ANDREA NATALI - Profile on Academia.edu (original) (raw)

Papers by ANDREA NATALI

Biomedicine & Pharmacotherapy, 2008

Dilated Cardiomyopathy (DCM) is a cardiac muscle disease characterized by reduced contractile fun... more Dilated Cardiomyopathy (DCM) is a cardiac muscle disease characterized by reduced contractile function and dilation of the left or both ventricular chambers. Classical pathogenetic mechanisms of DCM, such as genetic etiology, viral etiology and autoimmunity, can be considered a leading cause of DCM only in the minority of patients. It has been recently hypothesized that coronary microvascular dysfunction, together with 508 Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 503e512 © 2021 Elsevier Masson SAS. Tous droits réservés. -Document téléchargé le 06/12/2021 Il est interdit et illégal de diffuser ce document.

JCI Insight, 2018

Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (i... more Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION. Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time.

Diabetes, Obesity and Metabolism, Aug 2, 2018

Excess insulin secretion and hyperinsulinemia contribute to the progression of type 2 diabetes. H... more Excess insulin secretion and hyperinsulinemia contribute to the progression of type 2 diabetes. However, the mechanisms leading to insulin hypersecretion remain largely unknown. Based on our preliminary data, we examined whether triglycerides and very low-density lipoprotein (VLDL) are independently associated with insulin secretion, and whether the ethnicity/race modulates these associations. Fasting triglycerides and VLDL were measured in a multiethnic cohort of 630 nondiabetic adolescents. Insulin secretion, β-cell function parameters, insulin sensitivity and insulin clearance were estimated through a 3-h OGTT. Metabolic assessments were repeated after 2 years in 239 subjects. Triglycerides and triglyceride-rich VLDL (large and medium size fractions) were associated with both basal and glucose-stimulated insulin secretion, after adjustment for age, sex, ethnicity, BMI z-score, plasma glucose, and insulin sensitivity. Ethnicity per se had an impact on lipid profile and β-cell function, but did not modulate the effect of triglycerides/VLDL on insulin secretion. At follow-up, changes in triglyceride levels were proportional to changes in insulin secretion. These findings support the hypothesis that hypertriglyceridemia is an important stimulus for β-cell insulin release in youths under both fasting and fed conditions.

Nutrition & Diabetes, Aug 22, 2016

Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasi... more Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED -1.9 95% confidence interval (-3.4/ -0.4)kg, Po 0.03; CD -2.0 (-3.6/ -0.5)kg, P o 0.02) and waist circumference (ED -2.9 (-4.3/ -1.5)cm, P o0.002; CD -3.3 (-5.9/ -0.7)cm, P o 0.02), the ED only was associated with significant reductions of HbA1c (-0.3 (-0.50/ -0.02)%, P o 0.04), fasting plasma glucose (-1.0 (-1.8/ -0.3)mmol l -1 , P o0.01), postprandial glucose excursions (lunch -1.8 (-3.2/ -0.4)mmol l -1 , P o 0.01; dinner: -1.0 (-1.9/ -0.1)mmol l -1 , P o0.04) and other indices of glucose variability (s.d.: -0.5 (-0.7/ -0.2)mmol l -1 , P o0.02; Coefficient of variation: -6.6 (-10.4/ -2.7)%, Po 0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P o0.02) and lower glucose coefficients of variation (P o 0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D.

Objective Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin sec... more Objective Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. Research Design and Methods We estimated standardized EIC (EICISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EICISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555). Results Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, ~4 times more influential than insulin-resistance related...

The Journal of Clinical Endocrinology and Metabolism, Nov 14, 2018

One-hour postload hyperglycemia, defined as 1-hour plasma glucose (1hPG) $ 155 mg/dL during an or... more One-hour postload hyperglycemia, defined as 1-hour plasma glucose (1hPG) $ 155 mg/dL during an oral glucose tolerance test (OGTT), has been proposed as an independent predictor of type 2 diabetes. Recent evidence suggests that 1-hour hyperglycemia can be explained by enhanced duodenal glucose absorption, which in turn may increase the rate of appearance of oral glucose in the systemic circulation (RaO). However, the impact of RaO on 1hPG and 1-hour glucose excursions (incremental area under the curve calculated through the first hour after glucose ingestion; glucose iAUC 1h ) is still unknown. Objective: We quantified the relative contribution of postload RaO to 1hPG and glucose iAUC 1h with respect to other major glucose homeostatic mechanisms in nondiabetic participants.

Cardiovascular Diabetology, Sep 28, 2021

The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (... more 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 antinatriuretic 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.

Cardiovascular Diabetology, Sep 12, 2022

The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incide... more 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. 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 VO 2peak (+ 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.

Cardiovascular Diabetology, Apr 29, 2023

Background Obesity is an independent risk factor for cardiovascular disease (CVD) in patients wit... more Background Obesity is an independent risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). However, it is not known to what extent weight fluctuations might be associated with adverse outcomes. We aimed at assessing the associations between extreme weight changes and cardiovascular outcomes in two large randomised controlled trials of canagliflozin in patients with T2D and high cardiovascular (CV) risk. In the study populations of the CANVAS Program and CREDENCE trials, weight change was evaluated between randomization and week 52-78, defining subjects in the top 10% of the entire distribution of weight changes as gainers, subjects in the bottom 10% as losers and the remainder as stable. Univariate and multivariate Cox proportional hazards models were used to test the associations between weight changes categories, randomised treatment and covariates with heart failure hospitalisation (hHF) and the composite of hHF and CV death. Median weight gain was 4.5 kg in gainers and median weight loss was 8.5 kg in losers. The clinical phenotype of gainers as well as that of losers were similar to that of stable subjects. Weight change within each category was only slightly larger with canagliflozin than placebo. In both trials, gainers and losers had a higher risk of hHF and of hHF/ CV death compared with stable at univariate analysis. In CANVAS, this association was still significant by multivariate analysis for hHF/CV death in both gainers and losers vs. stable (hazard ratio -HR 1.61 [95% confidence interval -CI: 1.20-2.16] and 1.53 [95% CI 1.14-2.03] respectively). Results were similar in CREDENCE for gainers vs. stable (adjusted HR for hHF/CV death 1.62 [95% CI 1.19-2.16]) Conclusions Extremes of weight gain or loss were independently associated with a higher risk of the composite of hHF and CV death. In patients with T2D and high CV risk, large changes in body weight should be carefully assessed in view of individualised management.

Cardiovascular Diabetology

Background The prognostic value of common and frequently associated diabetic microvascular compli... more 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]), respectiv...

Cardiovascular Diabetology, 2021

Background Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whos... more 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...

Cardiovascular Diabetology, 2020

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well establishe... more The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen...

Atherosclerosis, 2022

Background and aims -Several protein biomarkers have been proposed to predict severity of the ath... more Background and aims -Several protein biomarkers have been proposed to predict severity of the atherosclerosis, but none has emerged as clinically meaningful. We aimed at selecting the most powerful protein biomarker/s among a list of 19 candidates exploring five different aspects of the atherosclerosis process: endothelial activation, inflammation, smooth muscle cell migration, plaque remodeling and apoptosis. Methods -Biomarkers were measured by Proximity Extension Assay in the SUMMIT study cohort (n=1,500), including patients with type 2 diabetes (66%) and established CV disease (50%) who underwent accurate ultrasound assessment of carotid atherosclerosis with total plaque area quantification. Results -In patients with evidence of carotid artery atherosclerosis (n=1,174), only seven biomarkers were identified as related to total plaque area in univariate analysis. With multivariable modeling, including major traditional CV risk factors, the ranking in terms of gain in explained variability of total plaque area was: CD40R-L (33%), PDGF (30%), CD40R (26%), followed by EGF (22%), CXCL1 (15%), and HBEGF and MMP-17 (both 11%). Only 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 2-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. Conclusion -CD40R stands among an extended set of plausible atherosclerosisrelated biomarkers a powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

European Heart Journal - Cardiovascular Imaging, 2020

Background Arterial hypertension (HT) is one of the main risk factors for the development of hear... more Background Arterial hypertension (HT) is one of the main risk factors for the development of heart failure with preserved ejection fraction (HFpEF). However, little is known regarding the hemodynamic and metabolic responses of patients with HT during the stress test. Purpose We assessed the hemodynamic and metabolic characteristics of HT subjects and patients with HFpEF and HT (HFpEF-HT) by combining cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE). Methods We studied 170 consecutive subjects, undergoing a symptom-limited graded ramp bicycle CPET-ESE: 52 stable (NYHA I-III) outpatients with HFpEF-HT (69 ± 13 years; 44 males, 85%), 86 well-controlled HT subjects (66 ± 10 years; 72 males, 84%) and 32 age and sex-matched healthy controls (59 ± 15 years; 24 males, 75%). During the exercise, we assessed oxygen consumption (VO2), cardiac output (CO) systemic vascular resistance (SVR) and arterial-venous oxygen content difference (AVO2diff). Results Peak syst...

$Research paper thumbnail of Value of combined cardiopulmonary and echocardiography stress test to characterize the haemodynamic and metabolic responses of patients with heart failure and mid-range ejection fraction$

European Heart Journal - Cardiovascular Imaging, 2019

To characterize heart failure (HF) with mid-range ejection fraction (HFmrEF), combining cardiopul... more To characterize heart failure (HF) with mid-range ejection fraction (HFmrEF), combining cardiopulmonary exercise test, and exercise stress echocardiography.

European Heart Journal - Cardiovascular Imaging, 2021

Funding Acknowledgements Type of funding sources: None. Aims. We tested the prognostic role of a ... more Funding Acknowledgements Type of funding sources: None. Aims. We tested the prognostic role of a risk score including bio-humoral evaluation, cardiopulmonary-echocardiographic stress (CPET-ESE) and lung ultrasound, in patients with heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF), and subjects at risk of developing HF (American College of Cardiology/American Heart Association Stages A and B). Methods and results. We evaluated 318 subjects: 94 in Stages A-B, 194 in Stage C (85 HFpEF and 109 HFrEF), and 30 age and sex-matched controls (Stage 0). During a median follow-up of 18.5 months, we reported 40 urgent HF visits, 31 HF hospitalisations and 10 cardiovascular deaths. Cox proportional-hazards regression for predicting adverse events identified five independent predictors and each was assigned a number of points proportional to its regression coefficient: Δstress-rest B-lines >10 (3 points), peak oxygen consumption <16 mL/kg/min (2 points), min...

$Research paper thumbnail of 1674 Is Arterial hypertension an intermediate step to heart failure with preserved ejection fraction?$

European Journal of Echocardiography, 2020

Background. Arterial hypertension (HT) is one of the main risk factors for the development of hea... more Background. Arterial hypertension (HT) is one of the main risk factors for the development of heart failure with preserved ejection fraction (HFpEF). The evaluation of cardiorespiratory fitness during the exercise may provide a clearer insight into this association. Purpose. We assessed the hemodynamic, respiratory and metabolic characteristics of HT subjects and patients with HFpEF and HT (HFpEF-HT), combining cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE). Methods. We studied 170 consecutive subjects, undergoing a symptom-limited graded ramp bicycle CPET-ESE: 52 stable (NYHA I-III) outpatients with HFpEF-HT (69 ± 13 years; 44 males, 85%) on optimal medical therapy, 86 well-controlled HT subjects (66 ± 10 years; 72 males, 84%) and 32 age and sex-matched healthy controls (59 ± 15 years; 24 males, 75%). Oxygen consumption (VO2), left ventricular (LV) ejection fraction (EF), global longitudinal strain (GLS), E/e' and LV compliance (expressed as end-diastolic volume [EDV] / E/e' ratio) were measured during exercise, including rest and peak lung ultrasound for B-lines evaluation. Results. HT patients showed peak VO2 values (18.7 ± 2 ml/min/kg) higher than HFpEF-HT (15.2 ± 2 ml/min/kg, p < 0.0001) but lower than controls (24.4 ± 7.3 ml/min/kg, p < 0.0001). Regardless of a similar EF, HT subjects had lower low-load (at 4 min of effort) GLS (18.2 ± 3%) than controls (20.9 ± 3%, p < 0.0001), but higher than HFpEF-HT (16.8 ± 5%, p = 0.04). Likewise, peak diastolic function (E/e' and LV compliance) was altered in HT patients (9.1 ± 2 and 13.4 ± 2) when compared to controls (6.2 ± 1 and 17.8 ± 2, all p < 0.0001), but less than in HFpEF (12.7 ± 3, p < 0.0001 and 12.1 ± 3, p = 0.003), as confirmed by peak B-lines (HFpEF-HT: 16 [interquartile range (IQR): 10 -22], HT: 8 [IQR: 4 -10] and controls: 0 [IQR: 0 -2]; p < 0.0001). LV hypertrophy was reported in 37 patients (27%); it was more common in HFpEF (24/37, 65%) and associated with a significantly worse peak VO2 and systo-diastolic profile (all p < 0.05). . HT subjects represent an intermediate step from healthy subjects to HFpEF, showing altered functional capacity and systodiastolic profile (Figure). LV hypertrophy characterises the clinical stage and portends a more severe cardiorespiratory fitness impairment.

Diabetologia

Aims/hypothesis Early time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy... more 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 m...

Journal of the American Society of Echocardiography, 2021

Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak... more Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO 2) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO 2 during exercise in a large cohort of patients within the heart failure (HF) spectrum. Methods: We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143). Results: Peak VO 2 significantly decreased from controls (23, 21.7-29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO 2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S 0), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e' (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R 2 = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S 0 showed the highest accuracy in predicting peak VO 2 < 10 mL/kg/minute (cut point # 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO 2 > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in comparison with the other cardiac variables of the model (P < .05). Conclusions: Peak VO 2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of workload, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C.