Treatment of Moderate Functional Mitral Regurgitation during Aortic Valve Replacement: A Cohort Study.

Background: Treatment of moderate functional mitral regurgitation (FMR) during aortic valve replacement (AVR) is controversial. This study aimed to evaluate the effect of different surgical strategies in patients with moderate FMR undergoing AVR. Methods: A total of 468 patients with moderate FMR undergoing AVR from January 2010 to December 2019 were retrospectively studied comparing 3 different surgical strategies, namely isolated AVR, AVR + mitral valve repair (MVr) and AVR + mitral valve replacement (MVR). Survival was estimated using the Kaplan-Meier method and compared with the log-rank test, followed by inverse probability treatment weighting (IPTW) analysis to adjust the between-group imbalances. The primary outcome was overall mortality. Results: Patients underwent isolated AVR (35.3%), AVR + MVr (30.3%), or AVR + MVR (34.4%). The median follow-up was 27.1 months. AVR + MVR was associated with better improvement of FMR during the early and follow-up period compared to isolated AVR and AVR + MVr (p < 0.001). Compared to isolated AVR, AVR + MVR increased the risk of mid-term mortality (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: 1.01-4.48, p = 0.046), which was sustained in the IPTW analysis (HR: 4.15, 95% CI: 1.69-10.15, p = 0.002). In contrast, AVR + MVr showed only a tendency to increase the risk of follow-up mortality (HR: 1.63, 95% CI: 0.72-3.67, p = 0.239), which was more apparent in the IPTW analysis (HR: 2.54, 95% CI: 0.98-6.56, p = 0.054). Conclusions: In patients with severe aortic valve disease and moderate FMR, isolated AVR might be more reasonable than AVR + MVr or AVR + MVR.

Iron Deficiency Might Impair the Recovery of Left Ventricular Function after Surgical Revascularization in Diabetic Patients: A Retrospective Study.

Background: Iron deficiency (ID) is one of the most common micronutrient deficiencies affecting public health. Studies show that ID affects the prognosis of patients with heart disease, including heart failure, coronary artery disease and myocardial infarction. However, there is limited information regarding the impact of ID on patients undergoing cardiac surgery. This study aimed to evaluate the influence of preoperative ID on the prognosis of type 2 diabetes mellitus (T2DM) patients undergoing coronary artery bypass grafting (CABG). Methods: In the Glycemic control using mobile-based intervention in patients with diabetes undergoing coronary artery bypass to promote self-management (GUIDEME) study, patients with T2DM undergoing CABG were prospectively recruited. In this study, only those patients with preoperative iron metabolism results were enrolled. Patients were grouped based on the presence of preoperative ID. The primary endpoint was defined as the significant improvement of follow-up ejection fraction (EF) compared to postoperative levels (classified according to the 75th percentile of the change, and defined as an improvement of greater than or equal to 5%). Univariable logistic regression was performed to explore the potential confounders, followed by multiple adjustment. Results: A total of 302 patients were enrolled. No deaths were observed during the study period. A higher incidence of the primary endpoint was observed in the ID group (25.4% vs 12.9%, p = 0.015). The postoperative and follow-up EF were similar beween the two groups. In the regression analysis, ID was noticed to be a strong predictor against the significant improvement of EF in both univariable (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.22-0.86, p = 0.017) and multivariable (OR: 0.43, 95% CI: 0.24-0.98, p = 0.043) logistic regression. In the subgroup analysis, ID was a predictor of significant improvement of EF in age ≤ 60 years, male, EF ≤ 60%, and on-pump CABG patients. Conclusions: In T2DM patients undergoing CABG, ID might negatively affect the early recovery of left ventricular systolic function in terms of recovery of EF 3-6 months after surgery, especially in patients age ≤ 60 years, males, EF ≤ 60% and in those undergoing on-pump CABG.

Clinical Outcomes After the Surgical Treatment of Hypertrophic Obstructive Cardiomyopathy With Left Ventricular Apical Aneurysm.

BACKGROUND: Left ventricular apical aneurysm (LVAA) is a rare complication of hypertrophic obstructive cardiomyopathy (HOCM). This study aimed to illustrate the clinical characteristics and surgical outcomes of these patients. METHOD: Patients with HOCM and LVAA who underwent modified extended Morrow myectomy and surgical left ventricular reconstruction (SLVR) between October 2012 and March 2021 were retrospectively recruited. Patients with coronary artery disease were excluded. Clinical characteristics were summarised. Time-to-event outcomes were calculated using the Kaplan-Meier method and compared by a log-rank test. RESULTS: Fifteen eligible patients were identified; the mean age was 39.9±17.2 years and 40.0% of them were female. All patients had dyspnoea, 46.7% presented with syncope and/or chest pain, and 13.3% had a family history of hypertrophic cardiomyopathy. The mean LVAA size was 36.9±12.3 mm in length and 28.5±11.3 mm in width. Echocardiography showed LV outflow tract obstruction in seven (46.7%) patients, mid-cavity LV obstruction in 12 (80.0%), while systolic anterior motion (SAM) was seen in seven (46.7%). The symptoms were resolved in all patients postoperatively. During a median follow-up of 22.0 months, one (6.7%) patient had sudden cardiac death, one (6.7%) had a haemorrhagic stroke, and the LVAA recurrence was 40.0%. Subgroup analysis showed that signs of SAM and larger LVAA (≥30 mm) were associated with an increased tendency for a longer hospital stay. CONCLUSIONS: Patients with HOCM and LVAA present with high-risk profiles. Modified extended Morrow myectomy combined with SLVR is useful in relieving the symptoms and improving the prognosis, although there might be recurrent LVAA.

Long-Term Outcomes of Left Ventricular Restoration in Patients Ineligible for Concomitant Coronary Artery Bypass Grafting.

BACKGROUND: The prognosis of severe coronary artery disease (CAD) patients undergoing left ventricular restoration (LVR) and ineligible for concomitant coronary artery bypass grafting (CABG) is unclear. This study illustrates the clinical characteristics and the long-term survival of these patients in a retrospective cohort. METHODS: From January 1999 to March 2021, a total of 78 patients underwent surgical left ventricular restoration without concomitant CABG at our center. The primary endpoint was the major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis was performed to calculate survival, and compared by log-rank test, followed by multiple adjustments using Cox regression. RESULTS: The mean age was 55.3 ± 11.4 years. There were 76 (97.4%) true and 2 (2.6%) pseudo-aneurysms. Forty-six (59.0%) patients presented NYHA functional class III or IV. The mean EuroSCORE was 10.6 ± 3.2. Concomitant surgeries included mitral valve repair (N = 3), mitral valve replacement (N = 2), tricuspid valve repair (N = 2), ventricular septal defect closure (N = 18), maze procedure (N = 1), and appendage ligation (N = 1). Reoperation for bleeding was performed in one patient (1.3%). Prolonged ventilation was observed in 21 (26.9%) patients. Fourteen (17.9%) patients presented with low cardiac output and were supported with IABP. Operative death occurred in one (1.3%) patient. The median duration of echocardiographic follow-up was 53 months (interquartile range, 81.5) and was obtained in 46 (59.0%) patients. Left ventricular ejection fraction (LVEF) improved from 41.1% ± 10.5% to 45.6% ± 7.9% (P < 0.001), and the left ventricular end-diastolic dimension (LVEDD) fell from 57.8 ± 6.6 mm to 52.0 ± 6.2 mm (P < 0.001). The median patient follow-up time was 79.5 months (interquartile range, 53.5). Overall, 1-, 5-, and 10-year survival rates were 98.7%, 95.5% and 82.3%, respectively. CONCLUSIONS: Patients with severe CAD and ineligible for concomitant CABG are in critical condition, and LVR could be a reliable approach to improving cardiac function with satisfactory early and long-term outcomes.

Prognostic value of carbohydrate antigen 125 in patients undergoing surgical left ventricular reconstruction.

BACKGROUND: Carbohydrate antigen 125 (CA125) is a biomarker often used in diagnosis of ovarian tumors. Studies also show that elevated CA125 implicates worse outcomes among patients with heart failure, while latter of which plays an important role in the pathophysiology of left ventricular aneurysm (LVA). However, the prognostic value of CA125 in LVA patients undergoing surgical left ventricular reconstruction (SLVR) remains unclear. METHODS: In this single-centered cohort study, a total of 309 patients with LVA undergoing SLVR were retrospectively recruited. Univariable regression analysis was performed to identify the potential confounders for each outcome, followed by multivariable adjustment to confirm the association between CA125 and outcomes. The primary outcome was the overall mortality, and the secondary outcome was the major adverse cardiovascular and cerebrovascular events (MACCE) and perioperative outcomes. A receiver operating characteristic (ROC) curve was use to find the optimal cut-off value of CA125. RESULTS: The median follow-up time was 55 months. The cohort was predominantly male (86.4%), with an average age of 58.6 years. Log (CA125) was associated with overall mortality (hazard ratio [HR]: 2.15, 95% confidence interval [CI]: 1.06-4.36, P = 0.033), prolonged hospital-stay time (HR:1.07, 95%CI: 1.03-1.12, P = 0.001) and increased risk of postoperative ventricular support (HR: 2.81, 95%CI: 1.10-7.18, P = 0.031) after multivariate adjustment. The optimal cut-off value for the CA125 for all-cause mortality was 13.825 U/ml with the area under curve of 0.675. CONCLUSION: Elevated-CA125 implicates poorer short- and long-term prognosis in LVA patients undergoing SLVR.

Results of different therapeutic strategies for left ventricular aneurysm with mitral regurgitation.

OBJECTIVE: This study aims to compare the midterm outcomes of left ventricular reconstruction (LVR) added to coronary artery bypass grafting (CABG) with those of CABG alone in patients with left ventricular aneurysm (LVA) and mild or moderate mitral regurgitation (MR). We also assessed the impact of LVR on the degree of MR. METHODS: A total of 130 patients (77 who underwent CABG plus LVR and 53 who underwent CABG alone) with concomitant mild or moderate MR were included in the study population. All-cause mortality was considered the primary endpoint. Major adverse cardiovascular and cerebrovascular events (MACCEs), including death, myocardial infarction, stroke, and subsequent mitral valve surgery, were considered secondary endpoints. Kaplan-Meier analysis was performed to evaluate event-free survival. MR was graded 0 to 4+ by echocardiogram. RESULTS: The median follow-up time among all patients was 22 months. There was a significant difference between the CABG plus LVR and CABG alone groups with regard to all-cause mortality ( P = 0.019). However, the statistical difference was not observed in cardiogenic mortality ( P = 0.186) and MACCEs ( P = 0.107). In the grade of MR, the two groups both resulted in the decreased grade of MR, but the CABG plus LVR group had a significant number of patients improving to 0 or 1+ ( P = 0.030). CONCLUSION: The clinical outcomes of CABG alone are comparable with those of CABG plus LVR in patients with LVA and mild or moderate MR. However, CABG+LVR demonstrated greater reduction in MR severity after surgery than CABG alone.

Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy.

Cardiac insulin resistance plays an important role in the development of heart failure, but the underlying mechanisms remain unclear. Here, we found that hypertrophic hearts exhibit normal cardiac glucose oxidation rates, but reduced fatty acid oxidation rates, compared to Sham controls under basal (no insulin) conditions. Furthermore, insulin stimulation attenuated insulin's effects on cardiac substrate utilization, suggesting the development of cardiac insulin resistance. Consistent with insulin resistance, p38-MAPK protein levels were reduced in hypertrophic hearts. By contrast, systemic hyperinsulin-euglycemic clamp indicated normal insulin sensitivity. Finally, electron microscopy revealed severe mitochondrial damage in the hypertrophic myocardium. Our results indicate that that cardiac insulin resistance caused by cardiac hypertrophy is associated with mitochondrial damage and cardiac dysfunction. Moreover, our findings suggest that cardiac insulin resistance is independent of systemic insulin resistance, which is also a risk factor for heart failure.

Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway.

AIMS: Enhanced aerobic glycolysis is an essential hallmark of malignant cancer. Blocking the glycolytic pathway has been suggested as a therapeutic strategy to impair the proliferation of tumor cells. Metformin, a widely used anti-diabetes drug, exhibits anti-tumor properties. However, the underlying molecular mechanism of its action linking glucose metabolism with the suppression of proliferation has not been fully clarified. MAIN METHODS: Stable isotope tracing technology and gas chromatography-mass spectrometry method were utilized to analyze the effect of metformin on glycolytic flux in HCC cells. Western blot and immunohistochemistry were utilized to analyze the expression of phosphofructokinase-1 (PFK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in HCC cells or xenograft tumor tissues. Lactate measurement and glucose uptake assay were used to analyze the level of lactate and glucose in the presence of frucose-2,6-diphosphate (F2,6BP) in HCC cells treated with metformin. KEY FINDINGS: We found that metformin significantly impaired hepatoma cell proliferation by inhibiting the glycolytic flux via PFK1 blockade. Interestingly, activation of PFK1 by F2,6BP reverses the inhibitory effect of metformin on hepatoma cell proliferation and glycolysis. Mechanistically, PFKFB3，a potent allosteric activator of PFK1, was markedly suppressed through inhibiting hypoxia-induced factor 1 (HIF-1α) accumulation mediated by metformin. SIGNIFICANCE: Taken together these data indicate that HIF-1α/PFKFB3/PFK1 regulatory axis is a vital determinant of glucose metabolic reprogramming in hepatocellular carcinoma, which gives new insights into the action of metformin in combatting liver cancer.

Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts.

Increasing evidence suggests that therapy-induced senescence (TIS), a novel therapeutic approach in which low doses of therapeutic drugs or radiation are used to induce senescence, suppresses tumor development. Our previous in vitro studies have demonstrated that a low dose of metformin promoted hepatoma cell senescence instead of apoptosis via activation of AMP-activated protein kinase (AMPK) and inactivation of Sirtuin 1 (SIRT1) deacetylase activity. However, the intricate relationship between AMPK and SIRT1, and how they cooperate to induce senescence remains elusive. We showed here that persistent exposure to a low concentration of metformin led to AMPK activation in a mouse xenograft model of human hepatocellular carcinoma (HCC), resulting in senescence. Intriguingly, AMPK counter-regulated SIRT1 via direct phosphorylation in metformin-mediated senescence in hepatoma cells. Taken together, these findings suggest that a low dose of metformin could potentially be used as a TIS-inducing therapeutic drug for HCC, and that this occurs by inducing senescence of HCC cells via the AMPK-SIRT1 pathway.

Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma.

Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.