Insulin resistance drives cognitive impairment in hypertensive pre-diabetic frail elders: the CENTENNIAL study.

AIMS: Pre-diabetes is a condition that confers an increased cardiovascular risk. Frailty is very common in hypertensive patients, and insulin resistance has been linked to frailty in older adults with diabetes. On these grounds, our aim was to evaluate the association between insulin resistance and cognitive impairment in hypertensive and pre-diabetic and frail older adults. METHODS AND RESULTS: We studied consecutive pre-diabetic and hypertensive elders with frailty presenting at the Avellino local health authority of the Italian Ministry of Health (ASL AV) from March 2021 to March 2022. All of them fulfilled the following inclusion criteria: a previous diagnosis of hypertension with no clinical or laboratory evidence of secondary causes, a confirmed diagnosis of pre-diabetes, age >65 years, Montreal Cognitive Assessment (MoCA) Score <26, and frailty. We enrolled 178 frail patients, of which 141 successfully completed the study. We observed a strong inverse correlation (r = -0.807; P < 0.001) between MoCA Score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The results were confirmed by a linear regression analysis using MoCA Score as dependent variable, after adjusting for several potential confounders. CONCLUSION: Taken together, our data highlight for the first time the association between insulin resistance and global cognitive function in frail elders with hypertension and pre-diabetes.

In this study, we demonstrate that insulin resistance correlates with cognitive impairment in a population of frail hypertensive older adults with pre-diabetes. • We successfully studied 141 patients with hypertension, pre-diabetes, and frailty. • We observed a correlation between two parameters used to assess cognitive decline and insulin resistance.

miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction.

BACKGROUND: Cardiac fibrosis represents a key element in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), a condition highly prevalent amongst geriatric patients, especially if diabetic. The microRNA 181c (miR-181c) has been shown to be associated with the response to exercise training in HFpEF patients and has been also linked to diabetic cardiovascular complications. However, the underlying mechanisms have not been fully elucidated. OBJECTIVE: To measure circulating miR-181c in elderly patients with HFpEF and diabetes mellitus (DM) and identify gene targets pathophysiologically relevant in HFpEF. METHODS: We quantified circulating miR-181c in frail older adults with a confirmed diagnosis of HFpEF and DM, and, as control, we enrolled age-matched subjects without HFpEF and without DM. We validated in human cardiac fibroblasts the molecular mechanisms linking miR-181c to a pro-fibrotic response. RESULTS: 51 frail patients were included :34 patients with DM and HFpEF and 17 age-matched controls. We observed that miR-181c was significantly upregulated (p < 0.0001) in HFpEF patients vs controls. We confirmed in vitro that miR-181c is targeting PRKN and SMAD7. CONCLUSIONS: We demonstrate that miR-181c levels are significantly increased in frail elderly adults with DM and HFpEF and that miR-181c targets PRKN and SMAD7 in human cardiac fibroblasts.

Extended-release metformin improves cognitive impairment in frail older women with hypertension and diabetes: preliminary results from the LEOPARDESS Study.

BACKGROUND: Women have a high risk of frailty independently of age and menopause state. Diabetes and hypertension increase the risk of frailty and cognitive impairment. Metformin has been employed in post-menopausal women and some reports have shown encouraging effects in terms of attenuated frailty. However, the impact on cognitive performance of a recently introduced extended-release formulation of metformin has never been explored. METHODS: We studied consecutive frail hypertensive and diabetic older women presenting at the ASL (local health authority of the Italian Ministry of Health) Avellino, Italy, from June 2021 to August 2022, who were treated or not with extended-release metformin. We included a control group of frail older males with diabetes and hypertension treated with extended-release metformin and a control group of frail older women with diabetes and hypertension treated with regular metformin. RESULTS: A total of 145 patients successfully completed the study. At the end of the 6-month follow-up, we observed a significantly different cognitive performance compared to baseline in the group of frail women treated with extended-release metformin (p: 0.007). Then, we compared the follow-up groups and we observed significant differences between frail women treated vs. untreated (p: 0.041), between treated frail women and treated frail men (p: 0.016), and between women treated with extended-release metformin vs. women treated with regular metformin (p: 0.048). We confirmed the crucial role of extended-release metformin applying a multivariable logistic analysis to adjust for potential confounders. CONCLUSIONS: We evidenced, for the first time to the best of our knowledge, the favorable effects on cognitive impairment of extended-release metformin in frail women with diabetes and hypertension.

Empagliflozin Improves the MicroRNA Signature of Endothelial Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Diabetes.

Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in a population of frail older adults with HFpEF and DM treated for 3 months with empagliflozin, metformin, or insulin. We identified a distinctive pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and to HFpEF patients treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin, whereas no significant differences in the profile of endothelial miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs involved in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to SGLT2 inhibition. SIGNIFICANCE STATEMENT: We have identified a novel microRNA signature functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. Moreover, the treatment with the SGLT2 inhibitor empagliflozin caused a modification of some of these microRNAs in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant for clinical practice inasmuch as we were able to establish novel biomarkers of disease and response to therapy.

SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients.

BACKGROUND: Frailty is a multidimensional condition often diagnosed in older adults with hypertension and diabetes, and both these conditions are associated with endothelial dysfunction and oxidative stress. We investigated the functional role of the SGLT2 (sodium glucose cotransporter 2) inhibitor empagliflozin in frail diabetic and hypertensive older adults. METHODS: We studied the effects of empagliflozin in consecutive hypertensive and diabetic older patients with frailty presenting at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to January 2022. Moreover, we performed in vitro experiments in human endothelial cells to measure cell viability, permeability, mitochondrial Ca2+, and oxidative stress. RESULTS: We evaluated 407 patients; 325 frail elders with diabetes successfully completed the study. We propensity-score matched 75 patients treated with empagliflozin and 75 with no empagliflozin. We observed a correlation between glycemia and Montreal Cognitive Assessment (MoCA) score and between glycemia and 5-meter gait speed (5mGS). At 3-month follow-up, we detected a significant improvement in the MoCA score and in the 5mGS in patients receiving empagliflozin compared with non-treated subjects. Mechanistically, we demonstrate that empagliflozin significantly reduces mitochondrial Ca2+ overload and reactive oxygen species production triggered by high glucose in human endothelial cells, attenuates cellular permeability, and improves cell viability in response to oxidative stress. CONCLUSIONS: Taken together, our data indicate that empagliflozin reduces frailty in diabetic and hypertensive patients, most likely by decreasing the mitochondrial generation of reactive oxygen species in endothelial cells.

Hyperglycemia and Physical Impairment in Frail Hypertensive Older Adults.

Background: Frailty is a multidimensional condition typical of elders. Frail older adults have a high risk of functional decline, hospitalization, and mortality. Hypertension is one of the most common comorbidities in elders. Hyperglycemia (HG) is frequently observed in frail older adults, and represents an independent predictor of worst outcomes, with or without diabetes mellitus (DM). We aimed at investigating the impact of HG on physical impairment in frailty. Methods: We studied consecutive older adults with frailty and hypertension at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to September 2021. Exclusion criteria were: age <65 years, no frailty, no hypertension, left ventricular ejection fraction <25%, previous myocardial infarction, previous primary percutaneous coronary intervention and/or coronary artery bypass grafting. Blood glucose, Hb1Ac, and creatinine were measured in all patients. Physical frailty was assessed applying the Fried Criteria; we performed a 5-meter gait speed (5mGS) test in all patients. Results: 149 frail hypertensive older adults were enrolled in the study, of which 82 had normoglycemia (NG), and 67 had HG. We observed a significantly slower 5mGS in the HG group compared to the NG group (0.52 ± 0.1 vs. 0.69 ± 0.06; p<0.001). Moreover, we found a strong and significant correlation between 5mGS and glycemia (r: 0.833; p<0.001). A multivariable linear regression analysis using 5mGS as a dependent variable revealed a significant independent association with glycemia (p<0.001) after adjusting for likely confounders. Conclusions: HG drives physical impairment in frail hypertensive older adults independently of DM.

L-Arginine Improves Cognitive Impairment in Hypertensive Frail Older Adults.

Cognitive impairment is a prevailing event in hypertensive patients and in frail older adults. Endothelial dysfunction has been shown to underlie both hypertension and cognitive dysfunction. Our hypothesis is that L-Arginine, which is known to ameliorate endothelial dysfunction, could counteract cognitive impairment in a high-risk population of hypertensive frail older adults. We designed a clinical trial to verify the effects of 4-weeks oral supplementation of L-Arginine on global cognitive function of hypertensive frail older patients. The study was successfully completed by 35 frail hypertensive elderly patients assigned to L-Arginine and 37 assigned to placebo. At follow-up, we found a significant difference in the Montreal Cognitive Assessment (MoCA) test score between the L-Arginine treated group and placebo (p: 0.0178). Moreover, we demonstrated that L-Arginine significantly attenuates Angiotensin II-induced mitochondrial oxidative stress in human endothelial cells. In conclusion, our findings indicate for the first time that oral L-Arginine supplementation significantly improves cognitive impairment in frail hypertensive older adults. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04962841.

Global cognitive function correlates with P-wave dispersion in frail hypertensive older adults.

P-Wave Dispersion (PWD) is an ECG parameter defined as the difference between the longest and the shortest P-Wave duration. PWD has been associated with hypertension, a leading cause of age-related cognitive decline. Moreover, hypertension is associated with vascular dementia and Alzheimer's Disease. Based on these considerations, we evaluated PWD and global cognitive function in frail hypertensive older adults with a previous diagnosis of cognitive decline. We evaluated consecutive frail hypertensive patients ≥65-year-old with a Mini-Mental State Examination (MMSE) score <26. Patients with evidence of secondary hypertension, history of stroke, myocardial infarction, or therapy with beta-blockers or acetylcholinesterase inhibitors were excluded. Beta-blocker therapy causes a significant decrease in PWD; patients treated with acetylcholinesterase inhibitors were not included to avoid confounding effects on cognitive function. By examining 180 patients, we found that PWD significantly correlated with MMSE score. Strikingly, these effects were confirmed in a linear multivariate analysis with a regression model. To our knowledge, this is the first study showing that PWD correlates with global cognitive function in frail hypertensive older adults.

Omega-3 fatty acids coordinate glucose and lipid metabolism in diabetic patients.

Omega 3 polyunsaturated fatty acids (n-3 PUFA) are known to have beneficial effects on cardiovascular and metabolic health. However, whether different sources of n-3 PUFA, for instance fatty fish vs vegetable oils, could elicit different effects on glucose and lipid metabolism, remains to be determined. Herein we examine recent findings showing that while a plant-based n-3 PUFA supplementation for six months can reduce fasting blood glucose, marine-based n-3 PUFA can instead reduce serum levels of triglycerides. We also discuss the potential molecular mechanisms that could underlie these different effects on the regulation of glycolipid metabolism.

Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: To assess whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves cognitive impairment in frail older adults with diabetes and heart failure with preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS: We designed a prospective study to assess cognitive and physical function in consecutive frail older adults with diabetes and HFpEF, comparing the effects of empagliflozin, metformin, and insulin. RESULTS: A total of 162 frail older adults with HFpEF and diabetes successfully completed the study. Montreal Cognitive Assessment scores at baseline and after 1 month were 19.80 ± 3.77 vs. 22.25 ± 3.27 (P < 0.001) in the empagliflozin group, 19.95 ± 3.81 vs. 20.71 ± 3.56 (P = 0.26) in the metformin group, and 19.00 ± 3.71 vs. 19.1 ± 3.56 (P = 0.81) in the insulin group. A multivariable regression analysis confirmed the beneficial effects of empagliflozin. Additionally, we observed a marked amelioration of physical impairment, assessed by the 5-m gait speed test, in the empagliflozin and metformin groups but not in the insulin group. CONCLUSIONS: This study is the first to show significant beneficial effects of the SGLT2 inhibitor empagliflozin on cognitive and physical impairment in frail older adults with diabetes and HFpEF.

Physical decline and cognitive impairment in frail hypertensive elders during COVID-19.

BACKGROUND: Hypertension is common in older adults and its incidence increases with age. We investigated the correlation between physical and cognitive impairment in older adults with frailty and hypertension. METHODS: We recruited frail hypertensive older adults during the COVID-19 pandemic, between March 2021 and December 2021. Global cognitive function was assessed through the Montreal Cognitive Assessment (MoCA), physical frailty assessment was performed following the Fried criteria, and all patients underwent physical evaluation through 5-meter gait speed test. RESULTS: We enrolled 203 frail hypertensive older adults and we found a significant correlation between MoCA score and gait speed test (r: 0.495; p<0.001) in our population. To evaluate the impact of comorbidities and other factors on our results, we applied a linear regression analysis with MoCA score as a dependent variable, observing a significant association with age, diabetes, chronic obstructive pulmonary disease (COPD), and gait speed test. CONCLUSIONS: Our study revealed for the first time a significant correlation between physical and cognitive impairment in frail hypertensive elderly subjects.

Correlation of physical and cognitive impairment in diabetic and hypertensive frail older adults.

BACKGROUND: Diabetes and hypertension are common in older adults and represent established risk factors for frailty. Frailty is a multidimensional condition due to reserve loss and susceptibility to stressors with a high risk of death, hospitalizations, functional and cognitive impairment. Comorbidities such as diabetes and hypertension play a key role in increasing the risk of mortality, hospitalization, and disability. Moreover, frail patients with diabetes and hypertension are known to have an increased risk of cognitive and physical impairment. Nevertheless, no study assessed the correlation between physical and cognitive impairment in frail older adults with diabetes and hypertension. METHODS: We evaluated consecutive frail older patients with diabetes and hypertension who presented at ASL (local health unit of the Italian Ministry of Health) Avellino, Italy, from March 2021 to October 2021. The inclusion criteria were: a previous diagnosis of diabetes and hypertension with no evidence of secondary causes; age > 65 years; a frailty status; Montreal Cognitive Assessment (MoCA) score < 26. RESULTS: 179 patients successfully completed the study. We found a strong and significant correlation between MoCA score and 5-m gait speed test (r: 0.877; p < 0.001). To further verify our results, we performed a linear multivariate analysis adjusting for potential confounding factors, with MoCA score as dependent variable, which confirmed the significant association with glycemia (p < 0.001). CONCLUSIONS: This is the first study showing a significant correlation between 5-m gait speed test and MoCA score in frail diabetic and hypertensive older adults.

Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia.

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.