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Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [ABSTRACT FROM AUTHOR]

Objectives: Considering the recent discovery of postconditioning, we investigated whether intermittent dyssynchrony immediately upon reperfusion induces cardioprotection as well. Background: Intermittent dyssynchrony, induced by ventricular pacing, preconditions myocardium. Methods: Isolated ejecting rabbit hearts were subjected to 30-min coronary occlusion and 2-h reperfusion. Control, left ventricular (LV) pacing preconditioning (LVPpreC) (3 × 5-min LV pacing), and LV pacing postconditioning (LVPpostC) (10 × 30-s LV pacing during early reperfusion) groups were studied. Mechanical effects of LV pacing were determined using local pressure-length loops (sonomicrometry), whereas effects on myocardial lactate release and coronary flow were assessed from coronary effluent and fluorescent microspheres, respectively. Anesthetized pigs underwent 60-min coronary occlusion and 3-h reperfusion in control and right ventricular (RV) pacing postconditioning groups (RVPpostC) (10 × 30-s RV pacing during early reperfusion). In all hearts, area at risk and infarct size were determined with blue dye and triphenyltetrazolium chloride staining, respectively. Results: Infarct size, normalized to area at risk, was 47.0 ± 12.3% in control rabbit hearts, but significantly smaller in LVPpreC (17.8 ± 6.4%) and LVPpostC hearts (17.9 ± 4.4%). Left ventricular pacing significantly altered regional mechanical work, but did not affect coronary flow or lactate release. In pigs, infarct size was significantly smaller in RVPpostC (9.8 ± 3.0%) than in control (20.6 ± 2.2%) animals. Conclusions: Intermittent dyssynchrony during early reperfusion reduces infarct size in 2 different animal models. Dyssynchrony-induced postconditioning cannot be attributed to graded reperfusion but may be induced by modulation of local myocardial workload. Dyssynchrony-induced postconditioning opens new possibilities for cardioprotection in the clinical setting. [Copyright &y& Elsevier]

Objectives: This study evaluated the safety and efficacy of inhaled treprostinil as add-on therapy to oral bosentan in patients with pulmonary arterial hypertension (PAH). Background: The addition of a long-acting prostacyclin analogue via the inhaled route might be a safe and effective strategy to optimize therapy in PAH patients on bosentan. Methods: Twelve patients with symptomatic PAH despite bosentan received either 30 μg of inhaled treprostinil 4 times daily (n = 6) or 45 μg 4 times daily (n = 6), via an ultrasonic nebulizer. Six-min walk distance (6MWD), functional class, and hemodynamics were assessed at baseline and 12 weeks. Results: One patient was excluded from analysis due to the subsequent finding of pulmonary capillary hemangiomatosis. In the remaining 11 patients, inhaled treprostinil was safe and well tolerated. Inhaled treprostinil was associated with an increase in 6MWD at 12 weeks (baseline 339 ± 86, 12 week, 1 h post-inhalation 406 ± 121 m, 67-m change, p = 0.01). An improvement in 6MWD of 49 m from baseline was noted during the trough period, just before inhalation of treprostinil (p = 0.009). The 6MWD improvement of at least 10% was noted in 1 of 6 patients receiving 30 μg versus 5 of 6 receiving 45 μg. Over 12 weeks, significant decreases were noted in mean pulmonary arterial pressure (−10%) and in pulmonary vascular resistance (−26%). Functional class improved from III to II in 9 of 11 patients. Conclusions: This trial suggests that inhaled treprostinil is safe, well tolerated, and associated with significant improvements in exercise capacity, functional class, and pulmonary hemodynamics in symptomatic patients with PAH on bosentan. [Copyright &y& Elsevier]

There is significant variability in postoperative neurological injury rates in patients with congenital heart disease, with early injuries impacting long-term neurodevelopmental outcomes; therefore, there is an urgent need for identifying effective strategies to mitigate such injuries. This study aims to assess the association between nadir intraoperative temperature (NIT) and early neurological outcomes in neonates undergoing congenital heart surgery. Analyzing data from 24,345 neonatal cardiac operations from the Society for Thoracic Surgeons Congenital Heart Surgery Database between 2010 and 2019, NIT was assessed using a mixed-effect logistic regression model, targeting major neurological injury (stroke, seizure, or deficit at discharge) as a primary endpoint. The study observed a shift from hypothermic circulatory arrest to cerebral perfusion with an increase in mean nadir temperature from 23.9 °C to 25.6 °C (P < 0.0001). Major neurological injury was noted in 4.9% of the cohort, with variations based on surgical procedure. After adjusting for risk, NIT was not significantly associated with major neurological injuries overall, but a lower NIT showed protective effects in the Norwood subgroup. Factors increasing the risk of major neurological injury included younger age at surgery, the Norwood procedure, longer cardiopulmonary bypass times, younger gestational age, presence of noncardiac abnormalities, and chromosomal anomalies. Whereas neurological injuries are prevalent after neonatal cardiac surgery, current practices lean towards higher core temperatures. This trend is supported by the nonsignificant impact of NIT on neurological outcomes. However, lower NIT in the Norwood subgroup indicates that reduced temperatures may be beneficial amidst specific risk factors. [ABSTRACT FROM AUTHOR]

Background: Registry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials.Objectives: The purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies.Methods: For each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark.Results: In the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR.Conclusions: These results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014). [ABSTRACT FROM AUTHOR]

Abstract: Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation. [Copyright &y& Elsevier]

Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation. [Copyright &y& Elsevier]

Background: There are conflicting data regarding the benefit of compression-only bystander cardiopulmonary resuscitation (CO-CPR) compared with CPR with rescue breathing (RB-CPR) after pediatric out-of-hospital cardiac arrest (OHCA).Objectives: This study sought to test the hypothesis that RB-CPR is associated with improved neurologically favorable survival compared with CO-CPR following pediatric OHCA, and to characterize age-stratified outcomes with CPR type compared with no bystander CPR (NO-CPR).Methods: Analysis of the CARES registry (Cardiac Arrest Registry to Enhance Survival) for nontraumatic pediatric OHCAs (patients aged ≤18 years) from 2013-2019 was performed. Age groups included infants (<1 year), children (1 to 11 years), and adolescents (≥12 years). The primary outcome was neurologically favorable survival at hospital discharge.Results: Of 13,060 pediatric OHCAs, 46.5% received bystander CPR. CO-CPR was the most common bystander CPR type. In the overall cohort, neurologically favorable survival was associated with RB-CPR (adjusted OR: 2.16; 95% CI: 1.78-2.62) and CO-CPR (adjusted OR: 1.61; 95% CI: 1.34-1.94) compared with NO-CPR. RB-CPR was associated with a higher odds of neurologically favorable survival compared with CO-CPR (adjusted OR: 1.36; 95% CI: 1.10-1.68). In age-stratified analysis, RB-CPR was associated with better neurologically favorable survival versus NO-CPR in all age groups. CO-CPR was associated with better neurologically favorable survival compared with NO-CPR in children and adolescents, but not in infants.Conclusions: CO-CPR was the most common type of bystander CPR in pediatric OHCA. RB-CPR was associated with better outcomes compared with CO-CPR. These results support present guidelines for RB-CPR as the preferred CPR modality for pediatric OHCA. [ABSTRACT FROM AUTHOR]

The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term “non-PAH PH” summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH. [Copyright &y& Elsevier]

Objectives: This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil. Background: There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies. Methods: Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 μg) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed. Results: Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated. Conclusions: This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199) [Copyright &y& Elsevier]

Objectives: The aim of this study was to compare the electrophysiologic substrate in ischemic cardiomyopathy (ICM) patients with and without sustained monomorphic ventricular tachycardia (SMVT). Background: Despite the universal presence of potentially arrhythmogenic left ventricular (LV) scarring, it is not clear why the majority of ICM patients never develop SMVT. Methods: Detailed electroanatomic mapping of the LV endocardium was performed in 17 stable control ICM patients (16 males) without clinical SMVT. They were compared with 17 ICM patients (15 males) with spontaneous SMVT. Standard definitions of low-voltage zones and fractionated, isolated, and very late potentials were used. Results: There were no significant baseline differences between the groups in terms of LV diameter, ejection fraction (27% vs. 28%), infarct territory, or time from infarction. However, control patients had smaller total low-voltage area ≤1.5 mv (30% of surface area vs. 55%, p < 0.001); smaller very low-voltage area <0.5 mv (7.3% vs. 29%, p < 0.001); higher mean voltage of low-voltage zones; fewer fractionated, isolated, and very late potentials with lower density of these scar-related electrograms per unit low-voltage area; and less SMVT inducibility. Potential conducting channels within dense scar and adjacent to the mitral annulus were more frequent in SMVT patients. Conclusions: Compared with ICM patients with SMVT, an otherwise similar control group demonstrated markedly smaller endocardial low-voltage zones, lower scar-related electrogram density, and fewer conducting channels with faster conduction velocity. These findings may explain why some ICM patients develop SMVT and others do not. [Copyright &y& Elsevier]

Objectives: This study evaluated the impact of left ventricular assist device (LVAD) support on survival and quality of life in inotrope-dependent heart failure patients ineligible for cardiac transplantation. Background: The role for LVADs as a bridge to cardiac transplantation has been established, but data supporting their role as permanent therapy in nontransplant candidates are limited. Methods: The INTrEPID (Investigation of Nontransplant-Eligible Patients Who Are Inotrope Dependent) trial was a prospective, nonrandomized clinical trial comparing LVAD with optimal medical therapy (OMT). Fifty-five patients with New York Heart Association functional class IV symptoms who failed weaning from inotropic support were offered a Novacor LVAD. Eighteen of these patients did not receive an LVAD owing to patient preference (n = 14) or unavailability of the device (n = 4) but consented to follow-up and constitute a contemporaneous control group. Results: The LVAD and OMT patients were well matched for demographic and disease severity measures, except OMT patients had a lower mean serum sodium (128 mg/dl vs. 134 mg/dl; p = 0.001) and a higher mean blood urea nitrogen concentration (59 vs. 40; p = 0.02). The LVAD-treated patients had superior survival rates at 6 months (46% vs. 22%; p = 0.03) and 12 months (27% vs. 11%; p = 0.02). Adverse event rates were higher in the OMT group. Eighty-five percent of the LVAD-treated patients had minimal or no heart failure symptoms. Five LVAD patients and 1 OMT patient improved sufficiently while on therapy to qualify for cardiac transplantation. Conclusions: Inotrope-dependent heart failure patients who are ineligible for transplantation have a high short-term mortality rate and derive a significant survival advantage from “destination” mechanical circulatory support. [Copyright &y& Elsevier]

: ObjectivesWe sought to assess the relationship between survival, peak exercise oxygen consumption (Vo2), and heart failure survival score (HFSS) in the current era of heart failure (HF) therapy.: BackgroundBased on predicted survival, HF patients with peak Vo2 <14 ml/min/kg or medium- to high-risk HFSS are currently considered eligible for heart transplantation. However, these criteria were developed before the widespread use of beta-blockers, spironolactone, and defibrillators—interventions known to improve the survival of HF patients.: MethodsPeak Vo2 and HFSS were assessed in 320 patients followed from 1994 to 1997 (past era) and in 187 patients followed from 1999 to 2001 (current era). Outcomes were compared between these two groups of patients and those who underwent heart transplantation from 1993 to 2000.: ResultsSurvival in the past era was 78% at one year and 67% at two years, as compared with 88% and 79%, respectively, in the current era (both p < 0.01). One-year event-free survival (without urgent transplantation or left ventricular assist device) was improved in the current era, regardless of initial peak Vo2: 64% vs. 48% for peak Vo2 <10 ml/min/kg (p = 0.09), 81% vs. 70% for 10 to 14 ml/min/kg (p = 0.05), and 93% vs. 82% for >14 ml/min/kg (p = 0.04). Of the patients with peak Vo2 of 10 to 14 ml/min/kg, 55% had low-risk HFSS and exhibited 88% one-year event-free survival. One-year survival after transplantation was 88%, which is similar to the 85% rate reported by the United Network for Organ Sharing for 1999 to 2000.: ConclusionsSurvival for HF patients in the current era has improved significantly, necessitating re-evaluation of the listing criteria for heart transplantation. [Copyright &y& Elsevier]

: ObjectivesWe sought to investigate to what extent intra-ventricular asynchrony (intraVA) and inter-ventricular asynchrony (interVA) determine left ventricular (LV) function in canine hearts with left bundle branch block (LBBB) during ventricular pacing.: BackgroundPacing therapy improves LV pump function in patients with heart failure and abnormal ventricular conduction supposedly due to resynchronization. However, the relationship between LV pump function and measures of asynchrony is not well established.: MethodsIn 15 experiments, LV (various sites) and biventricular (BiV) pacing was performed at atrioventricular (AV) delays of 20 to 140 ms. Measured were the maximum rate of increase (dP/dtmax) of LV pressure and LV stroke work (SW) (conductance catheter), interVA (time delay between the upslope of LV and RV pressures), and intraVA (from endocardial electrical activation maps).: ResultsInduction of LBBB increased interVA (−6.4 ± 8.6 to −28.4 ± 8.5 ms [RV earlier]) and intraVA (4.9 ± 2.4 to 18.0 ± 3.3 ms), whereas LV dP/dtmax and SW decreased (−13 ± 18% and −39 ± 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dtmax and SW (mean increases 14% to 21% and 11% to 15%, respectively) without changing diastolic function or preload. Optimal improvement in LV function was obtained consistently when intraVA returned to pre-LBBB values, while interVA remained elevated. Normalization of intraVA required AV delays shorter than the baseline PQ time during LV apex and BiV pacing, thus excluding endogenous LV activation, but AV delays virtually equal to the baseline PQ time (difference 4 ± 9 ms, p = NS) during pacing at (mid)lateral LV sites to obtain fusion between pacing-induced and endogenous activation.: ConclusionsIn LBBB hearts, optimal restoration of LV systolic function by pacing requires intra-ventricular resynchronization. The optimal AV delay to achieve this depends on both the site of pacing and baseline PQ time. [Copyright &y& Elsevier]

The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1'). Thus, Group 1 of PAH is now more homogeneous. [ABSTRACT FROM AUTHOR]

The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1′). Thus, Group 1 of PAH is now more homogeneous. [Copyright &y& Elsevier]