Estimated pulse wave velocity predicts mortality in patients with heart failure with preserved ejection fraction.

AIM: Estimated pulse wave velocity (ePWV), a newly established arterial stiffness (AS) parameter, predicts development of cardiovascular disease (CVD) and death in general population or patients with CVD risk factors. However, whether ePWV is associated with adverse outcome in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Our study aimed to evaluate the prognostic value of ePWV on clinical outcomes in HFpEF. METHODS AND RESULTS: We analyzed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1764). Cox proportional hazard model was used to explore the prognostic value of ePWV on the long-term clinical outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalization and heart failure hospitalization). Each ePWV increase by 1 m/s increased the risk for all-cause death by 16% (HR:1.16; 95% CI:1.10-1.23; P<0.001) and CVD mortality by 13% (HR:1.13; 95% CI:1.04-1.21; P=0.002) after adjusting for confounders. Patients were then grouped into 4 quartiles of ePWV. Our study indicated that the highest ePWV quartile (ePWV ≥12.806 m/s) was associated with increased risk of all-cause mortality (HR, 1.96; 95% CI, 1.43-2.69; P<0.001) and CVD mortality (HR, 1.72; 95% CI, 1.16-2.56; P=0.008) after adjusting for potential confounders. CONCLUSION: These results suggested ePWV is independently associated with increased all-cause mortality and CVD mortality in HFpEF patients, indicating ePWV is an appropriate predictor of prognosis in patients with HFpEF.

Prognostic impact of abnormal sodium burden in heart failure patients with preserved ejection fraction.

BACKGROUND: Sodium abnormality is common in patients with heart failure (HF) and is associated with adverse clinical outcomes. The aim of this study is to determine the impact of abnormal sodium burden on long-term mortality and hospitalization in HF with preserved ejection fraction (HFpEF). METHODS: We analysed participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline and follow-up data (n = 1717). Abnormal sodium burden was defined as the proportion of days with abnormal sodium plasma levels (either <135 mmol/L or > 145 mmol/L). To determine the independent prognostic impact of abnormal sodium burden on the long-term clinical adverse outcomes (The primary outcome was any cause death, the secondary outcomes include cardiovascular disease death, HF hospitalization, any cause hospitalization and the primary endpoint of the original study), a multivariable Cox proportional hazard model and time-updated Cox regression model were performed. RESULTS: Abnormal sodium burden occurred in 717 patients (41.76%). A high abnormal sodium burden was associated with 1.47 (95% CI, 1.15-1.89) higher risk with any cause mortality, 1.51 (95% CI, 1.08-2.09) higher risk with CVD death and 1.31 (95% CI, 1.02-1.69) higher risk with HF hospitalization when compared with no burden group. When sodium level changes over time were accounted for in time-updated models, abnormal sodium level was still associated with poor clinical outcomes. Diuretic and spironolactone usage did not show a statistical interaction effect on the prognostic significance. CONCLUSIONS: In HFpEF patients, abnormal sodium burden was an independent predictor long-term any-cause mortality and HF hospitalization.

Hemoglobin to red cell distribution width ratio: A predictor of clinical outcome and diuretic response in patients with acute heart failure.

BACKGROUND: Hemoglobin to Red Cell Distribution Width Ratio (HRR) is a novel inflammatory marker in the prognostic assessment of tumors. Nevertheless, its focus on the cardiovascular field is relatively limited, particularly regarding its correlation with diuretic responses and clinical outcomes. METHODS: This is a secondary analysis of the Renal Optimization Strategies Evaluation (ROSE AHF) clinical trial. The outcomes of interest included all-cause death, rehospitalization and diuretic responses. Multivariable Cox proportional hazard regression and linear regression models were performed, respectively. Prognostic outcomes and diuretic response were further evaluated in ejection fraction (EF) subgroups (preserved EF ≥ 50% and reduced EF<50%). RESULTS: A total of 351 patients were included in the present study and further categorized according to HRR median (0.7131) value at admission: low HRR group (n = 176) and high HRR group (n = 175). High HRR were found to be independently associated with decreased risk of all-cause death (HR = 0.51; 95% CI,0.30-0.87, P = 0.013), reduced risk of developing all-caused death or rehospitalization (HR = 0.62; 95% CI,0.39-0.98, P = 0.039). Furthermore, high HRR indicated lower cumulative urine output (OR: -992.33, P = 0.004) and less weight loss (OR: 3.08, P < 0.001) within 72 h after diuresis. Subgroup analysis revealed no significant interaction effect between EF and HRR in prognostic impact or diuretic responses, and HRR was negatively correlated with plasma volume. CONCLUSION: High HRR demonstrated a lower risk of developing adverse clinical outcomes and a poorer diuretic response that might be due to less volume overload in AHF patients.

Deformation Prediction Theory of Thermal Barrier Coatings near Cooling Holes under Thermal Cycling.

Thermal barrier coating (TBC) systems are widely adopted in gas turbine blades to improve the thermal efficiency of gas turbine engines. However, TBC failure will happen due to the thermal stress between the different layers of the TBC systems. The traditional two-layer theoretical model only considers TGO (thermally grown oxide) and a substrate in the inner cooling hole with the surface uncoated, which results in poor prediction of the deformations of the TBC systems. It should be mentioned that the effect of TBC is very important because the thickness of TBC is much larger than the TGO thickness. In this study, a new three-layer theoretical model was derived, which is composed of the cylindrical TGO and TBC mounted in the substrate with a circular hole, and the stress and strain of TGO near the cooling hole under the condition of the thermal cycles were calculated. The high temperature characteristics of TGO and the substrate including the high temperature strength and growth ratio were from the experiments. The results show that the strain of the developed three-layer model is irrelevant with increasing number of cycles, which indicates that TBC in the cooling hole significantly inhibits the deformation of TGO near the cooling hole. Therefore, aimed at confirming the feasibility of the three-layer theoretical model, the finite element analysis with coating in the cooling hole and on the surface was carried out with a three-layer axisymmetric model, which proves that the 3-layer theoretical model can predict the deformation trend near the cooling hole.

Mean corpuscular haemoglobin concentration and outcomes in heart failure with preserved ejection fraction.

AIMS: This study aims to evaluate the prognostic value of mean corpuscular haemoglobin concentration (MCHC) on clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analysed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1747). Patients were grouped into hypochromia or non-hypochromia group according to a MCHC cut-off level of 330 g/L. Cox proportional hazard model was used to explore the prognostic value of hypochromia on the long-term clinical outcomes (the primary endpoint [composite of cardiovascular mortality, HF hospitalization and aborted cardiac arrest], any-cause and HF hospitalization, all-cause and cardiovascular mortality). Patients were further stratified according to baseline estimated glomerular filtration rate (eGFR) to explore the impact of renal dysfunction on the prognostic value of hypochromia. Baseline hypochromia was prevalent (n = 662, 37.9%) and strongly associated with worse clinical outcomes. In patients with worse renal function (eGFR < 60 mL/min per 1.73 m2 ), hypochromia was independently associated with primary endpoint (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.23-1.98; P < 0.001), any-cause hospitalization (HR, 1.43; 95% CI, 1.20-1.71, P < 0.001) and HF hospitalization (HR, 1.40; 95% CI, 1.07-1.84; P = 0.015), whereas no significant association between hypochromia and these outcomes was found in patients with better renal function. CONCLUSIONS: Among HFpEF patients, hypochromia (i.e. MCHC ≤ 330 g/L) is independently associated with adverse clinical outcomes, especially when in the presence of co-morbidity renal dysfunction.

A Multimodal Deep Learning Approach to Predicting Systemic Diseases from Oral Conditions.

Background: It is known that oral diseases such as periodontal (gum) disease are closely linked to various systemic diseases and disorders. Deep learning advances have the potential to make major contributions to healthcare, particularly in the domains that rely on medical imaging. Incorporating non-imaging information based on clinical and laboratory data may allow clinicians to make more comprehensive and accurate decisions. Methods: Here, we developed a multimodal deep learning method to predict systemic diseases and disorders from oral health conditions. A dual-loss autoencoder was used in the first phase to extract periodontal disease-related features from 1188 panoramic radiographs. Then, in the second phase, we fused the image features with the demographic data and clinical information taken from electronic health records (EHR) to predict systemic diseases. We used receiver operation characteristics (ROC) and accuracy to evaluate our model. The model was further validated by an unseen test dataset. Findings: According to our findings, the top three most accurately predicted chapters, in order, are the Chapters III, VI and IX. The results indicated that the proposed model could predict systemic diseases belonging to Chapters III, VI and IX, with AUC values of 0.92 (95% CI, 0.90-94), 0.87 (95% CI, 0.84-89) and 0.78 (95% CI, 0.75-81), respectively. To assess the robustness of the models, we performed the evaluation on the unseen test dataset for these chapters and the results showed an accuracy of 0.88, 0.82 and 0.72 for Chapters III, VI and IX, respectively. Interpretation: The present study shows that the combination of panoramic radiograph and clinical oral features could be considered to train a fusion deep learning model for predicting systemic diseases and disorders.

Prone ventilation in intubated COVID-19 patients: a systematic review and meta-analysis

Abstract Background The efficacy and safety profiles of prone ventilation among intubated Coronavirus Disease 2019 (COVID-19) patients remain unclear. The primary objective was to examine the effect of prone ventilation on the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) in intubated COVID-19 patients. Methods Databases of MEDLINE, EMBASE and CENTRAL were systematically searched from inception until March 2021. Case reports and case series were excluded. Results Eleven studies (n = 606 patients) were eligible. Prone ventilation significantly improved PaO2/FiO2 ratio (studies: 8, n = 579, mean difference 46.75, 95% CI 33.35‒60.15, p < 0.00001; evidence: very low) and peripheral oxygen saturation (SpO2) (studies: 3, n = 432, mean difference 1.67, 95% CI 1.08‒2.26, p < 0.00001; evidence: ow), but not the arterial partial pressure of carbon dioxide (PaCO2) (studies: 5, n = 396, mean difference 2.45, 95% CI 2.39‒7.30, p= 0.32; evidence: very low), mortality rate (studies: 1, n = 215, Odds Ratio 0.66, 95% CI 0.32‒1.33, p= 0.24; evidence: very low), or number of patients discharged alive (studies: 1, n = 43, Odds Ratio 1.49, 95% CI 0.72‒3.08, p= 0.28; evidence: very low). Conclusion Prone ventilation improved PaO2/FiO2 ratio and SpO2 in intubated COVID-19 patients. Given the substantial heterogeneity and low level of evidence, more randomized- controlled trials are warranted to improve the certainty of evidence, and to examine the adverse events of prone ventilation.

Attenuation of Myocardial Dysfunction in Hypertensive Cardiomyopathy Using Non-R-Wave-Synchronized Cardiac Shock Wave Therapy.

Cardiac shock wave therapy (CSWT) is a novel therapeutic procedure for patients with angina that is refractory to conventional therapy. We investigated the potential mechanism and therapeutic efficacy of non-R-wave-triggered CSWT to attenuate myocardial dysfunction in a large animal model of hypertensive cardiomyopathy. Sustained elevated blood pressure (BP) was induced in adult pigs using a combination of angiotensin-II and deoxycorticosterone acetate (DOCA). Two sessions of non-R-wave-triggered CSWT were performed at 11 and 16 weeks. At 10 weeks, systolic and diastolic blood pressure, LV posterior wall thickness and intraventricular septum thickness significantly increased in both the hypertension and CSWT groups. At 20 weeks, +dP/dt and end-systolic pressure-volume relationship (ESPVR) decreased significantly in the hypertension group but not the CSWT group, as compared with week 10. A significant improvement in end-diastolic pressure-volume relationship (EDPVR) was observed in the CSWT group. The CSWT group exhibited significantly increased microvascular density and vascular endothelial growth factor (VEGF) expression in the myocardium. Cytokine array demonstrated that the CSWT group had significantly reduced inflammation compared with the hypertension group. Our results demonstrate that non-R-wave-triggered CSWT is safe and can attenuate LV systolic and diastolic dysfunction via enhancement of myocardial neovascularization and anti-inflammatory effect in a large animal model of hypertensive cardiomyopathy.

The use of cerebral oximetry in cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.

High prevalence of cerebral desaturation is associated with postoperative neurological complications in cardiac surgery. However, the evidence use of cerebral oximetry by correcting cerebral desaturation in the reduction of postoperative complications remains uncertain in the literature. This systematic review and meta-analysis aimed to examine the effect of cerebral oximetry on the incidence of postoperative cognitive dysfunction in cardiac surgery. Databases of MEDLINE, EMBASE, and CENTRAL were searched from their inception until April 2021. All randomized controlled trials comparing cerebral oximetry and blinded/no cerebral oximetry in adult patients undergoing cardiac surgery were included. Observational studies, case series, and case reports were excluded. A total of 14 trials (n = 2,033) were included in this review. Our pooled data demonstrated that patients with cerebral oximetry were associated with a lower incidence of postoperative cognitive dysfunction than the control group (studies = 4, n = 609, odds ratio [OR]: 0.15, 95% confidence interval [CI]: 0.04 to 0.54, P = 0.003, I2 = 88%; certainty of evidence = very low). In terms of postoperative delirium (OR: 0.75, 95%CI: 0.50-1.14, P = 0.18, I2 = 0%; certainty of evidence = low) and postoperative stroke (OR: 0.81 95%CI: 0.37-1.80, P = 0.61, I2 = 0%; certainty of evidence = high), no significant differences (P > 0.05) were reported between the cerebral oximetry and control groups. In this meta-analysis, the use of cerebral oximetry monitoring in cardiac surgery demonstrated a lower incidence of postoperative cognitive dysfunction. However, this finding must be interpreted with caution due to the low level of evidence, high degree of heterogeneity, lack of standardized cognitive assessments, and cerebral desaturation interventions.

Prone ventilation in intubated COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety profiles of prone ventilation among intubated Coronavirus Disease 2019 (COVID-19) patients remain unclear. The primary objective was to examine the effect of prone ventilation on the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) in intubated COVID-19 patients. METHODS: Databases of MEDLINE, EMBASE and CENTRAL were systematically searched from inception until March 2021. Case reports and case series were excluded. RESULTS: Eleven studies (n = 606 patients) were eligible. Prone ventilation significantly improved PaO2/FiO2 ratio (studies: 8, n = 579, mean difference 46.75, 95% CI 33.35‒60.15, p < 0.00001; evidence: very low) and peripheral oxygen saturation (SpO2) (studies: 3, n = 432, mean difference 1.67, 95% CI 1.08‒2.26, p < 0.00001; evidence: ow), but not the arterial partial pressure of carbon dioxide (PaCO2) (studies: 5, n = 396, mean difference 2.45, 95% CI 2.39‒7.30, p = 0.32; evidence: very low), mortality rate (studies: 1, n = 215, Odds Ratio 0.66, 95% CI 0.32‒1.33, p = 0.24; evidence: very low), or number of patients discharged alive (studies: 1, n = 43, Odds Ratio 1.49, 95% CI 0.72‒3.08, p = 0.28; evidence: very low). CONCLUSION: Prone ventilation improved PaO2/FiO2 ratio and SpO2 in intubated COVID-19 patients. Given the substantial heterogeneity and low level of evidence, more randomized- controlled trials are warranted to improve the certainty of evidence, and to examine the adverse events of prone ventilation.

Salt restriction and risk of adverse outcomes in heart failure with preserved ejection fraction.

BACKGROUND: The optimal salt restriction in patients with heart failure (HF), especially patients with heart failure with preserved ejection fraction (HFpEF), remains controversial. OBJECTIVE: To investigate the associations of cooking salt restriction with risks of clinical outcomes in patients with HFpEF. METHODS: Cox proportional hazards model and subdistribution hazards model were used in this secondary analysis in 1713 participants with HFpEF from the Americas in the TOPCAT trial. Cooking salt score was the sum of self-reported salt added during homemade food preparation. The primary endpoint was a composite of cardiovascular death, HF hospitalisation and aborted cardiac arrest, and secondary outcomes were all-cause death, cardiovascular death and HF hospitalisation. RESULTS: Compared with patients with cooking salt score 0, patients with cooking salt score >0 had significantly lower risks of the primary endpoint (HR=0.760, 95% CI 0.638 to 0.906, p=0.002) and HF hospitalisation (HR=0.737, 95% CI 0.603 to 0.900, p=0.003), but not all-cause (HR=0.838, 95% CI 0.684 to 1.027, p=0.088) or cardiovascular death (HR=0.782, 95% CI 0.598 to 1.020, p=0.071). Sensitivity analyses using propensity score matching baseline characteristics and in patients who prepared meals mostly at home yielded similar results. Subgroup analysis suggested that the association between overstrict salt restriction and poor outcomes was more predominant in patients aged ≤70 years and of non-white race. CONCLUSION: Overstrict cooking salt intake restriction was associated with worse prognosis in patients with HFpEF, and the association seemed to be more predominant in younger and non-white patients. Clinicians should be prudent when giving salt restriction advice to patients with HFpEF.

Osteogenic Circulating Endothelial Progenitor Cells are Associated with Vascular Aging of the Large Arteries in Rheumatoid Arthritis.

Background and Aim: Rheumatoid arthritis is associated with both abnormal bone metabolism and accelerated vascular aging but a mechanistic link was lacking. This study aims to investigate the role of osteocalcin (OCN)-expressing circulating endothelial progenitor cells (EPCs) in vascular aging, as determined by arterial calcifications in rheumatoid arthritis. Methods: We performed flow cytometry studies in 145 consecutive patients with rheumatoid arthritis to determine osteogenic circulating levels of OCN-positive (OCN+) CD34+KDR+ and OCN+CD34+ versus conventional early EPC CD34+CD133+KDR+. Total calcium load of the thoracic aorta (ascending plus descending) and the carotid arteries were assessed by non-contrast computed tomography (CT) and contrast CT angiography. Results: Osteogenic EPCs OCN+CD34+KDR+ (P = 0.002) and OCN+CD34+ (P = 0.001), together with clinical parameters of age, history of hypertension, systolic blood pressure, serum levels of triglycerides, HbA1c and creatinine, use of leflunomide and brachial-ankle pulse-wave velocity (all P < 0.05), were associated with the clustered presence of aortic and carotid calcification. Multivariable analyses revealed that circulating OCN+CD34+KDR+ (B = 14.4 [95% CI 4.0 to 24.8], P = 0.007) and OCN+CD34+ (B = 9.6 [95% CI 4.9 to 14.3], P < 0.001) remained independently associated with increased aortic calcium load. OCN+CD34+ EPC (B = 0.8 [95% CI 0.1 to 1.5], P = 0.023), but not OCN+CD34+KDR+ EPC (B = 1.2 [95% CI -0.2 to 2.6], P = 0.09), was further independently associated with carotid calcium load. In comparison, conventional early EPC CD34+CD133+KDR+ had no significant association with aortic or carotid calcium load (P = 0.46 and 0.88, respectively). Conclusion: Circulating level of osteogenic EPC is associated with increased vascular aging in terms of calcification of the large arteries in patients with rheumatoid arthritis. The findings may suggest a role of the bone-vascular axis underlying vascular aging in rheumatic diseases. Further research is needed to characterize the mechanistic links and basis of these observations.

Prognostic significance of blood urea nitrogen/creatinine ratio in chronic HFpEF.

BACKGROUND: The prognostic significance of blood urea nitrogen (BUN)/creatinine ratio specifically in chronic heart failure with preserved ejection fraction (HFpEF) patients remained unclear. We aimed to evaluate the association of BUN/creatinine ratio (baseline level and visit-to-visit variation) with the risk of adverse clinical outcomes among patients with chronic HFpEF. METHODS AND RESULTS: This is a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Of the enrolled 3445 participants in the TOPCAT trial, associations between BUN/creatinine and clinical outcomes were examined in a subset of 1521 (baseline measurements level) and 1453 (visit-to-visit variation) participants. A multivariable Cox proportional hazard model was used to assess the prognostic significance of BUN/creatinine ratio and BUN/creatinine ratio variation for the prespecified clinical outcomes. A higher BUN/creatinine ratio was associated with a higher risk of all-cause mortality (hazard ratio [HR] = 1.52, 95%CI, 1.21-1.91; p < .001) as well as cardiovascular disease mortality (HR = 1.83, 95%CI, 1.35-2.49; p < .001) in the fully adjusted model. Greater visit-to-visit variability in BUN/creatinine ratio tended to be independently associated with a higher risk of heart failure hospitalization and primary endpoint (p < .001 for both outcomes). Furthermore, those findings were consistent across participants stratified by the presence of chronic kidney disease at baseline. CONCLUSIONS: Higher BUN/creatinine ratio and greater BUN/creatinine ratio variability are independently associated with adverse outcomes in HFpEF participants in the TOPCAT trial.

The Use of Cerebral Oximetry in Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The evidence on the use of cerebral oximetry during surgery to minimize postoperative neurologic complications remains uncertain in the literature. The present authors aimed to assess the value of cerebral oximetry in the prevention of postoperative cognitive dysfunction, postoperative delirium, and postoperative stroke in adults undergoing surgery. DESIGN: A systematic review and meta-analysis. SETTING: The surgery room. PARTICIPANTS: Adult patients (ages ≥18 years) undergoing surgery. INTERVENTIONS: Cerebral oximetry monitoring. MEASUREMENTS AND MAIN RESULTS: Databases of Ovid MEDLINE, Ovid EMBASE, and CENTRAL were systematically searched from their inception until December 2020 for randomized controlled trials comparing cerebral oximetry monitoring with either blinded or no cerebral oximetry monitoring in adults undergoing surgery. Observational studies, case reports, and case series were excluded. Seventeen studies (n = 2,120 patients) were included for quantitative meta-analysis. Patients who were randomized to cerebral oximetry monitoring had a lower incidence of postoperative cognitive dysfunction (studies = seven, n = 969, odds ratio [OR] 0.23, 95% confidence interval [CI] 0.11-0.48, p = 0.0001; evidence = very low). However, no significant differences were observed in the incidence of postoperative delirium (studies = five, n = 716, OR 0.81, 95% CI 0.53-1.25, p = 0.35; evidence = high), and postoperative stroke (studies = seven, n = 1,087, OR 0.72, 95% CI 0.30-1.69, p = 0.45; evidence = moderate). CONCLUSION: Adult patients with cerebral oximetry monitoring were associated with a significant reduction of postoperative cognitive dysfunction. However, given the low certainty of evidence and substantial heterogeneity, more randomized controlled trials using standardized assessment tools for postoperative cognitive dysfunction and interventions of correcting cerebral desaturation are warranted to improve the certainty of evidence and homogeneity.

Clinical Significance of Mean and Pulse Pressure in Patients With Heart Failure With Preserved Ejection Fraction.

It remains debated whether pulse pressure is associated with left ventricular traits and adverse outcomes over and beyond mean arterial pressure (MAP) in patients with heart failure (HF) with preserved ejection fraction. We investigated these associations in 3428 patients with HF with preserved ejection fraction (51.5% women; mean age, 68.6 years) enrolled in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). We computed association sizes and hazards ratios with 1-SD increase in MAP and pulse pressure. In multivariable-adjusted analyses, association sizes (P≤0.039) for MAP were 0.016 cm and 0.014 cm for septal and posterior wall thickness, -0.15 for E/A ratio, -0.66 for E/e', and -0.64% for ejection fraction, independent of pulse pressure. With adjustment additionally applied for MAP, E/A ratio and longitudinal strain increased with higher pulse pressure with association sizes amounting to 0.067 (P=0.026) and 0.40% (P=0.023). In multivariable-adjusted analyses of both placebo and spironolactone groups, lower MAP and higher pulse pressure predicted the primary composite end point (P≤0.028) and hospitalized HF (P≤0.002), whereas MAP was also significantly associated with total mortality (P≤0.007). Sensitivity analyses stratified by sex, median age, and region generated confirmatory results with exception for the association of adverse outcomes with pulse pressure in patients with age ≥69 years. In conclusion, the clinical application of MAP and pulse pressure may refine risk estimates in patients with HF with preserved ejection fraction. This finding may help further investigation for the development of HF with preserved ejection fraction preventive strategies targeting pulsatility and blood pressure control.

Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction.

Rationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI. Methods: Mice were randomized to undergo intravenous administration of saline or 5×105 hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1×106) or hiPSC-CMs (1×106) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects. Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-γ, tumor necrosis factor-α, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10. Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI.

Myocardial repair of bioengineered cardiac patches with decellularized placental scaffold and human-induced pluripotent stem cells in a rat model of myocardial infarction.

BACKGROUND: The creation of a bioengineered cardiac patch (BCP) is a potential novel strategy for myocardial repair. Nevertheless, the ideal scaffold for BCP is unknown. OBJECTIVE: We investigated whether the decellularized placenta (DP) could serve as natural scaffold material to create a BCP for myocardial repair. METHODS AND RESULTS: A BCP was created by seeding human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs; 1 × 106/cm2) onto DP. The functional and electrophysiological properties of the BCP were first characterized by in vitro analysis and optical mapping. Next, in vivo therapeutic efficacy of the BCP was evaluated in a rat model of myocardial infarction (MI), created by left descending coronary artery ligation (MI + BCP group), and compared with MI alone (MI group), transplantation of DP (MI + DP group), and hiPSC-CMs (MI + CM group). Cytokine profiling demonstrated that the BCP contained multiple growth and angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, basic fibroblast growth factor, angiogenin, and angiopoietin-2. In vitro optical mapping showed that the BCP exhibited organized mechanical contraction and synchronized electrical propagation. RNA sequencing showed that DP enhanced the maturation of hiPSC-CMs compared with the monolayer of cultured hiPSC-CMs. At 4 weeks follow-up, the BCP significantly improved left ventricular (LV) function, as determined by LV ejection fraction, fractional shortening, + dP/dtmax, and end-systolic pressure-volume relationship, compared with the MI, MI + DP, and MI + CM groups. Moreover, histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI + DP, and MI + CM groups. CONCLUSIONS: Our results demonstrate that a DP scaffold contains multiple growth and angiogenic factors that enhance the maturation and survival of seeded hiPSC-CMs. Transplantation of a BCP is superior to DP or hiPSC-CMs alone in reducing infarct size and improving cell retention and neovascularization, thus providing a novel therapy for myocardial repair following MI.

Sex-specific pattern of left ventricular hypertrophy and diastolic function in patients with type 2 diabetes mellitus.

AIMS: Few prospective studies have evaluated sex-specific pattern, natural progression of left ventricular (LV) remodelling, and diastolic dysfunction in patients with type 2 diabetes (T2DM). The aim of this study was to study the sex-specific prevalence, longitudinal changes of LV remodelling, and diastolic dysfunction in patients with T2DM. Further, the prognostic value of diastolic function in women and men was also evaluated. METHODS AND RESULTS: A total of 350 patients with T2DM (mean age 61 ± 11 years; women, 48.3%) was recruited. Detailed echocardiography was performed at baseline and after 25 months. A major adverse cardiovascular event (MACE) was defined as cardiovascular death, heart failure hospitalization, or myocardial infarction. Despite a similar age, prevalence of hypertension and body mass index, women had a higher prevalence of LV hypertrophy and diastolic dysfunction at baseline and follow-up compared with men. A total of 21 patients developed MACE (5 cardiovascular death, 9 hospitalization for heart failure, and 7 myocardial infarction) during a median follow-up of 56 months. Women with diastolic dysfunction had a higher incidence of MACE than those with normal diastolic function but this association was neutral in men. Multivariable Cox-regression analysis indicated that diastolic dysfunction was associated with MACE in women [hazard ratio = 6.30; 95% confidence interval (CI) = 1.06-37.54; P < 0.05] but not men (hazard ratio = 2.29, 95% CI = 0.67-7.89; P = 0.19). CONCLUSION: LV hypertrophy and diastolic dysfunction, both at baseline and follow-up, were more common in women than men. Pre-clinical diastolic dysfunction was independently associated with MACE only in women with T2DM but was neutral in men.

Establishing a Swine Model of Post-myocardial Infarction Heart Failure for Stem Cell Treatment.

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major causes of mortality and morbidity around the world. Cell-based therapies for cardiac repair and improvement of left ventricular function after MI have attracted considerable attention. Accordingly, the safety and efficacy of these cell transplantations should be tested in a preclinical large animal model of HF prior to clinical use. Pigs are widely used for cardiovascular disease research due to their similarity to humans in terms of heart size and coronary anatomy. Therefore, we sought to present an effective protocol for the establishment of a porcine chronic HF model using closed-chest coronary balloon occlusion of the left circumflex artery (LCX), followed by rapid ventricular pacing induced with pacemaker implantation. Eight weeks later, the stem cells were administered by intramyocardial injection in the peri-infarct area. Then the infarct size, cell survival, and left ventricular function (including echocardiography, hemodynamic parameters, and electrophysiology) were evaluated. This study helps establish a stable preclinical large animal HF model for stem cell treatment.