Nrf2 mediated signaling axis in heart failure: Potential pharmacological receptor.

Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.

Global and regional cardiac dysfunction quantified by 18F-FDG PET scans can predict ventricular arrhythmia in patients with implantable cardioverter defibrillator.

BACKGROUND: A low appropriate therapy rate indicates that a minority of patients will benefit from their implantable cardioverter defibrillator (ICD). Quantitative measurements from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) may predict ventricular arrhythmia (VA) occurrence after ICD placement. METHODS: We performed a prospective observational study and recruited patients who required ICD placement. Pre-procedure image scans were performed. Patients were followed up for VA occurrence. Associations between image results and VA were analyzed. RESULTS: In 51 patients (33 males, 53.9 ± 17.2 years) analyzed, 17 (33.3%) developed VA. Compared with patients without VA, patients with VA had significantly larger values in scar area (17.7 ± 12.4% vs. 7.0 ± 7.9%), phase standard deviation (51.4° ± 14.0° vs. 34.0° ± 15.0°), bandwidth (172.9° ± 39.8° vs. 128.7° ± 49.9°), sum thickening score (STS, 29.5 ± 11.1 vs. 17.8 ± 13.2), and sum motion score (42.9 ± 11.5 vs. 33.0 ± 19.0). Cox regression analysis and receiver operating characteristic curve analysis showed that scar size, dyssynchrony, and STS were associated with VA occurrence (HR, 4.956, 95% CI 1.70-14.46). CONCLUSION: Larger left ventricular scar burden, increased dyssynchrony, and higher STS quantified by 18F-FDG PET may indicate a higher VA incidence after ICD placement.

Plasticity of left ventricular function with cardiac resynchronization therapy.

PURPOSE: To evaluate the clinical and echocardiographic effects of prolonged cessation and resumption of left ventricular pacing among patients with chronic cardiac resynchronization therapy (CRT). METHODS: This was a retrospective analysis of patients with long-term CRT who had loss of left ventricular pacing because of battery depletion. Clinical assessment and echocardiographic data were analyzed with comparisons between implant, chronic CRT, loss of CRT, and after resumption of CRT. RESULTS: There were 7 CRT responders who underwent 8 successful pulse generator replacements due to loss of CRT 6.3 ± 2.3 months after reaching elective replacement interval. With initial CRT implantation, QRS duration decreased from 171 ± 25 to 145 ± 28 ms (P < 0.001) and left ventricular ejection fraction increased from 27.6 ± 8.1 to 53.9 ± 9.6% (P < 0.001). At pulse generator replacement, worsening heart failure was present 6 of 7 patients with significant deterioration of left ventricular function and the left ventricular ejection fraction decreased to 43.4 ± 8.4%(P = 0.001). After resumption of CRT, clinical status and cardiac function recovered with left ventricular ejection fraction increasing to 53.7 ± 8.7% (P = 0.001). CONCLUSIONS: Prolonged loss of CRT is associated with significant deterioration of left ventricular function and functional status that is fully reversible with resumption of left ventricular pacing.

Elevated plasma ß-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy.

Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a "burned-out" state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non-heart failure manifestations of AC had higher plasma ß-hydroxybutyrate (ß-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher ß-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma ß-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma ß-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.

Tiaoxin Recipe, a Chinese herbal formula, inhibits microRNA-34a expression in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.

OBJECTIVE: To investigate the effect and underlying mechanisms of Tiaoxin Recipe (a Chinese herbal formula) treatment on Alzheimer's disease (AD). METHODS: Twelve-week-old APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as a model of AD-afflicted mice. One group of mice was treated with Tiaoxin Recipe by gastrogavage for 12 weeks, while two other groups were given intraperitoneal injections of nicotinamide adenine dinucleotide or FK866 for 4 weeks. Morris water maze and thioflavin S staining tests were performed to evaluate cognitive impairment and amyloid plaque deposition, respectively. Serum amyloid-ß1-42 (Aß1-42) content was detected using an enzyme-linked immunosorbent assay, and quantitative reverse transcription-polymerase chain reaction was performed to examine the expression levels of microRNA-34a (miR-34a) in cortex and hippocampus samples of the study mice. RESULTS: Compared with the normal control group, the memory and learning abilities of the APP/PS1 model group were found to be impaired (P < 0.01), as shown by the increased levels of senile plaque deposition in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01). Treatment with Tiaoxin Recipe significantly reduced memory impairment (P < 0.01) by reducing amyloid plaque accumulation in cortex and hippocampus (P < 0.01), miR-34a expression (P < 0.01) and serum Aß1-42 content (P < 0.01) in APP/PS1 mice. CONCLUSION: Tiaoxin Recipe is a viable complementary or alternative therapeutic treatment that is capable of delaying the development of early-stage AD by inhibiting the expression of miR-34a.

Predictors of non-response to cardiac resynchronization therapy implantation in patients with class I indications: the markedly dilated left ventricular end-diastolic dimension and the presence of fragmented QRS.

BACKGROUND: Cardiac resynchronization therapy (CRT) is a highly effective treatment in patients with a class I recommendation. However, a small proportion of the strictly selected patients still fail to respond. This study was designed to identify predictors of non-response in patients with class I indications for CRT and determine the non-response probability of the patients. METHODS: A total of 296 consecutive patients with a class I recommendation received CRT from January 2009 to January 2017 were retrospectively analyzed. Multivariate logistic regression analysis was performed to identify predictors for non-response (defined as cardiac death, heart transplantation, or HF hospitalization during 1-year follow-up). RESULTS: Among 296 patients, 30 (10.1%) met non-response. Multivariate analysis demonstrated that non-response to CRT was associated with a fragmented QRS (odd ratio (OR) = 2.86, 95% CI: 1.14-7.12; P = 0.025) and left ventricular end-diastolic dimension (LVEDD) ≥ 77 mm (OR = 3.02, 95% CI: 1.17-7.82; P = 0.022). Patients with both of the predictors had a non-response probability of 46.2% (95% CI: 19.1%-73.3%). CONCLUSION: In patients with left bundle branch block and wider QRS duration, the proportion of non-response to CRT is not low in real world. The presence of the dilated LVEDD or fragmented QRS is a strong predictor of non-response to CRT. The probability of non-response in the patients with the two predictors was 46.2%.

Does 'super-responder' patients to cardiac resynchronization therapy still have indications for neuro-hormonal antagonists? Evidence from long-term follow-up in a single center.

BACKGROUND: Whether cardiac resynchronization therapy super-responders (CRT-SRs) still have indications for neuro-hormonal antagonists or not remains uninvestigated. METHODS: We reviewed clinical data from 376 patients who underwent CRT implantation in Fuwai Hospital from 2009 to 2015 and followed up to 2017. CRT-SRs were defined by an improvement of the New York Heart Association functional class and left ventricular ejection fraction to ≥ 50% in absolute values at 6-month follow-up. All CRT-SRs were assigned into two groups on the basis of whether persistently receiving neuro-hormonal antagonists (NHA) (defined as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and ß-blockers) after 6-month follow-up and then we compared long-term outcome. RESULTS: A total of 60 patients met criteria for super-response. One of thirteen (7.7%) CRT-SRs without NHA had all-cause death, which also occurred in 2 of 47 (4.3%) in CRT-SRs with NHA (P = 0.526). However, 3 of 13 (23.1%) CRT-SRs without NHA had heart failure (HF) hospitalization, 1 of 47 (2.1%) CRT-SRs with NHA had this endpoint (P = 0.040). Besides, subgroup analysis indicated that, for ischemic etiology group, CRT-SRs receiving NHA had considerably lower incidence of HF hospitalization than those without NHA (0 vs. 75%, P = 0.014), which was not observed in non-ischemic etiology group (2.6% vs. 0, P = 1.000) during long-term follow-up. CONCLUSIONS: Our study found that for ischemic etiology, compared with CRT-SRs with NHA, CRT-SRs without NHA were associated with a higher risk of HF hospitalization. However, for non-ischemic etiology, we found that CRT-SRs with NHA or without NHA at follow-up were associated with similar outcomes, which needed further investigation by prospective trials.