Cardioprotective effects of glucagon-like peptide 1 receptor agonists in heart failure: Myth or truth?

Therapy with glucagon-like peptide 1 (GLP1) receptor agonists has raised great interest for its beneficial cardiovascular effects in preventing atherosclerosis and heart failure-related outcomes. However, while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect, controversies remain on its impact on heart failure. GLP1 receptor agonists appear to prevent hospitalization for new-onset heart failure and reduce symptoms in heart failure with preserved ejection fraction (as demonstrated by the recent STEP-HFpEF Trial). Still, GLP1 agonism has resulted in neutral or even harmful effects in patients with established heart failure with reduced ejection fraction (the LIVE trial). GLP1 receptor agonists benefit the cardiovascular system indirectly through their marked metabolic effects (improved weight management, glycemic control, blood pressure, systemic and tissue inflammation), while direct effects on the heart have been questioned. Nonetheless, weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular functions. Tirzepatide is a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide, representing an innovative treatment option in diabetes with a major impact on weight loss and promising cardiovascular benefits. Whether this class of therapies is going to change the history of heart failure is an ongoing debate.

At any Level of Adiposity, Relatively Elevated Leptin Concentrations Are Associated With Decreased Insulin Sensitivity.

CONTEXT: The impact of obesity on glucose homeostasis has high interindividual variability, which may be partially explained by different adipokine concentrations. Leptin regulates energy balance and metabolism, and although its plasma levels are proportional to fat mass, they vary significantly across individuals with the same level of adiposity. OBJECTIVE: We tested whether glucose homeostasis differs in subjects with similar degrees of adiposity but different leptin levels. METHODS: We analyzed 1290 healthy adults from the Relationship Between Insulin Sensitivity and Cardiovascular Disease study cohort (30-60 years; male/female, 577/713; body mass index [BMI], 25 ± 3 kg/m2) characterized for body composition and metabolic variables with a 75-g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, ß-cell function, and lipidomics. RESULTS: Individuals were divided into relatively high and low leptin (RHL and RLL) if they were above or below the sex-specific leptin-fat mass (%) regression. Despite similar glucose tolerance, RHL showed markedly higher fasting and oral glucose tolerance test insulin concentration (+30% and +29%, respectively; P < .0001) and secretion (+17% and +11%, respectively; P < .0001). Regardless of BMI, RHL individuals had lower whole-body (-17-23%, P < .0001) and adipose tissue insulin sensitivity (-24%, P < .0001) compared with RLL. Notably, lean RHL individuals showed similar insulin sensitivity and ß-cell function to RLL individuals with overweight/obesity. CONCLUSION: Subjects with leptin levels that are inappropriately elevated for their fat mass show whole-body/adipose tissue insulin resistance and hyperinsulinemia, regardless of BMI.

Early time-restricted carbohydrate consumption vs conventional dieting in type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Early time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy that involves restricting carbohydrate-rich food intake to the morning and early afternoon to align with circadian variations in glucose tolerance. We examined the efficacy, feasibility and safety of eTRC in individuals with type 2 diabetes under free-living conditions. METHODS: In this randomised, parallel-arm, open label, controlled trial, participants with type 2 diabetes and overweight/obesity (age 67.2±7.9 years, 47.8% women, BMI 29.4±3.7 kg/m2, HbA1c 49±5 mmol/mol [6.6±0.5%]) were randomised, using computer-generated random numbers, to a 12 week eTRC diet or a Mediterranean-style control diet with matched energy restriction and macronutrient distribution (50% carbohydrate, 30% fat and 20% protein). The primary outcome was the between-group difference in HbA1c at 12 weeks. Body composition, 14 day flash glucose monitoring and food diary analysis were performed every 4 weeks. Mixed meal tolerance tests with mathematical beta cell function modelling were performed at baseline and after 12 weeks. RESULTS: Twelve (85.7%) participants in the eTRC arm and 11 (84.6%) participants in the control arm completed the study, achieving similar reductions in body weight and fat mass. The two groups experienced comparable improvements in HbA1c (-3 [-6, -0.3] mmol/mol vs -4 [-6, -2] mmol/mol, corresponding to -0.2 [-0.5, 0]% and -0.3 [-0.5, -0.1]%, respectively, p=0.386), fasting plasma glucose, flash glucose monitoring-derived glucose variability and mixed meal tolerance test-derived glucose tolerance, insulin resistance, insulin clearance and plasma glucagon levels, without changes in model-derived beta cell function parameters, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and non-esterified fatty acid levels. The two diets similarly reduced liver function markers and triglyceride levels, being neutral on other cardiometabolic and safety variables. In exploratory analyses, diet-induced changes in body weight and glucometabolic variables were not related to the timing of carbohydrate intake. CONCLUSIONS/INTERPRETATION: The proposed eTRC diet provides a feasible and effective alternative option for glucose and body weight management in individuals with type 2 diabetes, with no additional metabolic benefits compared with conventional dieting. TRIAL REGISTRATION: ClinicalTrials.gov NCT05713058 FUNDING: This study was supported by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Italian Society of Diabetology (SID).

Distinct effects of type 2 diabetes and obesity on cardiopulmonary performance.

AIM: Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case-control and regression analyses. METHODS: Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography-cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO2peak ) normalized for fat-free mass (FFM). RESULTS: In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m2 , p = .0003) but comparable FFM. Patients with T2D achieved lower VO2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p = .0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO2peakFFM , T2D still displayed reduced VO2peak by 1.0 (-1.7/-0.3) ml/min/kgFFM , p = .0089, while the effect of BMI [-0.2 (-0.3/0.1) ml/min/kgFFM , p = .06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency. CONCLUSIONS: T2D is an independent negative determinant of VO2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI.

Haemodynamic and metabolic phenotyping of patients with aortic stenosis and preserved ejection fraction: A specific phenotype of heart failure with preserved ejection fraction?

AIMS: Degenerative aortic valve stenosis with preserved ejection fraction (ASpEF) and heart failure with preserved ejection fraction (HFpEF) display intriguing similarities. This study aimed to provide a non-invasive, comparative analysis of ASpEF versus HFpEF at rest and during exercise. METHODS AND RESULTS: We prospectively enrolled 148 patients with HFpEF and 150 patients with degenerative moderate-to-severe ASpEF, together with 66 age- and sex-matched healthy controls. All subjects received a comprehensive evaluation at rest and 351/364 (96%) performed a combined cardiopulmonary exercise stress echocardiography test. Patients with ASpEF eligible for transcatheter aortic valve replacement (n = 125) also performed cardiac computed tomography (CT). HFpEF and ASpEF patients showed similar demographic distribution and biohumoral profiles. Most patients with ASpEF (134/150, 89%) had severe high-gradient aortic stenosis; 6/150 (4%) had normal-flow, low-gradient ASpEF, while 10/150 (7%) had low-flow, low-gradient ASpEF. Both patient groups displayed significantly lower peak oxygen consumption (VO2 ), peak cardiac output, and peak arteriovenous oxygen difference compared to controls (all p < 0.01). ASpEF patients showed several extravalvular abnormalities at rest and during exercise, similar to HFpEF (all p < 0.01 vs. controls). Epicardial adipose tissue (EAT) thickness was significantly greater in ASpEF than HFpEF and was inversely correlated with peak VO2 in all groups. In ASpEF, EAT was directly related to echocardiography-derived disease severity and CT-derived aortic valve calcium burden. CONCLUSION: Functional capacity is similarly impaired in ASpEF and HFpEF due to both peripheral and central components. Further investigation is warranted to determine whether extravalvular alterations may affect disease progression and prognosis in ASpEF even after valve intervention, which could support the concept of ASpEF as a specific sub-phenotype of HFpEF.

Proatherogenic changes in lipoprotein particles associated with a high triglyceride to high-density lipoprotein cholesterol ratio in youths.

OBJECTIVE: A high triglyceride (TG) to high-density lipoprotein cholesterol (HDL) ratio (TG/HDL) predicts atherosclerosis and cardiovascular events. This study examined whether a proatherogenic distribution of plasma lipoprotein subclasses is associated with a high TG/HDL ratio in youths with obesity. METHODS: Lipoprotein particle concentration and size were measured by proton nuclear magnetic resonance in a multiethnic cohort of 592 adolescents with overweight/obesity (age 13 ± 3 years, 58% females, BMI z score 2.1 ± 0.8) who were phenotyped with a 3-hour oral glucose tolerance test and abdominal magnetic resonance imaging. RESULTS: The highest TG/HDL quartile showed a higher particle concentration of very low-density lipoprotein (VLDL; +178%, p < 0.0001), intermediate-density lipoprotein (+338%, p < 0.0001), and low-density lipoprotein (LDL; +42%, p < 0.0001), compared with the lowest quartile. The prevalence of large VLDL, very small LDL, and small HDL progressively increased across TG/HDL quartiles. The TG/HDL ratio correlated positively with the average particle size of VLDL (r = 0.37, p < 0.0001) and negatively with particle size of both LDL (r = -0.51, p < 0.0001) and HDL (r = -0.69, p < 0.0001). These associations were independent of sex, age, race/ethnicity, body mass, fasting plasma glucose, and insulin sensitivity. CONCLUSIONS: In youths with obesity, an elevated TG/HDL ratio is associated with high concentrations of proatherogenic lipoprotein subclasses. This phenotype may explain the increased cardiovascular risk associated with a high TG/HDL ratio.

Glomerular Hyperfiltration Predicts Kidney Function Decline and Mortality in Type 1 and Type 2 Diabetes: A 21-Year Longitudinal Study.

OBJECTIVE: To evaluate the prognostic value of glomerular hyperfiltration on long-term kidney-related outcomes and mortality in patients with diabetes. RESEARCH DESIGN AND METHODS: We retrospectively analyzed 21-year longitudinal data from 314 patients with long-standing type 1 or type 2 diabetes. Glomerular hyperfiltration was identified based on the age- and sex-specific distribution of measured glomerular filtration rate (mGFR) by 99mTc-DTPA dynamic renal scintigraphy. The primary outcome was a composite of doubling of serum creatinine, end-stage kidney disease (ESKD), or cardiorenal death. The kidney-specific outcome was a composite of doubling of serum creatinine, ESKD, or renal death. RESULTS: Over a median of 21.0 years, the primary composite outcome occurred in 25 (39.7%), 24 (38.1%), and 46 (24.5%) participants with high mGFR (H-mGFR) (n = 63), low mGFR (L-mGFR) (n = 63), or normal mGFR (N-mGFR) (n = 188), respectively. Compared with N-mGFR, the hazard ratio (HR) for the primary composite outcome was 2.09 (95% CI 1.25-3.49) in H-mGFR and 1.81 (1.05-3.16) in L-mGFR. The HR for the kidney-specific composite outcome was 4.95 (2.21-11.09) in H-mGFR and 3.81 (1.70-8.56) in L-mGFR. The HRs for doubling of serum creatinine and cardiorenal death were 4.86 (2.18-10.90) and 2.18 (1.24-3.83) in H-mGFR and 4.04 (1.77-9.20) and 2.26 (1.27-4.01) in L-mGFR, respectively. CONCLUSIONS: Glomerular hyperfiltration, similar to hypofiltration, increases the combined risk of worsening kidney function and mortality from cardiovascular or renal causes in patients with diabetes. These findings encourage the active screening of these patients to optimize risk stratification and treatment of subclinical kidney disease.

Impact of diabetes on cardiopulmonary function: the added value of a combined cardiopulmonary and echocardiography stress test.

Type 2 diabetes mellitus (T2DM) represents a major health issue worldwide, as patients with T2DM show an excess risk of death for cardiovascular causes, twice as high as the general population. Among the many complications of T2DM, heart failure (HF) deserves special consideration as one of the leading causes of morbidity and reduced life expectancy. T2DM has been associated with different phenotypes of HF, including HF with reduced and preserved ejection fraction. Cardiopulmonary exercise testing (CPET) can evaluate the metabolic and ventilatory alterations related to myocardial dysfunction and/or peripheral impairment, representing a unique tool for the clinician to study the whole HF spectrum. While CPET allows for a thorough evaluation of functional capacity, it cannot directly differentiate central and peripheral determinants of effort intolerance. Combining CPET with imaging techniques could provide even higher accuracy and further insights into the progression of the disease since signs of left ventricular systolic and diastolic dysfunction can be detected during exercise, even in asymptomatic diabetic individuals. This review aims to dissect the alterations in cardiopulmonary function characterising patients with T2DM and HF to improve patient risk stratification.

Epicardial adipose tissue thickness is associated with reduced peak oxygen consumption and systolic reserve in patients with type 2 diabetes and normal heart function.

AIM: To investigate the impact of epicardial adipose tissue (EAT) thickness on cardiopulmonary performance in patients with type 2 diabetes (T2D) and normal heart function. MATERIALS AND METHODS: We analysed EAT thickness in subjects with T2D and normal biventricular systo-diastolic functions undergoing a maximal cardiopulmonary exercise test combined with stress echocardiography, speckle tracking and pulmonary function assessment, as well as serum N-terminal pro B-type natriuretic peptide (NT-proBNP). RESULTS: In the 72 subjects enrolled, those with EAT thickness above the median (> 5 mm) showed higher body fat mass, smaller indexed left ventricular dimensions and marginally reduced diastolic function variables at rest. Higher EAT thickness was associated with lower peak oxygen uptake (VO2peak 17.1 ± 3.6 vs. 21.0 ± 5.7 ml/min/kg, P = .001), reduced systolic reserve (ΔS' 4.6 ± 1.6 vs. 5.8 ± 2.5 m/s, P = .02) and higher natriuretic peptides (NT-proBNP 64 [29-165] vs. 31 [26-139] pg/ml, P = .04), as well as chronotropic insufficiency and impaired heart rate recovery. Ventilatory variables and peripheral oxygen extraction were not different between groups. EAT was independently associated with VO2peak and linearly and negatively correlated with peak heart rate, heart rate recovery, workload, VO2 at the anaerobic threshold and at peak, and cardiac power output, and was directly correlated with natriuretic peptides. CONCLUSION: Higher EAT thickness in T2D is associated with worse cardiopulmonary performance and multiple traits of subclinical cardiac systolic dysfunction.

Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: a 21-year longitudinal study.

BACKGROUND: The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed. METHODS: We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination. RESULTS: After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45-3.26]) and 54% (HR 1.54 [1.01-2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52-10.26]), followed by CKD&DR (HR 2.95 [1.63-5.32]), and CAN&DR (HR 2.07 [1.11-3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87-2.67]), while increased by 203% (HR 3.03 [1.62-5.68]) and 692% (HR 7.92 [2.93-21.37]) in patients with two and three concomitant MVC, respectively. CONCLUSIONS: Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.

Effect of empagliflozin on left ventricular contractility and peak oxygen uptake in subjects with type 2 diabetes without heart disease: results of the EMPA-HEART trial.

BACKGROUND: The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incidence of heart failure and/or affect cardiac structure and function remains unclear. METHODS: The EMPA-HEART trial is aimed at verifying whether empagliflozin improves myocardial contractility (left ventricle global longitudinal strain, LV-GLS) and/or cardiopulmonary fitness (peak oxygen uptake, VO2peak) in subjects with type 2 diabetes (T2D) without heart disease. Patients with T2D, normal LV systolic function (2D-Echo EF > 50%), and no heart disease were randomized to either empagliflozin 10 mg or sitagliptin 100 mg for 6 months and underwent repeated cardiopulmonary exercise tests with echocardiography and determination of plasma biomarkers. RESULTS: Forty-four patients completed the study, 22 per arm. Despite comparable glycaemic control, modest reductions in body weight (- 1.6; [- 2.7/- 0.5] kg, p = 0.03) and plasma uric acid (- 1.5; [- 2.3/- 0.6], p = 0.002), as well as an increase in haemoglobin (+ 0.7; [+ 0.2/+ 1.1] g/dL, p = 0.0003) were evident with empagliflozin. No difference was detectable in either LV-GLS at 1 month (empagliflozin vs sitagliptin: + 0.44; [- 0.10/+ 0.98]%, p = 0.11) and 6 months of therapy (+ 0.53; [- 0.56/+ 1.62]%), or in VO2peak (+ 0.43; [- 1.4/+ 2.3] mL/min/kg, p = 0.65). With empagliflozin, the subgroup with baseline LV-GLS below the median experienced a greater increase (time*drug p < 0.05) in LV-GLS at 1 month (+ 1.22; [+ 0.31/+ 2.13]%) and 6 months (+ 2.05; [+ 1.14/+ 2.96]%), while sitagliptin induced a modest improvement in LV-GLS only at 6 months (+ 0.92; [+ 0.21/+ 0.62]%). CONCLUSIONS: Empagliflozin has neutral impact on both LV-GLS and exercise tolerance in subjects with T2D and normal left ventricular function. However, in patients with subclinical dysfunction (LV-GLS < 16.5%) it produces a rapid and sustained amelioration of LV contractility. Trial registration EUDRACT Code 2016-002225-10.

Prognostic value of 24-hour ambulatory blood pressure patterns in diabetes: A 21-year longitudinal study.

AIMS: To establish the long-term prognostic value of abnormal circadian blood pressure (BP) patterns in diabetes. MATERIALS AND METHODS: We retrospectively examined a cohort of 349 outpatients with diabetes who were screened for microvascular complications and followed up for 21 years. Dipping, nondipping and reverse-dipping status were defined based on 24-hour ambulatory BP monitoring (ABPM) as ≥10% reduction, <10% reduction, and any increase in average nighttime versus daytime systolic BP (SBP), respectively. RESULTS: After 6251 person-years of follow-up (median [range] follow-up 21.0 [1.1-22.0] years, 52% women, age 57.1 ± 11.9 years, 81.4% type 2 diabetes and 18.6% type 1 diabetes), a total of 136 deaths (39%) occurred. Compared with dippers, the nondippers and reverse dippers showed progressively higher prevalence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN) and postural hypotension. Reverse dippers showed a 13.4% (2.5-year) reduction in mean overall survival and a twofold increased risk of all-cause mortality after adjustment for traditional risk factors (hazard ratio 2.2 [95% confidence interval 1.3-3.8]). Each 1% decrease in nighttime versus daytime SBP ratio was independently associated with a 4% reduction in 20-year mortality risk. CONCLUSIONS: In patients with diabetes, reverse dipping is associated with a higher prevalence of CKD and CAN and more than doubled the adjusted risk of all-cause mortality over a 21-year observation.

Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk.

BACKGROUND AND AIMS: The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. METHODS: Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. RESULTS: In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. CONCLUSIONS: CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

Characterization of hemodynamic and metabolic abnormalities in the heart failure spectrum: the role of combined cardiopulmonary and exercise echocardiography stress test.

Heart failure (HF) is a complex clinical syndrome characterized by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalization is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterization of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and hemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography [ESE]). The purpose of this narrative review was to summarize the potential advantages of using an integrated CPET-ESE evaluation in the characterization of both subjects at risk of developing HF and patients with stable HF.

Ictogenesis of viral pneumonia: A comparison between SARS-CoV-2 and H1N1/H3N2.

Several studies reported acute symptomatic seizures as a possible neurological complication of COVID-19 pneumonia. Apart from metabolic imbalances, hypoxia, and fever, other ictogenic mechanisms are likely related to an immune-mediated damage. The same mechanisms are shared by other respiratory viruses. Since neurotropic properties of SARS-CoV-2 have been questioned, we investigated whether SARS-CoV-2 has a similar ictogenic potential to other respiratory non-neurotropic viruses. We conducted a retrospective study identifying 1141 patients with SARS-CoV-2 pneumonia and 146 patients with H1N1/H3N2 pneumonia. We found a similar prevalence of seizures in the two viral pneumonia (1.05% with SARS-CoV-2 vs 2.05% with influenza; p = 0.26). We detailed clinical, electroencephalographic, and neuroradiological features of each patient, together with the hypothesized pathogenesis of seizures. Previous epilepsy or pre-existing predisposing conditions (i.e., Alzheimer's disease, stroke, cerebral neoplasia) were found in one-third of patients that experienced seizures, while two-thirds of patients had seizures without known risk factors other than pneumonia in both groups. The prevalence of pre-existing predisposing conditions and disease severity indexes was similar in SARS-CoV-2 and H1N1/H3N2 pneumonia, thus excluding they could act as potential confounders. Considering all the patients with viral pneumonia together, previous epilepsy (p < 0.001) and the need for ventilatory support (p < 0.001), but not the presence of pre-existing predisposing conditions (p = 0.290), were associated with seizure risk. Our study showed that SARS-CoV-2 and influenza viruses share a similar ictogenic potential. In both these infections, seizures are rare but serious events, and can manifest without pre-existing predisposing conditions, in particular when pneumonia is severe, thus suggesting an interplay between disease severity and host response as a major mechanism of ictogenesis, rather than a virus-specific mechanism.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence.

The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.

Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure.

AIMS: We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress. METHODS AND RESULTS: We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO2 ) and peripheral extraction (AVO2 diff), regardless of body mass index. EAT was inversely correlated with peak VO2 and AVO2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91). CONCLUSION: In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.

Mechanisms of reduced peak oxygen consumption in subjects with uncomplicated type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance (i.e. impaired peak oxygen consumption, or VO2peak). In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations. METHODS: Eighty-eight adults with well-controlled and uncomplicated T2D and no criteria for HF underwent a maximal iCPET with speckle tracking echocardiography, vascular and endothelial function assessment, as well as a comprehensive biohumoral characterization. Effort intolerance was defined by a VO2peak below 80% of maximal predicted oxygen uptake. RESULTS: Forty-eight patients (55%) had effort intolerance reaching a lower VO2peak than T2D controls (16.5 ± 3.2 mL/min/kg, vs 21.7 ± 5.4 mL/min/kg, p < 0.0001). Despite a comparable cardiac output, patients with effort intolerance showed reduced peak peripheral oxygen extraction (11.3 ± 3.1 vs 12.7 ± 3.3 mL/dL, p = 0.002), lower VO2/work slope (9.9 ± 1.2 vs 11.2 ± 1.4, p < 0.0001), impaired left ventricle systolic reserve (peak S' 13.5 ± 2.8 vs 15.2 ± 3.0, p = 0.009) and global longitudinal strain (peak-rest ΔGLS 1.7 ± 1.5 vs 2.5 ± 1.8, p = 0.03) than subjects with VO2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups. CONCLUSIONS: Effort intolerance and reduced VO2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.

Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug.

Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia-reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin-angiotensin-aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.