Establishment of a scoring model for predicting clinical outcomes in patients with unilateral primary aldosteronism after superselective adrenal artery embolization.

OBJECTIVE: Superselective adrenal arterial embolization (SAAE) is a potential alternative treatment for patients with unilateral primary aldosteronism (PA) who refuse unilateral adrenalectomy. Therefore, we aimed to establish a scoring model to differentiate between hypertensive remission after SAAE. METHODS: This prospective cohort study involved 240 patients who underwent SAAE for unilateral PA. Patients were randomly divided into a model training set and a validation set at a ratio of 7:3. The clinical outcome was a response to hypertension remission, defined as complete, partial, or absent success at 6 months after SAAE. Multivariate logistic regression was performed to identify independent parameters and develop a nomogram to predict clinical outcomes after SAAE. The discrimination, calibration efficacy, and clinical utility of the predictive model were assessed. RESULTS: Five independent predictors were identified: female sex, duration of hypertension, defined daily dose of antihypertensive medication, diabetes, and target organ damage. The above five independent predictors were put into a predictive model that was presented as a nomogram. Using bootstrapping for internal validation, the C-statistic for the predictive model was 0.866 (95% confidence interval [CI]: 0.834 to 0.898). In the validation cohort, the area under the curve (AUC) of the nomogram for predicting hypertension remission after SAAE was 0.809. CONCLUSION: The present model is the first nomogram-based score that specifically predicts hypertension remission after SAAE in patients with unilateral PA using conventional parameters. This is an effective risk stratification tool that can be used by clinicians for timely and tailored preoperative risk discussions.

Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis.

BACKGROUND AND AIM: The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. METHODS AND RESULTS: PubMed, Embase, and the Cochrane Library were searched for cohort and case-control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). CONCLUSIONS: PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.

A controlled trial of percutaneous adrenal arterial embolization for hypertension in patients with idiopathic hyperaldosteronism.

Our prior study has suggested that percutaneous superselective adrenal arterial embolization (SAAE) with ethanol reduces blood pressure in patients with primary aldosteronism. This study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with idiopathic hyperaldosteronism. In this prospective, randomized, controlled trial, we randomly assigned patients with idiopathic hyperaldosteronism in a 1:1 ratio to undergo SAAE (n = 29) or receive MRA (n = 30) treatment. The primary endpoint was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The secondary endpoints included changes in office blood pressure, home blood pressure, correction of aldosterone-to-renin ratio, and adverse events at 6 months. The mean change in 24-h ambulatory systolic blood pressure from baseline to 6-month follow-up was significantly different between the two groups (-8.4 mmHg; 95% confidence interval, -15.2 to -2.1 mmHg; P < 0.01). Office, home, and ambulatory blood pressure reduction at 6 months was more pronounced in the SAAE group than the MRA group (all P < 0.05). Aldosterone-to-renin ratio was lower in the SAAE group than the MRA group at 1 and 3 months (both P < 0.01), while it had no difference between the two groups at 6 months. None of the patients experienced serious adverse events in the perioperative and 6-month follow-up periods. SAAE, as a hormonal debulking procedure, is superior to MRA in blood pressure control and correction of biochemical abnormalities in patients with idiopathic hyperaldosteronism.

A modified single-catheter approach for improving adrenal venous sampling in patients with primary aldosteronism.

OBJECTIVES: Adrenal vein sampling (AVS) is an established procedure for assessing subtype patients with primary aldosteronism (PA). However, it is technically challenging, with high failure rates, which limits its application in clinical practice. Our study aimed to evaluate the safety and efficacy of a single-catheter modified approach for AVS. METHODS: The clinical, angiographic, and procedural data of 182 consecutive patients who underwent AVS procedures between May 2020 and May 2023 were collected and analyzed. The single-catheter modified approach was performed as a single 5 F Tiger catheter with only one-time manual reshaping, which was recommended for sequential bilateral adrenal cannulations. RESULTS: Of the 182 consecutive patients, 174 (95.6%) had successful bilateral adrenal cannulation. The single-catheter modified approach was successfully performed to cannulate the right adrenal vein in 176 (96.7%) patients, while another six (3.3%) patients needed at least a second manual reshaping for 5 F Tiger catheters. For left adrenal cannulation, a single-catheter modified approach was successfully used in 179 (98.4%) patients, whereas 5 F Tiger catheters with at least second-time manual reshaping were used in the remaining three (1.6%) patients. The procedural period was 15.6 ± 10.8 min, the fluoroscopy time was 4.2 ± 1.5 min, and the diagnostic contrast was 15.5 ± 4.8 mL. The incidence of procedure-related complications associated with AVS was 1.1%. The cumulative summation assessment illustrated that the learning curve for the operating procedure required up to 29 cases, indicating that the procedure time was shortened after 29 cases. CONCLUSIONS: The single-catheter modified approach is an effective, safe, and feasible technique for AVS treatment. In particular, this improved method is not difficult for beginners with high technical success rates.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

PURPOSE: The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). METHODS: Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. RESULTS: A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (ß, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (ß, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (ß, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (ß, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (ß, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (ß, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. CONCLUSIONS: Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Effect of PCSK9 antibodies on coronary plaque regression and stabilization derived from intravascular imaging in patients with coronary artery disease: A meta-analysis.

BACKGROUND: Despite extensive evidence demonstrating the beneficial effects of the additional PCSK9 antibodies with high-density statins treatment on cardiovascular clinical outcomes, the potent causes underlying these effects remain elusive. This meta-analysis aimed at exploring the underlying causes to assess the effect of PCSK9 antibodies on the regression and stabilization of coronary plaque derived from intravascular imaging in statin-treated patients with coronary artery disease (CAD). METHODS: PubMed, Embase, and Cochrane Library were searched from inception to February 1, 2023, for randomized controlled trials (RCTs), nonrandomized studies without language restrictions if they described the association between PCSK9 antibodies with coronary plaque regression and stabilization evaluated by intravascular imaging in statin-treated patients with CAD. Meta-analyses were performed for mean difference (MD) and odds ratio (OR) using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. RESULTS: A total of 9 studies (7 RCTs and 2 non-RCTs) with 2290 CAD patients were identified and included. Among statin-treated CAD patients, the addition use of PCSK9 antibodies was associated with IVUS-derived percent atheroma volume (PAV) (4 studies with 1875 participants; MD, -1.26; 95% CI, -1.51 to -1.00; P < 0.01), total atheroma volume (TAV) (4 studies with 1875 participants; MD, -7.23; 95% CI, -11.28 to -3.18; P < 0.01), incidence of PAV regression (4 studies with 1875 participants; OR, 2.24; 95% CI, 1.81 to 2.77; P < 0.01) and incidence of TAV regression (3 studies with 1256 participants; OR, 1.66; 95% CI, 1.33 to 2.09; P < 0.01) in Caucasians instead of Asians from multiple countries; OCT-derived minimum fibrous cap thickness (FCT) (6 studies with 841 participants; MD, 25.16; 95% CI, 14.06 to 36.27; P < 0.01), incidence of thin-capped fibroatheroma (TCFA) regression (2 studies with 222 participants; OR, 2.56; 95% CI, 1.42 to 4.61; P < 0.01) and maximum lipid arc (4 studies with 280 participants; MD, -14.96; 95% CI, -22.10 to -7.83; P < 0.01) in Asians and Caucasians without races restrictions. CONCLUSIONS: PCSK9 antibodies resulted in significantly greater coronary plaque regression and stabilization in statin-treated CAD patients, mostly Caucasians from multiple countries. Further studies are needed to assess the effect for Asian patients.

Association between high-mobility group box 2 and subclinical hypertension-mediated organ damage in young adults.

Background: Hypertension-mediated organ damage (HMOD) is an emerging problem among young adults. The potential role of chronic immune-mediated inflammation in the pathogenesis of HMOD is increasingly being recognized. High-mobility group box 2 (HMGB2) is known for its role in the modulation of innate immunity and exerts signaling functions that affect various inflammatory diseases. However, the association between HMGB2 and HMOD in young adults remains unclear. Objectives: The aim of this study was to explore the association between HMGB2 and subclinical HMOD in young adults. Design: This is a cross-sectional study. Methods: Body composition, carotid ultrasound, carotid-femoral PWV (cf-PWV) measures, echocardiography, serum HMGB2 levels, and serum classic cardiometabolic risk factors were measured in 988 untreated young adults. We estimated the risk related to serum HMGB2 using multivariable-adjusted linear and logistic regression models. Then, we conducted a pathway overrepresentation analysis to examine which key biological pathways may be linked to serum HMGB2 in young adults with HMOD. Results: Among the 988 untreated young adults, we identified four distinct hypertension phenotypes: normotension (40.0%), white-coat hypertension (16.0%), masked hypertension (20.9%), and sustained hypertension (23.1%). High levels of serum HMGB2 were related to increased carotid intima-media thickness (cIMT) and left ventricular mass index (LVMI), higher cf-PWV and blood pressure, and a lower estimated glomerular filtration rate (eGFR). Linear regression analysis showed that serum HMGB2 was positively associated with cf-PWV and negatively associated with eGFR in all patients. Multivariate analysis showed that high levels of serum HMGB2 were associated with high odds of subclinical HMOD (damage in at least one organ). Biological pathway analysis indicated that patients with high serum HMGB2 levels had increased activity of pathways, related to endothelial dysfunction, inflammatory processes, and atherosclerosis. Conclusion: High serum concentrations of HMGB2 are associated with an increased risk of subclinical HMOD in untreated young adults.

Adrenal Ablation Versus Mineralocorticoid Receptor Antagonism for the Treatment of Primary Aldosteronism: A Single-Center Prospective Cohort Study.

BACKGROUND: Superselective adrenal arterial embolization (SAAE) is an alternative treatment for patients with primary aldosteronism (PA). This single-center prospective cohort study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with PA who refused unilateral adrenalectomy. METHODS: Of the 140 PA patients who were enrolled in the study and completed 12-month follow-up, 74 patients underwent SAAE and 66 received MRA treatment. The clinical and biochemical outcome was compared at 1, 6, and 12 months after the procedure. RESULTS: Baseline clinical and biochemical characteristics of the patients were similar between groups. Office, home, and ambulatory blood pressure reduction at 1 month after discharge was more pronounced in the SAAE group than MRA group (all P < 0.05) while the blood pressure reduction was comparable between the 2 groups at 6 and 12 months. Patients who underwent SAAE took less antihypertensive medications than the MRA group during 12-month follow-up (P < 0.01). Both SAAE and MRA treatment improved renin suppression, aldosterone-to-renin ratio elevation, and hypokalemia at 6 and 12 months, whereas only SAAE but not MRA reduced plasma aldosterone levels. Moreover, SAAE achieved higher rates of complete clinical and biochemical success than MRA (both P < 0.01). Logistic regression found that complete clinical and biochemical success was only directly associated with diagnosis of unilateral PA in contrast to bilateral PA (P < 0.01). CONCLUSIONS: The present study provides evidence that SAAE is a reasonable choice of treatment in patients with either unilateral or bilateral PA in terms of clinical and biochemical outcomes. This study was registered at Chictr.org.cn (ChiCTR2100045896).

The role of transient receptor potential ankyrin 1 in age-related endothelial dysfunction.

Oxidative stress plays a key role in age-related vascular disease. The present study aimed to investigate the role of an antioxidant channel, transient receptor potential ankyrin 1 (TRPA1), in age-related endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were grown to induce replicative senescence, and 6-month-old young, 12-month-old middle-aged, and 24-month-old aged mice were used. TRPA1 was downregulated in senescent HUVECs, so were endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), and uncoupling protein 2 (UCP2). Activating TRPA1 with cinnamaldehyde prevented downregulation of eNOS, Nrf2, and UCP2, inhibited superoxide production and apoptosis, and preserved nitric oxide bioavailability in senescent HUVECs. TRPA1, phosphorylated eNOS, Nrf2 and UCP2 were significantly downregulated in aged aortas compared with young aortas after a compensatory upregulation in middle-aged aortas. Dietary administration of cinnamaldehyde for 12 months prevented mitochondrial dysfunction, improved endothelium-dependent relaxation, and increased expression of eNOS, Nrf2, and UCP2 in aged aortas. Importantly, the effects of cinnamaldehyde can be blocked by a TRPA1 antagonist HC-030031. These findings suggest that TRPA1 may play a critical role in age-related endothelial dysfunction and may become a therapeutic target for the treatment and prevention of age-related vascular disease.

Renal denervation in a patient with a highly tortuous renal artery using a guide extension catheter: a case report.

BACKGROUND: Catheter-based renal denervation (RDN) has been introduced to treat resistant hypertension. Although the technology of RDN has been largely improved, denervation of tortuous renal arteries remains challenging. CASE PRESENTATION: This is a case report of a 49-year-old man with drug resistant hypertension. The patient was selected for RDN after ruling out possible causes of secondary hypertension. Computed tomography angiography showed a highly tortuous left renal artery. An Iberis multielectrode ablation catheter failed to reach the target vessel with a regular guiding catheter. A 5-French extension catheter was introduced into the proximal segment of the main left renal artery to provide extra support force, which enabled successful ablation of the highly tortuous left renal artery. His ambulatory blood pressure was significantly decreased at 1 month follow-up. CONCLUSIONS: It is feasible and effective to use a guide extension catheter for denervation of highly tortuous renal arteries. The present study provides a useful method to ablate tortuous and angled renal arteries and branches.

Dietary chlorogenic acid ameliorates oxidative stress and improves endothelial function in diabetic mice via Nrf2 activation.

OBJECTIVES: Chlorogenic acid (CGA) is an antioxidant dietary factor. We investigated the effects of CGA on endothelial cell dysfunction in diabetic mice and the mechanistic role of nuclear factor erythroid-related factor 2 (Nrf2) in the antioxidant effect of CGA. METHODS: Diabetic (db/db) mice were fed normal chow or chow containing 0.02% CGA for 12 weeks. Human umbilical vein endothelial cells (HUVECs) and mouse aortas were treated with normal or high glucose. RESULTS: CGA treatment induced upregulation of Nrf2 in HUVECs in a dose-dependent manner. CGA pretreatment prevented reactive oxygen species generation and preserved nitric oxide bioavailability in HUVECs and aortas from wild-type but not Nrf2-/- mice. CGA improved endothelium-dependent relaxation in high glucose-treated aortas from wild-type and db/db mice, but not Nrf2-/- mice. Dietary CGA improved endothelium-dependent relaxation in db/db mice. CONCLUSIONS: CGA ameliorates endothelial dysfunction in diabetic mice through activation of the Nrf2 anti-oxidative pathway.

Feasibility and effectiveness of a single-catheter approach for adrenal vein sampling in patients with primary aldosteronism.

BACKGROUND: Adrenal vein sampling (AVS) is the preferred method for subtyping patients with primary aldosteronism, while the procedure is technically challenging. This study evaluated the feasibility and effectiveness of a single-catheter approach for AVS. METHODS: A retrospective analysis of 106 consecutive patients who underwent AVS was performed to determine the procedural success and complication rates. Bilateral AVS procedures were performed using a single 5-Fr Tiger catheter with repeated manual reshaping. RESULTS: We successfully advanced the catheter into the bilateral adrenal veins of all patients and reached a 90.6% procedural success rate of AVS. The procedural period was 33.0 ± 8.2 min, the fluoroscopy period was 5.8 ± 1.7 min, and the diagnostic contrast used was 17.3 ± 5.5 ml. Only one patient (0.9%) had a hematoma at the femoral puncture site. No other complications were observed. The operation period gradually shortened as the cumulative number of operations increased. The number of procedures required to overcome the learning curve was about 33 cases. CONCLUSIONS: The single-catheter approach is feasible and effective for AVS. Moreover, this approach required a relatively short learning curve for an inexperienced trainee.

Development and validation of a prognostic prediction model for antithrombotic-related chronic subdural hematoma in patients with recent acute myocardial infarction.

BACKGROUND: Antithrombotic therapy is a cornerstone of acute myocardial infarction (AMI) treatment and is thought to be associated with an increased risk of chronic subdural hematoma (CSDH). However, no well-established model exists to predict subsequent antithrombotic treatment outcomes after CSDH in patients with recent AMI. We aimed to identify a prognostic model to predict the 6-month outcome of treatment with antithrombotic therapy. METHODS: This multicenter retrospective analysis involved 553 patients with recent AMI with antithrombotic-related CSDH. Several candidate clinical variables and biomarkers were examined in the training cohort (Chengdu training cohort; n=368). Patients with unfavorable outcomes had experienced at least 1 of the following: major adverse cardiovascular events (MACE), recurrence, or a modified Rankin scale (mRS) score of 2 to 6. To develop a 6-month outcome prediction model, three approaches were used: (I) a demographic variable model, (II) a clinical marker model and (III) a decision-driven model. A clinical outcome prediction model based on the superior predictors was assessed by logistic regression analysis. The nomogram for the final model was internally validated using a bootstrap procedure and externally validated in an independent cohort (Anhui cohort; n=185). RESULTS: Model A produced 7 predictors of unfavorable outcomes, while models B and C yielded 2 and 1 predictors, respectively. The areas under the curve (AUC) increased from 0.743 [model A; 95% confidence interval (CI): 0.680-0.782] to 0.889 (model A + B + C; 95% CI: 0.851-0.916). The final prediction model included age, systolic blood pressure (SBP), body mass index (BMI), the Glasgow Coma Scale (GCS), the estimated glomerular filtration rate (eGFR), the early resumption of antithrombotic therapy, hematoma thickness and the presence of abdominal obesity, frailty and previous bleeding. Internal and external validation of the selected final model revealed adequate C-statistics and calibration slope values (internal validation: 0.81 and 0.78; external validation: 0.80 and 0.76, respectively). CONCLUSIONS: This model provided a risk stratification tool to predict unfavorable outcomes in patients with recent AMI with antithrombotic-related CSDH. Because the study was based on ten readily practical and available variables, it may be widely applicable to guide management and complement clinical assessment.

Tom70 protects against diabetic cardiomyopathy through its antioxidant and antiapoptotic properties.

Mitochondrial dysfunction plays a critical role in the pathogenesis of diabetic cardiomyopathy. Translocase of mitochondrial outer membrane 70 (Tom70) primarily facilitates the import of mitochondrial preproteins that may be involved in the regulation of oxidative stress and mitochondrial function. This study aimed to investigate the role of Tom70 in the development of myocardial injury in leptin receptor-deficient (db/db) diabetic mice. Tom70 siRNA or an overexpressing lentivirus was intramuscularly injected into mouse hearts or used to treat cultured neonatal cardiomyocytes. We found that Tom70 was downregulated in the diabetic hearts compared with the level in the wild-type hearts and that knocking down Tom70 exacerbated cardiac hypertrophy, fibrosis, and ventricular dysfunction in the db/db mice. Similarly, the in vitro data demonstrated that silencing Tom70 enhanced high-glucose and high-fat (HGHF) medium treatment-induced mitochondrial superoxide production, decreased ATP production and the mitochondrial membrane potential, and enhanced cell apoptosis in neonatal cardiomyocytes. Importantly, overexpression of Tom70 alleviated HGHF medium-induced oxidative stress, mitochondrial dysfunction, and cell apoptosis. Furthermore, in vivo data confirmed that reconstitution of Tom70 ameliorated cardiac hypertrophy, interstitial fibrosis, and ventricular dysfunction in the db/db mice. In addition, Tom70 overexpression mitigated mitochondrial fragmentation and dysfunction in the hearts of the db/db mice. Taken together, these findings suggest that downregulation of Tom70 contributes to the development of diabetic cardiomyopathy and that reconstitution of Tom70 may be a new therapeutic strategy for the prevention and treatment of diabetic cardiomyopathy.

Trajectories of Waist-to-Hip Ratio and Adverse Outcomes in Heart Failure with Mid-Range Ejection Fraction.

BACKGROUND: Waist-to-hip ratio (WHR) is a strong predictor of mortality in patients with heart failure (HF). However, common WHR trajectories are not well established in HF with mid-range ejection fraction (HFmrEF) persons, and their relationship to clinical outcomes remains uncertain. METHOD: We prospectively enrolled 1,396 participants with HFmrEF (left ventricular ejection fraction 40-49%) from April 2013 through April 2017. The waist and hip circumferences of the subjects were measured at regular intervals, and the WHR was calculated as waist circumference divided by hip circumference. Latent mixture modeling was performed to identify WHR trajectories. We then used Cox proportional-hazard models to examine the association between WHR trajectory patterns and incident HF, incident cardiovascular disease (CVD), and all-cause mortality. RESULTS: We identified four distinct WHR trajectory patterns: lean-moderate increase (9.2%), medium-stable/increase (32.7%), heavy-stable/increase (48.0%), and heavy-moderate decrease (10.1%). After multivariable adjustment, the heavy-stable/increase and heavy-moderate decrease patterns were associated with an increased all-cause mortality risk (heavy-stable/increase: adjusted hazard ratio [HR] 3.18, 95% confidence interval [CI] 2.75-4.62; heavy-moderate decrease: adjusted HR 2.32, 95% CI 1.71-3.04), incident CVD risk (heavy-stable/increase: adjusted HR 4.03, 95% CI 2.39-4.91; heavy-moderate decrease: adjusted HR 3.05, 95% CI 2.34-4.09), and incident HF risk (heavy-stable/increase: adjusted HR 2.72, 95% CI 2.05-3.28; heavy-moderate decrease: adjusted HR 2.39, 95% CI 1.80-3.03) with reference to the lean-moderate increase pattern. CONCLUSION: Among patients with HFmrEF, the trajectories of WHR gain are associated with poor outcomes. These findings highlight the importance of abdominal fat accumulation management during the progression of HFmrEF.

Cinnamaldehyde Ameliorates Vascular Dysfunction in Diabetic Mice by Activating Nrf2.

BACKGROUND: Oxidative stress is known to be associated with the development of diabetes. Cinnamaldehyde (CA) is a spice compound in cinnamon that enhances the antioxidant defense against reactive oxygen species (ROS) by activating nuclear factor erythroid-related factor 2 (Nrf2), which has been shown to have a cardioprotection effect. However, the relationship between CA and Nrf2 in diabetic vascular complications remains unclear. METHODS: Leptin receptor-deficient (db/db) mice were fed normal chow or diet containing 0.02% CA for 12 weeks. The vascular tone, blood pressure, superoxide level, nitric oxide (NO) production, renal morphology, and function were measured in each group. RESULTS: CA remarkably inhibited ROS generation, preserved NO production, increased phosphorylated endothelial nitric oxide synthase (p-eNOS), attenuated the upregulation of nitrotyrosine, P22 and P47 in aortas of db/db mice, and apparently ameliorated the elevation of type IV collagen, TGF-ß1, P22, and P47 in kidney of db/db mice. Feeding with CA improved endothelium-dependent relaxation of aortas and mesenteric arteries, and alleviated the remodeling of mesenteric arteries in db/db mice. Additionally, dietary CA ameliorated glomerular fibrosis and renal dysfunction in diabetic mice. Nrf2 and its targeted genes heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1) were slightly increased in db/db mice and further upregulated by CA. However, these protective effects of CA were reversed in Nrf2 downregulation mice. CONCLUSIONS: A prolonged diet of CA protects against diabetic vascular dysfunction by inhibiting oxidative stress through activating of Nrf2 signaling pathway in db/db mice.

Roles of arterial pressure volume index and arterial velocity pulse index trajectories in risk prediction in hypertensive patients with heart failure with preserved ejection fraction.

Background: Arterial pressure volume index (API) and arterial velocity pulse index (AVI) contribute to the development of vascular damage and cardiovascular disease. However, the relationship between common API/AVI trajectories and cardiovascular outcomes in hypertensive patients with heart failure with preserved ejection fraction (HFpEF) is unknown.Methods: A total of 488 consecutive hypertensive patients with HFpEF who repeatedly underwent API/AVI measurements were prospectively examined. We then applied API/AVI measurements into actual clinical practice. Latent mixture modeling was performed to identify API/AVI trajectories. Hazards ratios (HRs) were measured using Cox proportional hazard models.Results: We identified four distinct API/AVI trajectory patterns: low (7.6%), moderate (43.8%), high (28.9%), and very high (19.7%). Compared with the low group, higher API trajectories were associated with increased risk of total cardiovascular events (high group, adjusted HR: 2.91, 95% confidence interval [CI]: 1.97-4.26; very high group, adjusted HR: 2.46, 95%CI: 1.18-3.79). Consistently, higher AVI trajectories were also associated with a higher risk of total cardiovascular events (high group, adjusted HR: 2.58, 95%CI: 1.23-5.47; very high group, adjusted HR: 3.12, 95%CI: 1.83-6.08), compared with the low trajectory group.Conclusion: High API/AVI trajectories are strong predictors of cardiovascular risk in hypertensive patients with HFpEF. Among these patients, measuring API/AVI may improve risk stratification and provide additional information to tailor treatment strategies.

Cinnamaldehyde Ameliorates High-Glucose-Induced Oxidative Stress and Cardiomyocyte Injury Through Transient Receptor Potential Ankyrin 1.

Oxidative stress plays a critical role in diabetic cardiomyopathy. Transient receptor potential ankyrin subtype 1 (TRPA1) has antioxidative property. In this study, we tested whether activation of TRPA1 with cinnamaldehyde protects against high-glucose-induced cardiomyocyte injury. Cinnamaldehyde remarkably decreased high-glucose-induced mitochondrial superoxide overproduction, upregulation of nitrotyrosine, P22, and P47, and apoptosis in cultured H9C2 cardiomyocytes (P < 0.01), which were abolished by a TRPA1 antagonist HC030031 (P < 0.01). Nrf2 and its induced genes heme oxygenase-1 (HO-1), glutathione peroxidase-1 (GPx-1), and quinone oxidoreductase-1 (NQO-1) were slightly increased by high glucose (P < 0.01) and further upregulated by cinnamaldehyde (P < 0.05 or P < 0.01). Feeding with cinnamaldehyde (0.02%)-containing diet for 12 weeks significantly decreased cardiac nitrotyrosine levels (P < 0.01), fibrosis, and cardiomyocyte hypertrophy (P < 0.05), while increased expression of antioxidative enzymes (HO-1, GPx-1, NQO-1, and catalase) (P < 0.01) in the myocardial tissue of db/db diabetic mice. These results suggest that cinnamaldehyde protects against high-glucose-induced oxidative damage of cardiomyocytes likely through the TRPA1/Nrf2 pathway.

Impact of Normal Weight Central Obesity on Clinical Outcomes in Male Patients With Premature Acute Coronary Syndrome.

There is a lack of studies that evaluate the association between normal weight central obesity and subsequent outcomes in patients with premature acute coronary syndrome (ACS). We evaluated 338 consecutive male patients (aged ≤ 55 years) with premature ACS. The primary outcomes were all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE). We compared the hazard ratios (HRs) in patients with and without normal weight central obesity using multivariable Cox proportional hazard models. All-cause mortality (16.8%) of patients with normal weight central obesity was much higher than those (7.1%) without normal weight central obesity (P = .008). The incidence of MACCE in patients with and without normal weight central obesity were 40.7 and 23.6% (P = .001), respectively. After multivariable adjustment, the risks of all-cause mortality and MACCE were significantly higher in patients with normal weight central obesity than those without normal weight central obesity (adjusted HR: 1.83; 95% confidence interval [CI]: 1.04-3.31; P = .004 and adjusted HR: 1.62; 95% CI: 1.18-2.27; P = .017, respectively). In conclusion, the risks of all-cause mortality and MACCE were significantly higher in male patients with premature ACS with normal weight central obesity than in those without normal weight central obesity.