Reddy, Yogesh N V

Abstract Background and Aims Exercise stress echocardiography is recommended as an alternative to invasive testing for diagnosing heart failure with preserved ejection fraction (HFpEF), but an evidence-based operational framework guiding its application is lacking. Methods Patients with chronic unexplained dyspnoea underwent invasive haemodynamic exercise testing with simultaneous echocardiography to test the hypotheses that (i) the current diagnostic algorithms (H2FPEF, HFA-PEFF, and HFpEF-ABA scores) could be enhanced when combined with exercise echocardiography; and (ii) incorporating resting left atrial (LA) compliance (LA reservoir strain divided by E/e′) could further improve diagnostic triage, using separate cut points optimizing sensitivity and specificity. Findings were then validated in an international multicentre cohort. Results Of 482 patients, HFpEF was present in 386 and non-cardiac dyspnoea in 96. Sensitivity to detect HFpEF was only 55%–60% and accuracy 61%–67% using individual diagnostic scores with currently recommended exercise echocardiography. Addition of abnormal resting LA compliance to exercise echocardiography increased sensitivity to 84%–85% but increased the false-positive rate to 31%–43%. Applying separate cut points that optimize specificity and sensitivity (either exercise E/e′ ≥ 13.8 or resting LA compliance ≤1.6% to rule-in HFpEF; both exercise E/e′ < 7.2 and resting LA compliance >4.4% to rule-out HFpEF, remaining patients indeterminate who require invasive testing) improved sensitivity to 95%–99% among definitively classified patients and reduced the number of patients that require invasive exercise testing from ∼60% to ∼30%. Findings were replicated in a multicentre, international validation cohort of patients undergoing rest–exercise echocardiography and invasive exercise testing. Conclusions Currently used non-invasive approaches to HFpEF diagnosis have inadequate sensitivity, indicating that exercise echocardiography cannot supplant invasive testing. Addition of LA strain imaging with optimized rule-in or rule-out values improves diagnostic triage by expanding non-invasive rule-in/rule-out classifications while identifying patients who still require invasive testing in the evaluation of HFpEF.

Objective To evaluate the clinical effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in reducing the risk of hospital admission for heart failure and mortality in a contemporary nationwide cohort of patients with heart failure with preserved ejection fraction (HFpEF). Design Nationwide cohort study (REFINE-HFpEF). Setting 170 veteran health medical centres across the US, 1 January 2014 to 31 December 2021. Participants 2177 patients with type 2 diabetes and HFpEF; 1129 patients were newly prescribed SGLT2 inhibitors and 1048 were newly prescribed dipeptidyl peptidase 4 (DPP4) inhibitors or sulfonylureas. Main outcome measures The primary outcome was a composite of all cause mortality and hospital admission for heart failure. Secondary outcomes included all cause mortality only and serial changes in body weight. Hazard ratios were derived from Cox proportional hazards models, incorporating inverse probability of treatment weighting based on propensity scores to account for confounding. Results From a validated cohort of 179 288 patients with type 2 diabetes and HFpEF, the study included 1129 new users of SGLT2 inhibitors (active treatment) and 1048 new users of DPP4 inhibitors or sulfonylureas (comparators). After a median follow-up of 2.63 years, 46.4% of the study population had at least one hospital admission for heart failure (n=1011) and the overall mortality rate was 45.9% (n=1000). Use of SGLT2 inhibitors was associated with a relative risk reduction in the primary composite outcome of 18% compared with the use of DPP4 inhibitors or sulfonylureas (hazard ratio 0.82, 95% confidence interval 0.70 to 0.96; P=0.01). The adjusted hazard ratio for all cause mortality only was 0.73 (0.60 to 0.89; P=0.002). Weight loss was similar in the two groups. Conclusions In this large, contemporary, nationwide cohort of patients with HFpEF, type 2 diabetes, and high event rates, starting SGLT2 inhibitors was associated with a significantly lower risk of hospital admission for heart failure and all cause mortality compared with starting treatment with DPP4 inhibitors or sulfonylureas.

Abstract Aims Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. Methods Consecutively evaluated patients with HFpEF undergoing invasive haemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, haemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. Results Of 925 patients with HFpEF, 319 (34.5%) had estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension. At rest, reduced kidney function was associated with lower haemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR < 30, P < .001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR < 30, P < .001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anaemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01–5.59) for eGFR 60–90 to HR 16.77 (95% CI 6.65–42.28) for eGFR < 30 (vs. reference eGFR ≥ 90)]. Conclusions Kidney dysfunction in patients with HFpEF is characterized by more severe PVD at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.