Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. METHODS AND RESULTS: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31-73), 150 W (125-175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05-0.11), 0.06 mmol/L/W (0.05-0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03-0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7-5.5) in HFpEF, 5.2 L/min/m2 (4.3-6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0-9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175-1986) vs. 1758 mL/min (1361-2282; P = 0.024) in NCD and 3117 mL/min (2667-3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). CONCLUSIONS: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.

The effects of empagliflozin on measured glomerular filtration rate and estimated extracellular and plasma volumes in patients with type 2 diabetes.

AIMS: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. MATERIALS AND METHODS: In this prespecified substudy of the randomized, placebo-controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between-group change in mGFR, measured by the 51 Cr-EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. RESULTS: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention-to-treat analysis. Treatment with empagliflozin reduced mGFR by -7.9 mL/min (95% confidence interval [CI] -11.1 to -4.7; P < 0.001), estimated ECV by -192.5 mL (95% CI -318.0 to -66.9; P = 0.003) and estimated PV by -128.9 mL (95% CI -218.0 to 39.8; P = 0.005) at Week 13. CONCLUSIONS: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events.

Parameters associated with improvement of systolic function in patients with heart failure.

AIMS: Identifying clinical and echocardiographic parameters associated with improvement in systolic function in outpatients with heart failure with reduced ejection fraction (HFrEF) could lead to more targeted treatment improving systolic function and outcome. METHODS: In a retrospective cohort study, echocardiographic examinations from the first and final visit of 686 patients with HFrEF at the heart failure clinic at Gentofte Hospital were retrieved and analysed. Parameters associated with left ventricular ejection fraction (LVEF) improvement and survival according to LVEF improvement were assessed using linear regression and Cox regression, respectively. Beta-coefficients (ß-coef) are standardised. Strain values are absolute. RESULTS: While undergoing heart failure treatment, 559 (81.5%) patients improved systolic function ( Δ LVEF >0%), with 100 (14.6%) being super responders defined by LVEF improvement >20%. After multivariable adjustment, LVEF improvement was significantly associated with a less impaired global longitudinal strain (ß-coef 0.25, p<0.001), higher tricuspid annular plane systolic excursion (ß-coef 0.09, p=0.018), smaller left ventricular internal dimension in diastole (ß-coef -0.15, p=0.011), lower E-wave/A-wave ratio (ß-coef -0.13, p=0.003), higher heart rate (ß-coef 0.18, p<0.001) and absence of ischaemic cardiomyopathy (ß-coef -0.11, p=0.010) and diabetes (ß-coef -0.081, p=0.033) at baseline. Mortality incidence rates differed with LVEF improvement ( Δ LVEF <0% vs Δ LVEF >0%, 8.3 vs 4.3 per 100 person years, p=0.012). Greater improvement in LVEF was associated with significantly lower mortality risk (tertile 1 vs tertile 3, HR 3.23, 95% CI 1.39 to 7.51, p=0.006). CONCLUSION: In this outpatient HFrEF cohort, most patients improved systolic function. Heart failure aetiology, comorbidities and echocardiographic measures of heart structure and function were significantly, independently associated with future LVEF improvement. Greater LVEF improvement was significantly associated with lower mortality.

Uric acid in advanced heart failure: relation to central haemodynamics and outcome.

OBJECTIVE: The role of hyperuricaemia as a prognostic maker has been established in chronic heart failure (HF) but limited information on the association between plasma uric acid (UA) levels and central haemodynamic measurements is available. METHODS: A retrospective study on patients with advanced HF referred for right heart catherisation. Regression analyses were constructed to investigate the association between UA and haemodynamic variables. Cox models were created to investigate if UA was a significant predictor of adverse outcome where log1.1(UA) was used to estimate the effect on outcome associated with a 10% increase in UA levels. RESULTS: A total of 228 patients were included (77% males, age 49±12 years, mean left ventricular ejection fraction (LVEF) of 17%±8%). Median UA was 0.48 (0.39-0.61) mmol/L. UA level was associated to pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) in univariable (both p<0.001) and multivariable regression analysis (p<0.004 and p=0.025 for PCWP and CI). When constructing multivariable Cox models including PCWP, CI, central venous pressure, age, estimated glomerular filtration rate (eGFR), use of loop diuretics and LVEF, log1.1(UA) independently predicted the combined endpoint (left ventricular assist device, total artificial heart implantation, heart transplantation or all-cause mortality) (hazard ratio (HR): 1.10 (1.03-1.17), p=0.004) as well as all-cause mortality (HR: 1.15 (1.06-1.25), p=0.001). CONCLUSIONS: Elevated UA is associated with greater haemodynamic impairment in advanced HF. In adjusted Cox models (age, eGFR, LVEF and haemodynamics), UA predicts the combined endpoint and all-cause mortality in long-term follow-up.

Pressure-flow responses to exercise in aortic stenosis, mitral regurgitation and diastolic dysfunction.

BACKGROUND: Haemodynamic exercise testing is important for evaluating patients with dyspnoea on exertion and preserved ejection fraction. Despite very different pathologies, patients with pressure (aortic stenosis (AS)) and volume (mitral regurgitation (MR)) overload and diastolic dysfunction after recent acute myocardial infarction (AMI) reach similar filling pressure levels with exercise. The pressure-flow relationships (the association between change in cardiac output (∆CO) and change in pulmonary arterial wedge pressure (∆PAWP) may provide insight into haemodynamic adaptation to exercise in these groups. METHODS AND RESULTS: One hundred sixty-eight subjects aged >50 years with a left ventricular ejection fraction of ≥50% underwent invasive exercise testing. They were enrolled in four different studies: AS (40 patients), AMI (52 patients), MR (43 patients) and 33 healthy subjects. Haemodynamic data were measured at rest, at 25 W, 75 W and at peak exercise. In all groups, PAWP increased with exercise. The greatest increase was observed in patients with AMI (from 12.7±3.9 mm Hg to 33.1±8.2 mm Hg, p<0.0001) and patients with AS (from 11.8±3.9 mm Hg to 31.4±6.1 mm Hg, p<0.0001), and the smallest was observed in healthy subjects (from 8.3±2.4 mm Hg to 21.1±7.5 mm Hg, p<0.0001). In all groups, the relative pressure increase was greatest at the beginning of the exercise. CO increased most in healthy patients (from 5.3±1.1 to 16.0±3.0 L/min, p<0.0001) and least in patients with AS (from 5.3±1.2 L/min to 12.4±2.6 L/min, p<0.0001). The pressure-flow relationships (∆PAWP/∆CO) and differed among groups (p=0.02). In all groups, the pressure-flow relationship was steepest in the initial phase of the exercise test. The AMI and AS groups (2.3±1.2 mm Hg/L/min and 3.0±1.3 mm Hg/L/min, AMI and AS, respectively) had the largest overall pressure-flow relationship; the healthy group had the smallest initially and at peak exercise (1.3±1.1 mm Hg/L/min) followed by MR group (1.9±1.4 mm Hg/L/min). CONCLUSION: The pressure-flow relationship was steepest in the initial phase of the exercise test in all groups. The pressure-flow relationship differs between groups. TRIAL REGISTRATION NUMBERS: NCT01974557, NCT01046838, NCT02961647 and NCT02395107.

SARS-CoV-2 Surface Swabs in Locations With Public Access-Potential for Improved Source Control.

The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on surfaces at public locations has been minimally described. By swab testing, we investigated the presence of SARS-CoV-2 on surfaces in public locations during the pandemic in February 2022. The viability of SARS-CoV-2 was not tested. Almost 25% of surfaces were positive for SARS-CoV-2; this was most pronounced in supermarkets.

Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through ß3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial.

BACKGROUND: ß3-AR (ß3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the ß3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. METHODS: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. RESULTS: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P=0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P=0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. CONCLUSIONS: Oral treatment with the ß3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: 2016-002367-34.

Risk Estimates of Imminent Cardiovascular Death and Heart Failure Hospitalization Are Improved Using Serial Natriuretic Peptide Measurements in Patients With Coronary Artery Disease and Type 2 Diabetes.

Background Baseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long-term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6 months based on 2 serial NP measurements. Methods and Results Consecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6 months using either BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal pro-BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6-month follow-up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient-years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6 months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT-proBNP, P<0.0001), with a majority of moderate-risk patients (6-month risk between 1% and 10%) being reclassified on the basis of the second NP sample. Conclusions Serial NP measurements improved prediction of imminent cardiovascular death or HFH in patients with coronary artery disease and type 2 diabetes. The absolute risk estimates provided may aid clinicians in decision-making and help patients understand their short-term risk profile.

Association between early detected heart failure stages and future cardiovascular and non-cardiovascular events in the elderly (Copenhagen Heart Failure Risk Study).

BACKGROUND: Early stages of heart failure (HF) are associated with an increased risk of hospitalization and increased mortality, however the course of progression and the impact of non-cardiovascular comorbidities on adverse events in elderly high-risk patients are unknown. AIM: To examine the risk of future cardiovascular (CV) and non-CV events in early stages of HF in a cohort of elderly patients (age ≥ 60 with ≥ 1 risk factor for HF and without known or clinically suspected HF). METHODS: A total of 400 patients (American Heart Association HF stage A: N = 177; stage B: N = 150; stage C: N = 73) from the Copenhagen Heart Failure Risk Study were identified and followed for the main composite outcome of a HF hospitalization (HFH), ischemic heart disease (IHD), stroke, and all-cause death, recorded within the Danish nationwide registries. Non-CV hospitalization was a secondary outcome. Absolute risk was calculated by the Aalen-Johansen estimator. RESULTS: The median follow-up time was 3.3 years, total number of events were 83, and the 3-year risk (95% confidence interval) of the main outcome was 12.8% (7.8-17.9), 22.8% (16.1-29.6) and 31.8% (21.0-42.6) for patients with stage A, B, and C, respectively. 1.1% (0.0-2.7), 3.4% (1.0-6.3) and 10.0% (2.8-16.3) experienced HFH as their first event, whereas 37.3% (30.2-44.4), 49.7% (41.6-57.8) and 54.8% (43.4-66.2) were admitted for non-CV causes as their first event. CONCLUSION: The risk of HFH, IHD, stroke and all-cause death increased with severity of HF stage, and 10% of patients with undiagnosed HF stage C were admitted for HF within 3 years. However, the risk of non-CV hospitalizations was greater compared to the risk of experiencing HFH.

Randomized Controlled Trial of the Hemodynamic Effects of Empagliflozin in Patients With Type 2 Diabetes at High Cardiovascular Risk: The SIMPLE Trial.

Treatment with the sodium-glucose cotransporter 2 inhibitor (SGLT-2i) empagliflozin significantly reduces cardiovascular events in patients with type 2 diabetes (T2D); however, the mechanisms behind the reduction in cardiovascular (CV) events are unknown. We investigated whether SGLT-2i treatment affected central hemodynamics during rest and exercise in 34 patients with diabetes in this investigator-initiated, randomized, placebo-controlled, double-blinded trial. The primary end point was change in pulmonary capillary wedge pressure (PCWP) at a submaximal ergometer workload (25 W) after 13 weeks of SGLT-2i treatment (25 mg once daily) compared with placebo. Secondary end points included changes in resting hemodynamics. Baseline and follow-up hemodynamic assessments were performed at rest, submaximal exercise (25 W), and peak exercise using right heart catheterization. Treatment with empagliflozin for 13 weeks in patients with T2D at high CV risk did not reduce left heart filling pressure more than placebo at submaximal exercise. At rest, we observed that empagliflozin reduced PCWP at a magnitude of clinical significance.

Effect of empagliflozin on myocardial structure and function in patients with type 2 diabetes at high cardiovascular risk: the SIMPLE randomized clinical trial.

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by - 11.5 g/m2 (95% CI - 56.4; 33.4, p = 0.03) with empagliflozin compared to - 1.4 g/m2 (95% CI - 36.5; 33.8, p = 0.63) for placebo. The proportion of patients with LV hypertrophy was reduced by 16.3% (p = 0.04) in the empagliflozin group compared to 1.1% in the placebo group (p = 1.00). The proportion of patients with left atrial volume index > 34 mL/m2 was reduced by 20.0% (p = 0.02) with empagliflozin compared to 9.5% for placebo (p = 0.45) and the E/e' ratio decreased (∆-0.8 (1.9) vs. ∆0.5 (2.0), p < 0.01). 13 weeks empagliflozin treatment in patients with type-2 diabetes at high CV risk significantly reduced LV mass, improved LV geometry and improved diastolic function compared to placebo.

Comprehensive Physiological Modeling Provides Novel Insights Into Heart Failure With Preserved Ejection Fraction Physiology.

Background Although a rapid rise in left atrial pressure during exertion is considered pathognomonic of heart failure with preserved ejection fraction (HFpEF), the fundamental circulatory determinants of this response are not clear, impacting upon the development of more effective therapies. We aimed to comprehensively describe the circulatory mechanics of patients with HFpEF at rest and during exercise in comparison with controls. Methods and Results We performed simultaneous right-heart catheterization and echocardiography at rest and during exercise in 22 healthy control volunteers and 60 patients with confirmed HFpEF. Using detailed individual patient-level hemodynamic and left ventricular ejection fraction data we performed computer simulations to evaluate the circulatory parameters including the estimated stressed blood volumethat contribute to the resting and exercise pulmonary capillary pressure. At rest and during exercise, left ventricular stiffness (V30, the end-diastolic pressure-volume relationship at a filling pressure of 30 mm Hg), left ventricular elastance, and arterial elastance were all significantly greater in HFpEF than in controls. Stressed blood volume was significantly greater in HFpEF (26.9±5.4 versus 20.2±4.7 mL/kg, P<0.001), becoming even more pronounced during exercise (40.9±3.7 versus 27.5±7.0 mL per 70 kg, P<0.001). During exercise, the magnitude of the change in stressed blood volume (r=0.67, P<0.001) and left ventricular stiffness (r=-0.44, P<0.001) were key determinants of the rise in pulmonary capillary wedge pressure. Further detailed modeling studies showed that the hemodynamic response to exercise results from a complex non-linear interaction between circulatory parameters. Conclusions The circulatory determinants of HFpEF physiology are complex. We identified stressed blood volume at rest and during exercise is a novel, key factor, therebyrepresenting an important potential therapeutic target.

Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

Determinants and consequences of heart rate and stroke volume response to exercise in patients with heart failure and preserved ejection fraction.

AIMS: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses. METHODS AND RESULTS: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m2 , healthy participants: +24 ± 12 mL/m2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF. CONCLUSION: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.

The contribution of cardiac and extracardiac factors to NT-proBNP concentrations in patients with advanced heart failure before and after left ventricular assist device implantation.

The clinical significance of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients undergoing left ventricular assist device (LVAD) implantation is not fully explored. NT-proBNP concentrations are influenced by body composition, renal function and intracardiac pressures; dynamic measures pre- and post-LVAD implantation. We sought to identify the individual contribution of cardiac and extracardiac factors to NT-proBNP concentrations in advanced heart failure patients before and after LVAD implantation. We retrospectively collected data from 63 patients implanted with a LVAD with NT -proBNP measurements (2006-2019). Hemodynamic measurements were obtained through right heart catheterization (RHC). Univariable linear regression and multivariable stepwise regression models were used to analyze variables associated with NT-proBNP concentrations in the pre- and post-LVAD setting. Paired t-test was performed on a subpopulation of 13 patients with complete data. We found significant differences in all extracardiac (BMI, creatinine, eGFR) and all invasive hemodynamic measurements pre-LVAD compared to post-LVAD. NT-proBNP decreased by 83 %, in the subpopulation of 13 patients: 736 pmol/L [IQR 498-1330] to 126 pmol/L [IQR 74.8-241.7]. In multivariable analysis, only creatinine remained significantly associated with NT-proBNP before LVAD implant (p = 0.016), whereas pulmonary capillary wedge pressure (PCWP) was the only independent variable associated with NT-proBNP after LVAD implant (p < 0.0001). Creatinine and PCWP were the only independent factors associated with NT-proBNP concentrations before and after LVAD implantation, respectively. Invasive hemodynamic measurements were more closely associated with NT-proBNP concentration after LVAD than extracardiac factors and reversely pre-LVAD, suggesting that NT-proBNP serves as a useful biomarker of cardiac conditions post-LVAD implantation.

Blood pressure and mortality in patients with type 2 diabetes and a recent coronary event in the ELIXA trial.

BACKGROUND: The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure. METHODS: We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization. RESULTS: Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99-1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04-1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86-1.04) P = 0.26; P for interaction 0.005). CONCLUSIONS: The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010.