Hydrogen sulfide alleviates heart failure with preserved ejection fraction in mice by targeting mitochondrial abnormalities via PGC-1α.

AIM: Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H2S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H2S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF. METHODS: Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific-Cse (Cystathionine γ-lyase, a major H2S-producing enzyme) knockout mice (CSEcko) were given high-fat diet (HFD) and l-NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H2S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot. RESULTS: Challenging with HFD and l-NAME in mice not only caused HFpEF but also inhibited the production of endogenous H2S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSEcko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS. CONCLUSION: Our findings have demonstrated that H2S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H2S supplementation in multifactorial HFpEF.

Temporal trends in the prevalence and severity of aortic stenosis within a contemporary and diverse community-based cohort.

BACKGROUND: Data on the epidemiology of aortic stenosis (AS) are primarily derived from single center experiences and administrative claims data that do not delineate by degree of disease severity. METHODS: An observational cohort study of adults with echocardiographic AS was conducted January 1st, 2013-December 31st, 2019 at an integrated health system. The presence/grade of AS was based on physician interpretation of echocardiograms. RESULTS: A total of 66,992 echocardiogram reports for 37,228 individuals were identified. The mean ± standard deviation (SD) age was 77.5 ± 10.5, 50.5% (N = 18,816) were women, and 67.2% (N = 25,016) were non-Hispanic whites. The age-standardized AS prevalence increased from 589 (95% Confidence Interval [CI] 580-598) to 754 (95% CI 744-764) cases per 100,000 during the study period. The age-standardized AS prevalences were similar in magnitude among non-Hispanic whites (820, 95% CI 806-834), non-Hispanic blacks (728, 95% CI 687-769), and Hispanics (789, 95% CI 759-819) and substantially lower for Asian/Pacific Islanders (511, 95% CI 489-533). Finally, the distribution of AS by degree of severity remained relatively unchanged over time. CONCLUSIONS AND RELEVANCE: The population prevalence of AS has grown considerably over a short timeframe although the distribution of AS severity has remained stable.

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria.

BACKGROUND: Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD. METHODS: Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria. RESULTS: Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m2 was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose. CONCLUSIONS: Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m2, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.

Predicting early discharge and readmission following pancreaticoduodenectomy [S079].

INTRODUCTION: Implementing enhanced recovery after surgery (ERAS) protocols for major abdominal surgery has been shown to decrease length of stay (LOS) and postoperative complications, including mortality and readmission. Little is known to guide which patients undergoing pancreaticoduodenectomy (PD) should be eligible for ERAS protocols. METHODS AND PROCEDURES: A retrospective chart review of all PD performed from 2010 to 2018 within an integrated healthcare system was conducted. A predictive score that ranges from 0 to 4 was developed, with one point assigned to each of the following: obesity (BMI > 30), operating time > 400 min, estimated blood loss (EBL) > 400 mL, low- or high-risk pancreatic remnant (based on the presence of soft gland or small duct). Chi-squared tests and ANOVA were used to assess the relationship between this score and LOS, discharge before postoperative day 7, readmission, mortality, delayed gastric emptying (DGE), and pancreatic leak/fistula. RESULTS: 291 patients were identified. Mean length of stay was 8.5 days in those patients who scored 0 compared to 16.2 days for those who scored 4 (p = 0.001). 30% of patients who scored 0 were discharged before postoperative day 7 compared to 0% of those who scored 4 (p = 0.019). Readmission rates for patients who scored 0 and 4 were 12% and 33%, respectively (p = 0.017). Similarly, postoperative pancreatic fistula occurred in 2% versus 25% in these groups (p = 0.007). CONCLUSION: A simple scoring system using BMI, operating time, EBL, and pancreatic remnant quality can help risk-stratify postoperative PD patients. Those with lower scores could potentially be managed via an ERAS protocol. Patients with higher scores required longer hospitalizations, and adjunctive therapy such as medication and surgical technique to decrease risk of delayed gastric emptying and pancreatic fistula could be considered.

Pancreatic Neuroendocrine Tumor: Rationale for Centralization in an Integrated Health Care System.

OBJECTIVES: Given the complex surgical management and infrequency of pancreatic neuroendocrine tumor, we hypothesized that treatment at a center of excellence improves survival. METHODS: Retrospective review identified 354 patients with pancreatic neuroendocrine tumor treated between 2010 and 2018. Four hepatopancreatobiliary centers of excellence were created from 21 hospitals throughout Northern California. Univariate and multivariate analyses were performed. The χ2 test of clinicopathologic factors determined which were predictive for overall survival (OS). RESULTS: Localized disease was seen in 51% of patients, and metastatic disease was seen in 32% of patients with mean OS of 93 and 37 months, respectively (P < 0.001). On multivariate survival analysis, stage, tumor location, and surgical resection were significant for OS (P < 0.001). All stage OS for patients treated at designated centers was 80 and 60 months for noncenters (P < 0.001). Surgery was more common across stages at the centers of excellence versus noncenters at 70% and 40%, respectively (P < 0.001). CONCLUSIONS: Pancreatic neuroendocrine tumors are indolent but have malignant potential at any size with management often requiring complex surgeries. We showed survival was improved for patients treated at a center of excellence, where surgery was more frequently utilized.

Centralization of pancreatic cancer treatment within an integrated healthcare system improves overall survival.

BACKGROUND: Higher-volume centers for pancreatic cancer surgeries have been shown to have improved outcomes such as length of stay. We examined how centralization of pancreatic cancer care within a regional integrated healthcare system improves overall survival. METHODS: We conducted a retrospective study of 1621 patients treated for pancreatic cancer from February 2010 to December 2018. Care was consolidated into 4 Centers of Excellence (COE) in surgery, medical oncology, and other specialties. Descriptive statistics, bivariate analysis, Chi-square tests, and Kaplan-Meier analysis were performed. RESULTS: Neoadjuvant chemotherapy use rose from 10% to 31% (p < .001). The median overall survival (OS) improved by 3 months after centralization (p < .001), but this did not reach significance on multivariate analysis. CONCLUSIONS: Our results suggest that in a large integrated healthcare system, centralization improves overall survival and neoadjuvant therapy utilization for pancreatic cancer patients.

Effect of Chinese herbal medicines on the overall survival of patients with muscular dystrophies in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Muscular dystrophies are a rare, severe, and genetically inherited group of disorders characterized by progressive loss of muscle fibers, leading to muscle weakness. The current treatment plan for muscular dystrophies includes the use of steroids to slow muscle deterioration by dampening the inflammatory response. AIM OF THE STUDY: Chinese herbal medicine (CHM) has been offered as an adjunctive therapy in Taiwan's medical healthcare plan, making it possible to track CHM usage in patients with muscular dystrophic disease. Therefore, we explored the long-term effects of CHM use on the overall mortality of patients with muscular dystrophies. MATERIALS AND METHODS: A total of 581 patients with muscular dystrophies were identified from the database of Registry for Catastrophic Illness Patients in Taiwan. Among them, 80 and 201 patients were CHM users and non-CHM users, respectively. Student's t-test, chi-squared test, Cox proportional hazard model, and Kaplan-Meier curve (log-rank test) were used for evaluation. Association rules and network analyses were performed to explore the combination of CHMs used in muscular dystrophies. RESULTS: Compared to non-CHM users, there were more female patients, more comorbidities, including chronic pulmonary disease and peptic ulcer disease in the CHM user group. Patients with prednisolone usage exhibited a lower risk of overall mortality than those who did not, after adjusting for age, sex, use of CHM, and comorbidities. CHM users showed a lower risk of overall mortality after adjusting for age, sex, prednisolone use, and comorbidities. The cumulative incidence of the overall survival was significantly higher in CHM users. Association rule and network analysis showed that one main CHM cluster was commonly used to treat patients with muscular dystrophies in Taiwan. The cluster includes Yin-Qiao-San, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Zhi-Ke (Citrus aurantium L.), Yu-Xing-Cao (Houttuynia cordata Thunb.), Che-Qian-Zi (Plantago asiatica L.), and Da-Huang (Rheum palmatum L.). CONCLUSIONS: Our data suggest that adjunctive therapy with CHM may help to reduce the overall mortality among patients with muscular dystrophies. The identification of the CHM cluster allows us to narrow down the key active compounds and may enable future therapeutic developments and clinical trial designs to improve overall survival in these patients.

Targeting of CAT and VCAM1 as Novel Therapeutic Targets for DMD Cardiomyopathy.

Duchenne muscular dystrophy (DMD) related cardiomyopathy is the leading cause of early mortality in DMD patients. There is an urgent need to gain a better understanding of the disease molecular pathogenesis and develop effective therapies to prevent the onset of heart failure. In the present study, we used DMD human induced pluripotent stem cells (DMD-hiPSCs) derived cardiomyocytes (CMs) as a platform to explore the active compounds in commonly used Chinese herbal medicine (CHM) herbs. Single CHM herb (DaH, ZK, and CQZ) reduced cell beating rate, decreased cellular ROS accumulation, and improved structure of DMD hiPSC-CMs. Cross-comparison of transcriptomic profiling data and active compound library identified nine active chemicals targeting ROS neutralizing Catalase (CAT) and structural protein vascular cell adhesion molecule 1 (VCAM1). Treatment with Quecetin, Kaempferol, and Vitamin C, targeting CAT, conferred ROS protection and improved contraction; treatment with Hesperidin and Allicin, targeting VCAM1, induced structure enhancement via induction of focal adhesion. Lastly, overexpression of CAT or VCAM1 in DMD hiPSC-CMs reconstituted efficacious effects and conferred increase in cardiomyocyte function. Together, our results provide a new insight in treating DMD cardiomyopathy via targeting of CAT and VCAM1, and serves as an example of translating Bed to Bench back to Bed using a muti-omics approach.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate.

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Phosphorus Additives and Albuminuria in Early Stages of CKD: A Randomized Controlled Trial.

BACKGROUND: Little is known about the effects of phosphorus additives on patients with kidney disease. STUDY DESIGN: Randomized, double-blind, crossover trial. SETTING & PARTICIPANTS: 31 adults with early stages of presumed chronic kidney disease (estimated glomerular filtration rate ≥ 45mL/min/1.73m2; urine albumin-creatinine ratio sex-specific cutoff points: men ≥ 17mg/g, women ≥ 25mg/g). INTERVENTION: Higher versus lower phosphorus intake for 3 weeks. Higher phosphorus intake was achieved by the addition of commercially available diet beverages and breakfast bars to diet. OUTCOMES: Change in 24-hour urine albumin excretion and plasma fibroblast growth factor 23 level. MEASUREMENTS: Two 24-hour urine collections and a single fasting blood draw at the end of each period. RESULTS: Mean baseline values for phosphorus intake, 24-hour urine phosphorus excretion, and estimated glomerular filtration rate were 1,113±549 (SD) mg/d, 688±300mg/d, and 74.6±22.0mL/min/1.73m2. Median urine albumin excretion of 82.7 (IQR, 39.6-174.1) mg/d. Although phosphorus intake from study products increased by 993mg/d (P<0.001) during the higher compared to lower phosphorus additive period, background phosphorus intake decreased by 151mg/d (P=0.004). Higher phosphorus additive consumption increased 24-hour urine phosphorus excretion by 505 (95% CI, 381 to 629) mg/d (P<0.001), but did not significantly increase albuminuria (higher vs lower: 14.3%; 95% CI, -2.5% to 34.0%; P=0.1) or fibroblast growth factor 23 level (higher vs lower: 3.4%; 95% CI, -5.9% to 13.6%; P=0.4). LIMITATIONS: Small sample size, short duration of intervention, changes in background diet during the intervention. CONCLUSIONS: A 3-week consumption of higher phosphorus food additives did not significantly increase albuminuria. Further studies are needed to confirm these results.

Incident chronic kidney disease: trends in management and outcomes.

BACKGROUND: Management trends in early chronic kidney disease (CKD) and their associations with clinical outcomes have not previously been reported. METHODS: We evaluated incident (Stage G3A) CKD patients from an integrated health care system in 2004-06, 2007-09 and 2010-12 to determine adjusted trends in screening (urinary protein quantification), treatment [prescription for angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and statin] and nephrology referral. For the same time periods, adjusted rates for mortality, progression to Stage G4 CKD and hospitalization for myocardial infarction or heart failure were calculated and compared across time periods. RESULTS: There were 728, 788 and 956 patients with incident CKD in 2004-06, 2007-09 and 2010-12, respectively. Adjusted rates of proteinuria quantification (31, 39 and 51 screens/100 person-years), statin prescription (53, 63 and 64 prescriptions/100 person-years) and nephrology referral (2, 3 and 5 referrals/100 person-years) all increased over time (P for trend <0.001 in all cases). ACEI/ARB prescription rates did not change (88, 83 and 80 prescriptions/100 person-years, P = 0.68). Adjusted death rates (7, 5 and 6 deaths/100 person-years), CKD progression (9, 10 and 7 progressors/100 person-years) and cardiovascular hospitalization (10, 8 and 9 hospitalizations per 100/person-years) did not change (P for trend >0.4 in all cases). CONCLUSION: In this integrated health care system, management of incident CKD over the past decade has intensified.

Serum phosphorus and mortality in the Third National Health and Nutrition Examination Survey (NHANES III): effect modification by fasting.

BACKGROUND: Serum phosphorus levels have been associated with mortality in some but not all studies. Because dietary intake prior to measurement can affect serum phosphorus levels, we hypothesized that the association between serum phosphorus level and mortality is strongest in those who have fasted longer. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Nationally representative sample of 12,984 participants 20 years or older in the Third National Health and Nutrition Examination Survey (1988-1994). FACTORS: Serum phosphorus level, fasting duration (dichotomized as ≥ 12 or < 12 hours). OUTCOMES: All-cause and cardiovascular mortality determined by death certificate data from the National Death Index. MEASUREMENTS: Serum phosphorus measured in a central laboratory and fasting duration recorded as time since food or drink other than water was consumed. RESULTS: Individuals fasting 12 or more hours had lower serum phosphorus levels than those fasting less than 12 hours (3.34 vs 3.55 mg/dL; P < 0.001) and higher correlation with repeat measurement (0.66 vs 0.53; P = 0.002). In multivariable-adjusted Cox regression models, the highest quartile of serum phosphorus was associated with increased mortality in participants fasting 12 or more hours (adjusted HR, 1.74; 95% CI, 1.38-2.20; reference, lowest quartile) but not in participants fasting less than 12 hours (adjusted HR, 1.08; 95% CI, 0.89-1.32; P for interaction = 0.002). Relationships were consistent using 8 hours as the fasting cutoff point or cardiovascular mortality as the outcome. LIMITATIONS: Observational study, lack of fibroblast growth factor 23 or intact parathyroid hormone measurements. CONCLUSIONS: Fasting but not nonfasting serum phosphorus levels were associated with increased mortality. Risk prognostication based on serum phosphorus may be improved using fasting levels.

Association of a reduction in central obesity and phosphorus intake with changes in urinary albumin excretion: the PREMIER study.

BACKGROUND: Excess adiposity and dietary factors may be important determinants of urinary albumin excretion (UAE). STUDY DESIGN: Observational analysis of PREMIER, a randomized trial designed to lower blood pressure using behavioral interventions (counseling on weight loss, healthy diet, and exercise). SETTING & PARTICIPANTS: 481 participants with normal kidney function who provided adequate 24-hour urine collections at baseline and 6 months. PREDICTORS: Change in waist circumference; 24-hour urine sodium, potassium, and phosphorus excretion; and protein intake estimated from urea nitrogen. OUTCOMES & MEASUREMENTS: The primary outcome was change in log-transformed 24-hour UAE over 6 months. RESULTS: After 6 months, the proportion of individuals with UAE ≥10 mg/d decreased from 18.7% to 12.7% (P < 0.001). Changes in mean waist circumference (-4.2 ± 6.6 [SD] cm), 24-hour excretion of sodium (-28.2 ± 71.7 mmol/d), potassium (+8.4 ± 27.8 mmol/d), phosphorus (-27.7 ± 314.1 mg/d), and protein intake (-1.7 ± 19.4 g/d) were observed. After adjustment for relevant covariates, the following variables were associated significantly with reduction in ln(UAE) in separate models: decrease in waist circumference (P = 0.001), decrease in 24-hour urine phosphorus excretion (P < 0.001), and decrease in protein intake (P = 0.01). In a multivariable model including these 3 predictors, decreases in waist circumference (P = 0.002) and 24-hour urine phosphorus excretion (P = 0.03), but not change in protein intake (P = 0.5), remained associated significantly with reduction in ln(UAE). These associations remained significant even after adjustment for changes in blood pressure and insulin resistance. Baseline UAE and metabolic syndrome modified the relationship of waist circumference with ln(UAE); specifically, individuals with higher UAE and baseline metabolic syndrome experienced greater reductions in ln(UAE) from decreases in waist circumference. LIMITATIONS: Observational study with potential for confounding. CONCLUSIONS: In adults with normal kidney function, decreases in waist circumference and 24-hour urine phosphorus excretion are associated with reductions in UAE. These findings support the rationale for clinical trials to determine whether reducing dietary phosphorus intake or waist circumference could prevent chronic kidney disease or slow its progression.

An alternative approach to determining therapeutic choices in advanced non-small cell lung carcinoma (NSCLC): maximizing the diagnostic procedure and the use of low-volume lung biopsies.

BACKGROUND: Accurate mutational analysis, especially epidermal growth factor receptor (EGFR) mutations, of diagnostic biopsies from all Asian NSCLC patients is crucial to their clinical management, but faces problems. Here, we explore, within usual hospital constraints, the practicalities of incorporating mutational analysis in every newly diagnosed case of NSCLC, namely, maximizing tissue acquisition during the diagnostic procedure and determining the maximum quantity and quality of DNA sequence data available from these biopsies. METHODS: Sixty-eight Chinese patients were enrolled. Thirty-five underwent surgical resections for early-stage tumors. Thirty-three underwent diagnostic procedures, i.e., needle aspirates under bronchoscopic or computed tomographic/fluoroscopic guidance, or forceps biopsies via bronchoscopy. Separate samples for research purposes were obtained from these 33 patients during the diagnostic procedure. All samples were analyzed for mutations in EGFR exons 18 to 21, p53 exons 4 to 9, and Kras exon 2. RESULTS: No deaths occurred in this study. Success rates in obtaining sequence data from surgical samples versus low-volume samples for EGFR, p53, and Kras were 100% versus 85%, 100% versus 82%, and 100% versus 85%, respectively. Sequencing nine polymerase chain reaction products from each low-volume sample resulted in the exhaustion of all extracted DNA from three samples. CONCLUSIONS: Acquiring a separate low-volume lung biopsy sample for mutational analysis in lung cancer patients during the diagnostic procedure is feasible and may be a valuable complement to the usual diagnostic workflow in future.