phenotype, as indicated by an increase in mRNA levels of IL-1β, TNF-α, and IL-6 (2 to 10-fold, n=5, p<0.05). Conversely, treatment with LMW HA suppressed mRNA levels of TNF-α (0.5-fold, n=4, p<0.05). These results implicate HMW HA as pro-inflammatory and LMW HA as anti-inflammatory. Conclusions: MI upregulates HAS2 expression and induces HA synthesis. Considering the upregulation early after MI of enzymes to produce HMW HA, it stands to reason that such changes exaggerate the post-MI inflammatory response. Such changes may directly guide macrophage function and could impact ventricular remodeling. [ABSTRACT FROM AUTHOR]

BACKGROUND: Artificial intelligence–enhanced ECG analysis shows promise to detect ventricular dysfunction and remodeling in adult populations. However, its application to pediatric populations remains underexplored. METHODS: A convolutional neural network was trained on paired ECG–echocardiograms (≤2 days apart) from patients ≤18 years of age without major congenital heart disease to detect human expert–classified greater than mild left ventricular (LV) dysfunction, hypertrophy, and dilation (individually and as a composite outcome). Model performance was evaluated on single ECG–echocardiogram pairs per patient at Boston Children’s Hospital and externally at Mount Sinai Hospital using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS: The training cohort comprised 92377 ECG–echocardiogram pairs (46261 patients; median age, 8.2 years). Test groups included internal testing (12631 patients; median age, 8.8 years; 4.6% composite outcomes), emergency department (2830 patients; median age, 7.7 years; 10.0% composite outcomes), and external validation (5088 patients; median age, 4.3 years; 6.1% composite outcomes) cohorts. Model performance was similar on internal test and emergency department cohorts, with model predictions of LV hypertrophy outperforming the pediatric cardiologist expert benchmark. Adding age and sex to the model added no benefit to model performance. When using quantitative outcome cutoffs, model performance was similar between internal testing (composite outcome: AUROC, 0.88, AUPRC, 0.43; LV dysfunction: AUROC, 0.92, AUPRC, 0.23; LV hypertrophy: AUROC, 0.88, AUPRC, 0.28; LV dilation: AUROC, 0.91, AUPRC, 0.47) and external validation (composite outcome: AUROC, 0.86, AUPRC, 0.39; LV dysfunction: AUROC, 0.94, AUPRC, 0.32; LV hypertrophy: AUROC, 0.84, AUPRC, 0.25; LV dilation: AUROC, 0.87, AUPRC, 0.33), with composite outcome negative predictive values of 99.0% and 99.2%, respectively. Saliency mapping highlighted ECG components that influenced model predictions (precordial QRS complexes for all outcomes; T waves for LV dysfunction). High-risk ECG features include lateral T-wave inversion (LV dysfunction), deep S waves in V1 and V2 and tall R waves in V6 (LV hypertrophy), and tall R waves in V4 through V6 (LV dilation). CONCLUSIONS: This externally validated algorithm shows promise to inexpensively screen for LV dysfunction and remodeling in children, which may facilitate improved access to care by democratizing the expertise of pediatric cardiologists. [ABSTRACT FROM AUTHOR]

Introduction: While left atrial volume has been shown to be a powerful predictor of adverse outcomes, the significance of left atrial function (LAF) is not clear in patients with advanced ischemic cardiomyopathy (ICM). Methods: Patients with advanced ICM, who underwent cardiac magnetic resonance (CMR) between January 2002 and January 2013, were included in our study. Maximum and minimum left atrial volumes and left atrial ejection fraction were calculated using the biplane area-length method. A multivariable Cox proportional hazards model was used to evaluate the association of LAFwith all-cause mortality. Results: We evaluated 424 patients over a mean follow-up of 5.0 years, during which 143 patients died. The mean LA EF was 36.7 (16.0) [0.27 - 83.9]. On multivariable analysis, LA EF was a significant predictor of death (HR=0.97 [0.85,0.98], p <0.001), after adjusting for previously identified clinical predictors (See Table 2). Importantly, LA EF emerged as a more potent predictor than left atrial volume and severity of ischemic mitral regurgitation. Additionally, an interaction with left ventricular end systolic index (LVESVi) also emerged as a novel and significant predictor of adverse outcomes (See Figure 1). Conclusion: Decreasing LAF is a potent predictor of mortality in patients with advanced ICM. Furthermore, the risk of declining LAF is heightened in the setting of more advanced left ventricular remodeling and attenuated in the setting of smaller left ventricular size. [ABSTRACT FROM AUTHOR]

Introduction: Increased left ventricular (LV) mass and concentric remodeling (i.e. increased Mass (M): Volume (V) ratio) are important risk markers of heart failure (HF) with preserved ejection fraction (HFpEF). Pre-clinical (animal) data suggest cyclic GMP (cGMP) plays a central role in processes against maladaptive LV remodeling, but population data are lacking. Both nitric oxide and natriuretic peptide (NP) signaling regulate cGMP production. We evaluated whether plasma cGMP was associated with parameters of LV structure in a community cohort free of HF at baseline and if this was independent of N-terminal pro-B-type NP (NT-proBNP). Methods: We studied 610 men and 607 post-menopausal women aged between 45-84 years, enrolled in the Multi-Ethnic Study of Atherosclerosis, who had cGMP and cardiac MRI measures of LV structure assessed at baseline (2000-02). We performed multivariable adjusted linear regression for cross sectional analyses, to test the associations of plasma cGMP [log transformed, continuous, comparing the 90th vs the 10th percentile] with LV structural parameters. Results: Participants had mean (SD) age of 63 (8.6) years and mean (SD) cGMP level of 4.8 (2.6) pmol/mL. Higher cGMP levels were inversely associated with LV mass, M:V ratio, and LV mass indexed to body surface area, after adjusting for demographic, lifestyle and cardiovascular risk factors. (Table , Model 2, and Figure). There remained a statistically significant inverse relationship of cGMP with these LV parameters, even after further adjustment for NT-proBNP, which is upstream of cGMP production (Model 3). There was no statistically significant interaction by sex. Conclusion: Lower cGMP levels are associated with greater LV mass and M:V ratio. This suggests that relative cGMP deficiency may be a risk factor for concentric LV remodeling. These data provide rationale for the study of therapies that increase cGMP as a way to prevent LV remodeling and the development of HFpEF. [ABSTRACT FROM AUTHOR]

Introduction: Aortic stenosis (AS) may lead to left ventricular (LV) dysfunction with inadequate LV remodeling or may result in excessive LV hypertrophy. We hypothesized that circulatory Dickkopf-related protein 1 (DKK-1) as experimental regulator of myocardial repair could identify patients with a maladaptive LV response to AS. Maladaptive response may be defined by inadequate remodeling resulting in LV dysfunction or excessive hypertrophy. Methods: There were 53 adult patients demonstrated to have AS by echocardiogram or cardiac MRI completed between Jan 1st, 2016 and Dec 31st, 2017. Study patients were compared with 239 patients without AS. Patient and imaging data were collected. DKK-1 level was measured using Human DKK-1 quantikine ELISA kit. Values of DKK-1 were skewed, so non-parametric tests were used to determine the associations between DKK-1 and LV and AS parameters in echocardiography and cardiac MRI. Spearman's Rank Order Correlation, Wilcoxon Rank Sum Test, and analysis of variance (ANOVA) were used to assess associations. Results: Among the 53 patients with AS, 29 (54.7%) were mild, 6 (11.3%) were moderate, and 18 (34%) were severe as per standard imaging criteria. In the study group, 32 (60.4%) were male, 21 (39.6%) were female, with a mean age of 72.2 years (range 47-90). In patients with AS, the median DKK-1 was 427.57 pg/mL, mean LV ejection fraction was 48.07%, mean LV mass was 147.5 g, and mean LV mass index was 69.1 g/m2. There was a statistically significant inverse correlation between DKK-1 and LV ejection fraction (correlation coefficient -0.28, p<0.05) only in patients with AS. There was an inverse trend of a correlation between DKK-1 and LV mass and mass index (correlation coefficient -0.3 and -0.23, respectively). There was no association between the severity of AS (aortic valve area, maximum velocity, or mean pressure gradient) and the level of DKK-1. Conclusions: In conclusion, DKK-1 might be a predictor of a maladaptive response in AS patients. In patients with elevated DKK-1 level, there is an associated diminished myocardial repair and LV dysfunction. In patients with low DKK-1 level there is a trend towards the development of accentuated LV hypertrophy. Our findings support further prospective clinical investigations of DKK-1 and other Wnt-regulatory molecules in patients with AS in the future. [ABSTRACT FROM AUTHOR]

Introduction: Tetralogy of Fallot (TOF) accounts for 10% of congenital heart disease (CHD) and is an important cause of adverse right ventricular (RV) remodeling requiring surgical re-interventions. Clinical predictors of adverse RV remodeling are imprecise. Hypothesis: Genomic factors may predispose to adverse RV remodeling. Methods and Results: We performed whole genome sequencing in 513 non-syndromic surgically repaired TOF patients negative for 22q11del. Using an ACMG pipeline for variant interpretation, we identified pathogenic single nucleotide variants and copy number variants in genes involved in cardiac development, CHD and other cardiac disorders in 27.1% of the cohort. In a nested case-control analysis, we evaluated the association of rare and low-frequency protein-altering variants with risk of adverse RV remodeling using gene collapsing analysis and conducted a pathway enrichment analysis (Gene Set Enrichment Analysis). We defined cases as those with moderate/severe RV dysfunction/dilatation on cardiac imaging and/or requiring pulmonary valve replacement (PVR) (n=294), and controls as those with no/mild RV dilatation/dysfunction and no PVR (n=204). The analysis was adjusted for age at repair, age at last follow-up, sex, ethnicity, and transannular patch. The median age at TOF repair was 16 months (range:6-44), and the median age at PVR (n=159) was 24 years (range:16-38). Freedom from adverse RV remodeling was 87.4% (95% CI:83.7-90.2) and 57.3% (95% CI: 52.0-62.2) at 10 and 20 years respectively. Twenty-three genes were differentially enriched for potentially deleterious variants between cases and controls (p<0.001). Genes associated with cytoskeleton organization, inflammation, fatty acid metabolism were enriched for variants in cases. Genes involved in apoptosis signalling and growth processes were enriched for variants in controls. Conclusion: Whole genome sequencing identified pathways that contribute to adverse RV remodeling in TOF as well as pathways that are protective in TOF. Knowledge of genetic susceptibility may inform management strategies to preserve RV function in at risk patients as well as provide new pharmacological targets for developing drugs to promote RV adaptation. [ABSTRACT FROM AUTHOR]

Introduction: High-mobility group box 1 (HMGB1), a necrotic cell-derived damage-associated molecular-pattern protein molecule, reportedly enhances bone marrow mesenchymal stem cell (MSC) recruitment to damaged tissue for tissue regeneration. Hypothesis: We hypothesized that systemic HMGB1 administration suppress adverse LV remodeling in a rat heart failure with preserved ejection fraction (HFpEF) model. Methods: Eight Dahl salt-sensitive rats (6 weeks old) were fed a high-salt diet for 5 weeks. HMGB1 (3 mg/kg) or PBS (control; 3 ml/kg) was administered to HFpEF model rats for 4 days via femoral vein injection. LV hypertrophy and adverse remodeling was evaluated by ultrasonography, immunostaining, and RT-PCR. Results: Results: Six weeks after each administration, the LVEF were preserved between each group (HMGB1 vs control; 76±2 vs. 70±7%; n.s). The thickness of LV anterior wall was significantly shorter in HMGB1 group than in the control (2.4±0.2 vs. 2.9±0.3mm; p<0.01). The weight of the harvested heart and bilateral kidney were significantly heavier in the control than in HMGB1 group (heart; 1.5±0.04 vs. 2.0±0.02, bilateral kidney; 3.9±0.2 vs. 4.5±0.2g; p<0.05, p<0.05, respectively). LV remodeling exhibiting extracellular collagen deposition was significantly attenuated in HMGB1 group, unlike in control (fibrotic area; 2.0±0.8 vs. 4.6±2.3%; p<0.05), especially the tissue fibrosis was enhanced around the coronary arteries. QT-PCR analysis in each LV anterior wall demonstrated that HGF (3.4±1.6 vs. 2.0±0.9%; n.s) and TSG-6 mRNA expression (3.5±1.9 vs. 2.3±1.2%; n.s) tended to be higher in HMGB1 group compared to the control. The confocal-laser microscopy revealed that there were more CD90+/PDGFRα+ cells around the coronary artery in HMGB1 group unlike that in the control. Conclusions: Systemic HMGB1 administration reduced LV fibrosis in a HFpEF model rat, suggesting that HMGB1 administration might be a new therapeutic strategy for HFpEF. [ABSTRACT FROM AUTHOR]

Background: The protective effects of exogenous hydrogen sulfide (H2S) administration have been shown in ischemic heart failure and pressure overload-induced cardiomyopathy. However, current formulations are derived from inorganic salts, which have shortcomings in the precision and control of H2S release. In the current study, we sought to: A) determine if the novel, orally active, slow-releasing H2S donor, SG1002 that has completed a Phase I clinical trial attenuates left ventricular (LV) dysfunction following myocardial ischemia/reperfusion (I/R) injury, and B) evaluate the role of pro-angiogenic microRNA (miR)-126 in this protection. Methods and Results: After baseline echocardiography, adult male CD1 mice underwent myocardial infarction (MI) by left coronary artery ligation for 30 minutes followed by reperfusion for 28 days. Mice received either Na2S (100 μg/kg, ip) at the time of reperfusion as an induction dose followed by SG1002 in the diet to achieve a dosage of 40 mg/kg/day or volume-matched saline (vehicle) and regular chow as control throughout the study. Our results showed that SG1002 significantly preserved left ventricular ejection fraction (LVEF; Mean ± SEM) compared to vehicle-treated animals up to 28 days following MI (Fig. A). Interestingly, SG1002-treated mice also exhibited a significant increase in miR-126 levels 28 days post-MI compared to vehicle group (Fig. B). This finding was also paralleled with a significant increase in capillary density in the infarct region as determined by caveolin-1 staining (Fig. C). Conclusions: Our data suggest that SG1002 protects against MI-induced adverse LV remodeling and heart failure with reduced EF, possibly via induction of pro-angiogenic miR-126 and thus contributing to increased vascular density in the infarct region over time. We propose that SG1002 may offer therapeutic benefits to prevent adverse LV remodeling and ischemic heart failure following MI. [ABSTRACT FROM AUTHOR]

Introduction: Female hearts are less susceptible to injury following myocardial infarction (MI) likely due to estrogen working through the nitric oxide (NO) pathway. NO exerts effects largely via S-nitrosylation (S-NO) of cysteine thiols. Male mice with a targeted deletion of S-nitrosoglutathione reductase (GSNOR), a denitrosylase that regulates S-NO, have better outcomes after MI than controls. The outcomes of GSNOR-/- females, which exhibit greater nitrosative stress than GSNOR-/- males, is not known. Hypothesis: We hypothesized that female GSNOR-/- mice exhibit greater pathological remodeling, worsening left ventricular function, and increased oxidative stress and inflammation following MI. Methods: MI was induced in 3-5-month old male and female GSNOR-/- mice and controls (C57Bl/6J), via left anterior descending coronary artery occlusion (N=4-5). Serial echocardiography was performed prior to MI and 1,4 and 8-weeks post-MI to assess ejection fraction (EF) and left ventricular volumes both at diastole and systole. At 8 weeks, cardiomyocytes (CMs) were isolated and ROS generation (2',7'-dichlorofluorescein) and peroxynitrite (dihydrorhodamine 123) levels were determined by fluorescence. Macrophages were isolated from spleen. Pro-inflammatory markers, TNFα, IL1β and iNOS mRNA levels were determined by qRT-PCR. Results: GSNOR-/- females had greater (P<0.05), but GSNOR-/- males less (P<0.05) left ventricular dilation than controls at 8 weeks post-MI. EF was significantly worse in GSNOR-/- females (18 ± 2%) than GSNOR-/- males (29 ± 2%) at 8 weeks post-MI. In isolated CMs, ROS generation was ~4-fold greater (P<0.001) and peroxynitrite ~2-fold greater (P<0.05) in GSNOR-/- females. In isolated macrophages, TNFα, IL1β and iNOS mRNA levels were elevated (P<0.05) in GSNOR-/- female compared to GSNOR-/- male. Conclusions: The significantly lower EF and pathological remodeling of the LV volumes both at diastole and systole in GSNOR-/- females following MI are in part due to increased oxidative stress and inflammation. These data suggest that S-NO plays an important role in sex-specific cardiac protection following myocardial injury and suggest the importance of taking sex into account when exploring novel therapeutic treatments for myocardial injury. [ABSTRACT FROM AUTHOR]

Introduction: Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular outcomes. There is limited data about modifiable factors associated with progression of LV hypertrophy in the elderly. Hypothesis: The study aimed to describe the changes in LV mass and geometry over time in a predominantly elderly multiethnic cohort and to explore the relations between the change of LV mass and clinical variables. Methods: We analyzed data from participants in the Northern Manhattan Study (NOMAS) who underwent serial echocardiographic studies, comparing the baseline and the most recent echocardiograms. We recorded changes in LV mass and geometry and correlated them with baseline characteristics using linear regression models. Results: 826 participants (age: 64.2 ± 8.0 years) were included in the analysis (time between measurements: 8.5 ± 2.7 years). Overall, LV mass index increased from 45.0 ± 12.7 to 50.3 ± 14.6 g/m2.7 (p < 0.001). There were 548 (66.3%) participants with LV mass increase; 258 participants (31.2%) showed a worsening LV geometry (new hypertrophy pattern). Multivariable analysis showed that change in LV mass index was independently associated with baseline LV mass index (β estimate: -17.200, [standard error: 1.514], p < 0.001), hypertension (2.011 [0.822], p=0.015), body mass index (0.295 [0.133], p=0.027) and waist-to-height ratio (1.351 [0.642], p=0.036). Waste-to-height ratio remained significantly associated with LV mass increase even after adjustment for BMI (p=0.036) Conclusions: In the elderly, LV mass progresses over time. Central obesity indicators add prognostic value over BMI for risk of LV mass increase. [ABSTRACT FROM AUTHOR]

Introduction: Using speckle tracking echocardiography (STE), emerging attention is brought to left atrium (LA) that is very complex due to close coupling with left ventricle (LV). LA volume (LAV) and emptying function (LAEF) reflect diastolic function and may serve as a predictor for cardiovascular outcomes. We sought to examine the relation between LV and LA properties in hypertension (HTN) by 3-dimensional STE (3D-STE). Methods: We measured LAV, LAEF and LA strain and estimated LA stiffness in 58 controls (age 67±11), 60 HTN without hypertrophy (LVH-) (69±11), 76 LVH+ (70±11) and 102 hypertensive heart failure (HHF) {40 HF with preserved EF (HFpEF, 77±14) and 62 HF with reduced EF (HFrEF, 68±16)}. We measured LV mass, EF, strain and E/e'. Pulmonary capillary wedge pressure (PCWP) was calculated as 10.8 - 12.4 x log (active LAEF / minimum LAV) as we reported. We estimated Tau and LV end-diastolic stress as isovolumic relaxation time / (ln 0.9 x systolic BP - ln PCWP) and as PCWP x end-diastolic dimension / thickness. LV myocardial and LA chamber stiffness was estimated as LV stress / strain and as PCWP / LAV change. Results: There was no difference in BP among HTN. LVEF in HFrEF decreased associated with increased LV mass and systolic stress (LVEF: control; 67±6, LVH-; 69±6, LVH+; 67±9, HFpEF; 62±9, HFrEF; 38±8*%, *p<0.05 vs control). Tau was prolonged even in LVH- (35±13, 43±15*, 52±17*, 59±16*, 67±19*ms). Stiffness increased in HHF groups (LV stiffness: 0.6±0.3, 0.6±0.4, 0.6±0.3, 0.9±0.8*, 2.3±1.7*, LA stiffness: 0.3±0.1, 0.3±0.2, 0.4±0.2, 0.7±0.5*, 0.9±0.6*mmHg/ml) associated with increased PCWP and LV diastolic stress (PCWP: 7±3, 8±4, 9±4, 15±4*, 17±5*mmHg, diastolic stress: 11±4, 10±8, 11±7, 16±6*, 24±11*Kdynes/cm2). Total LAEF and LA strain gradually decreased from LVH- to HFrEF, whereas active LAEF decreased in HHF groups (36±10, 37±11, 34±10, 20±10*, 17±10*%) associated with increased PCWP and stiffness. On multivariate analysis, LV stiffness is an independent predictor for HHF among STE parameters. Conclusions: LA properties were significantly affected by LV diastolic remodeling by pressure overload. HFrEF has the most negative impact on LA properties. Noninvasive assessment of the relation between LA and LV properties by STE may have a clinical potential. [ABSTRACT FROM AUTHOR]

BACKGROUND: Progressive remodeling of cardiac gene expression underlies decline in cardiac function, eventually leading to heart failure. However, the major determinants of transcriptional network switching from normal to failed hearts remain to be determined. METHODS: In this study, we integrated human samples, genetic mouse models, and genomic approaches, including bulk RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, to identify the role of chromatin remodeling complex INO80 in heart homeostasis and dysfunction. RESULTS: The INO80 chromatin remodeling complex was abundantly expressed in mature cardiomyocytes, and its expression further increased in mouse and human heart failure. Cardiomyocyte-specific overexpression of Ino80, its core catalytic subunit, induced heart failure within 4 days. Combining RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, we revealed INO80 overexpression-dependent reshaping of the nucleosomal landscape that remodeled a core set of transcription factors, most notably the MEF2 (Myocyte Enhancer Factor 2) family, whose target genes were closely associated with cardiac function. Conditional cardiomyocyte-specific deletion of Ino80 in an established mouse model of heart failure demonstrated remarkable preservation of cardiac function. CONCLUSIONS: In summary, our findings shed light on the INO80-dependent remodeling of the chromatin landscape and transcriptional networks as a major mechanism underlying cardiac dysfunction in heart failure, and suggest INO80 as a potential preventative or interventional target. [ABSTRACT FROM AUTHOR]

Background: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.Methods: The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.Results: The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent P<1×10-8. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (P<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).Conclusions: We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling. [ABSTRACT FROM AUTHOR]

Background--Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. ethods and Results--Bone marrow cells from CD1 lc-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD1lc+ green fluorescent protein-positive DCs expressing CD1 lb and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-lß, interleukin-18, and tumor necrosis factor-&agr;, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6Chigh monocytes and F4/80+ CD206- M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6Clow monocytes and F4/80+ CD206+ macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group. Conclusions--These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis. [ABSTRACT FROM AUTHOR]

Background: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE).Methods: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks.Results: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT.Conclusions: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. [ABSTRACT FROM AUTHOR]