Mitral E-wave to stroke volume ratio displays stronger diagnostic performance to identify elevated left ventricular filling pressures than mitral E/e' during passive leg lift: A cross-sectional study employing simultaneous echocardiography and catheterization.

BACKGROUND: Elevated filling pressure is a hallmark of heart failure (HF) and portends poor prognosis. Accurate diagnosis is challenging, given that patients with normal filling pressure at rest develop disproportionate elevation with sudden preload increase. We aimed to test the accuracy of the ratio between mitral inflow velocity (E) and left ventricular stroke volume (SV) to identify patients with elevated filling pressure with passive leg lifting (PLL) and compare this with other echocardiographic surrogates of filling pressure. METHODS: Doppler echocardiography and right heart catheterization (RHC) were simultaneously performed in 37 patients (11 males, mean age 67 ± 12 years) with exertional dyspnea. Twenty-six healthy controls (14 males, mean age 60 ± 12 years) were added as reference. SV, cardiac output (CO), tricuspid regurgitation peak gradient (TRG), mitral E-wave (E) and early myocardial velocity (e') were obtained at rest and with PLL. E/SV, E/CO and E/e' were calculated and correlated with invasive pulmonary capillary wedge pressures (PCWP) with PLL. RESULTS: During PLL, E/SV (AUC = 0.94) displayed stronger diagnostic ability to identify PCWP >15 mmHg than E/e' (AUC = 0.81), mitral E/A ratio (0.76) and resting invasive PCWP (0.84). An E/SV cutoff of >1.0 showed 88% sensitivity and 75% specificity to identify elevated PCWP. Further, 10 patients (27%) were reassigned during PLL from normal to postcapillary pulmonary hypertension (postCPH), and 6 patients (16%) switched diagnosis from precapillary PH (preCPH) to postCPH. CONCLUSION: The novel E/SV ratio identifies patients with elevated PCWP with PLL and displays stronger diagnostic performance than routinely utilized echocardiographic measures such as E/e' in addition to resting, catheterization derived PCWP.

Higher prevalence of coronary microvascular dysfunction in asymptomatic individuals with high levels of lipoprotein(a) with and without heterozygous familial hypercholesterolaemia.

BACKGROUND AND AIMS: Microvascular dysfunction underlies many cardiovascular disease conditions; little is known regarding its presence in individuals with high levels of lipoprotein(a) [Lp(a)]. The aim of the present study was to determine the frequency of microvascular dysfunction among such subjects with and without concomitant familial hypercholesterolemia (FH). METHODS: Four groups of asymptomatic individuals aged 30-59 years, without manifest cardiovascular disease, were recruited (n = 30 per group): controls with Lp(a) < 30 nmol/L, mutation-confirmed FH with Lp(a) < 30 nmol/L, or >125 nmol/L, and individuals with isolated Lp(a) > 125 nmol/L. Participants underwent evaluation of myocardial microvascular function by measuring coronary flow reserve (CFR) using transthoracic Doppler echocardiography, and of peripheral microvascular endothelial function by peripheral arterial tonometry. RESULTS: The groups were balanced in age, sex, and body mass index. Each of the three dyslipoproteinaemic groups had a greater proportion of individuals with impaired coronary flow reserve, 30%, compared to 6.7% of controls (p = 0.014). The median CFR levels did not differ significantly between the four groups, however. Cholesterol-lowering treatment time was longer in the individuals with normal than in those with impaired CFR in the FH + Lp(a) > 125 group (p = 0.023), but not in the group with FH + Lp(a) < 30 (p = 0.468). There was no difference in peripheral endothelial function between the groups. CONCLUSIONS: Coronary microvascular dysfunction is more prevalent in asymptomatic individuals with isolated Lp(a) elevation and in heterozygous FH both with and without high Lp(a) compared to healthy controls. Cholesterol-lowering treatment could potentially prevent the development of microvascular dysfunction.

Acyl ghrelin increases cardiac output while preserving right ventricular-pulmonary arterial coupling in heart failure.

AIM: Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular-pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right-sided haemodynamics in HFrEF assessed by RVPAC. METHODS AND RESULTS: The Karolinska Acyl ghrelin Trial was a randomized double-blind placebo-controlled trial of acyl ghrelin versus placebo (120-min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5-4.6) to 4.6 (3.9-6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3-7.6) to 6.3 (4.8-7.5) mm·(m/s)-1 , P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3-6.4) to 4.8 (4.2-5.8) mm·(m/s)-1 , P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. CONCLUSION: Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure.

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction.

AIMS: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. METHODS AND RESULTS: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). CONCLUSIONS: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.

Cognitive Behavioral Therapy Improves Quality of Life in Patients With Symptomatic Paroxysmal Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is often associated with troubling symptoms leading to impaired quality of life (QoL) and high health care use. Symptom preoccupation, that is, fear of cardiac-related symptoms and avoidance behavior, potentially contributes to disability in AF but is not targeted by current interventions. OBJECTIVES: We sought to evaluate the effect of online cognitive behavior therapy (AF-CBT) on QoL in patients with symptomatic paroxysmal AF. METHODS: Patients with symptomatic paroxysmal AF (n = 127) were randomly assigned to receive AF-CBT (n = 65) or standardized AF education (n = 62). Online AF-CBT lasted 10 weeks and was therapist guided. The main components were exposure to cardiac-related symptoms and reduction of AF-related avoidance behavior. Patients were evaluated at baseline, posttreatment, and at the 3-month follow-up. Primary outcome was AF-specific QoL as assessed by the Atrial Fibrillation Effect on Quality of Life summary score (range: 0-100) at the 3-month follow-up. Secondary outcomes included AF-specific health care consumption and AF burden assessed by 5-day continuous electrocardiogram recording. The AF-CBT group was followed for 12 months. RESULTS: AF-CBT led to large improvements in AF-specific QoL (Atrial Fibrillation Effect on Quality of Life summary score) by 15.0 points (95% CI: 10.1-19.8; P < 0.001). Furthermore, AF-CBT reduced health care consumption by 56% (95% CI: 22-90; P = 0.025). The AF burden remained unchanged. Results on self-assessed outcomes were sustained 12 months after treatment. CONCLUSIONS: In patients with symptomatic paroxysmal AF, online CBT led to large improvements in AF-specific QoL and reduced health care use. If these results are replicated, online CBT may constitute an important addition to AF management. (Internet-Delivered Cognitive Behavior Therapy for Atrial Fibrillation; NCT03378349).

Long-term outcomes in heart failure with preserved ejection fraction: Predictors of cardiac and non-cardiac mortality.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with cardiovascular (CV) and non-CV events, but long-term risk is poorly studied. We assessed incidence and predictors of the long-term CV and non-CV events. METHODS AND RESULTS: Patients presenting with acute HF, EF ≥ 45%, and N-terminal pro-brain natriuretic peptide > 300 ng/L were enrolled in the Karolinska-Rennes study in 2007-11 and were reassessed after 4-8 weeks in a stable state. Long-term follow-up was conducted in 2018. The Fine-Gray sub-distribution hazard regression was used to detect predictors of CV and non-CV deaths, investigated separately from baseline acute presentation (demographic data only) and from the 4-8 week outpatient visit (including echocardiographic data). Of 539 patients enrolled [median age 78 (interquartile range: 72-84) years; 52% female], 397 patients were available for the long-term follow-up. Over a median follow-up time from acute presentation of 5.4 (2.1-7.9) years, 269 (68%) patients died, 128 (47%) from CV and 120 (45%) from non-CV causes. Incidence rates per 1000 patient-years were 62 [95% confidence interval (CI) 52-74] for CV and 58 (95% CI 48-69) for non-CV death. Higher age and coronary artery disease (CAD) were independent predictors of CV death, and anaemia, stroke, kidney disease, and lower body mass index (BMI) and sodium concentrations of non-CV death. From the stable 4-8 week visit, anaemia, CAD, and tricuspid regurgitation (>3.1 m/s) were independent predictors of CV death, and higher age of non-CV death. CONCLUSIONS: In patients with acute decompensated HFpEF, over 5 years of follow-up, nearly two-thirds of patients died, half from CV and the other half from non-CV causes. CAD and tricuspid regurgitation were associated with CV death. Stroke, kidney disease, lower BMI, and lower sodium were associated with non-CV death. Anaemia and higher age were associated with both outcomes. [Correction added on 24 March 2023, after first online publication: In the first sentence of the Conclusions, 'two-thirds' has been inserted before 'of patients died...' in this version.].

Recommendations for the Use of Echocardiography in the Evaluation of Rheumatic Heart Disease: A Report from the American Society of Echocardiography.

Acute rheumatic fever and its chronic sequela, rheumatic heart disease (RHD), pose major health problems globally, and remain the most common cardiovascular disease in children and young people worldwide. Echocardiography is the most important diagnostic tool in recognizing this preventable and treatable disease and plays an invaluable role in detecting the presence of subclinical disease needing prompt therapy or follow-up assessment. This document provides recommendations for the comprehensive use of echocardiography in the diagnosis and therapeutic intervention of RHD. Echocardiographic diagnosis of RHD is made when typical findings of valvular and subvalvular abnormalities are seen, including commissural fusion, leaflet thickening, and restricted leaflet mobility, with varying degrees of calcification. The mitral valve is predominantly affected, most often leading to mitral stenosis. Mixed valve disease and associated cardiopulmonary pathology are common. The severity of valvular lesions and hemodynamic effects on the cardiac chambers and pulmonary artery pressures should be rigorously examined. It is essential to take advantage of all available modalities of echocardiography to obtain accurate anatomic and hemodynamic details of the affected valve lesion(s) for diagnostic and strategic pre-treatment planning. Intraprocedural echocardiographic guidance is critical during catheter-based or surgical treatment of RHD, as is echocardiographic surveillance for post-intervention complications or disease progression. The role of echocardiography is indispensable in the entire spectrum of RHD management.

SOdium-glucose CO-transporter inhibition in patients with newly detected Glucose Abnormalities and a recent Myocardial Infarction (SOCOGAMI).

AIMS/HYPOTHESIS: Established dysglycaemia (impaired glucose tolerance [IGT] or type 2 diabetes [T2DM]) is a risk factor for further cardiovascular events in patients with coronary artery disease. Sodium-glucose cotransporter 2 inhibitors reduce this risk. The aim of the present investigation was to test the hypothesis that empagliflozin exerts beneficial effects on myocardial function in patients with a recent acute coronary syndrome and newly detected dysglycaemia. METHODS: Forty-two patients (mean age 67.5 years, 81 % male) with recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected IGT (n = 27) or T2DM (n = 15) were randomised to 25 mg of empagliflozin daily (n = 20) or placebo (n = 22) on top of ongoing therapy. They were investigated with oral glucose tolerance tests, stress-perfusion cardiac magnetic resonance imaging (CMR) and echocardiography at three occasions: before randomisation, after seven months on study drug and three months following cessation of such drug. Primary outcome was a change in left ventricular (LV) end-diastolic volume (LVEDV) and secondary outcomes were a change in a) systolic and diastolic LV function; b) coronary flow reserve; c) myocardial extracellular volume (ECV) in non-infarcted myocardium; d) aortic pulse wave velocity. RESULTS: Empagliflozin induced a significant decrease in fasting and post load glucose (p < 0.05) and body weight (p < 0.01). Empagliflozin did not influence LVEDV, LV systolic or mass indexes, coronary flow reserve, ECV or aortic pulse wave velocity. Echocardiographic indices of LV diastolic function (E/e' and mitral E/A ratio) were not influenced. No safety concerns were identified. CONCLUSIONS/INTERPRETATION: Empagliflozin had predicted effects on the dysglycaemia but did not influence variables expressing LV function, coronary flow reserve and ECV. An explanation may be that the LV function of the patients was within the normal range.

Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the PROMIS-HFpEF study.

AIM: Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS-HFpEF cohort. METHODS AND RESULTS: Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high-throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler-based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n = 54; 30%) had higher body mass index (32 [28-40] vs. 27 [23-30] kg/m2 ; p < 0.001), lower N-terminal pro-B-type natriuretic peptide (466 [193-1133] vs. 1120 [494-1990] pg/ml; p < 0.001), smaller indexed left ventricular (LV) end-diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non-indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00-1.04; p = 0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01-1.05; p = 0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR. CONCLUSION: Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated.

A novel echocardiographic estimate of pulmonary vascular resistance employing the hydraulic analogy to Ohm's law.

Background: Assessment of pulmonary vascular resistance (PVR) is critical for accurate diagnosis and optimal pharmacotherapy in pulmonary hypertension. We aimed to test the diagnostic performance of a novel, Doppler-based method to evaluate PVR based on Ohm's law (PVRecho) using pragmatic estimates of pulmonary capillary wedge pressure (PCWP). Methods and results: Simultaneous right heart catheterization (RHC) and echocardiography was performed in a derivation cohort of 111 patients in sinus rhythm referred for PH evaluation and PVRecho independently validated in 238 patients. PVRecho was calculated using pulmonary artery mean pressure estimates (PAMPecho) obtained from peak tricuspid gradient employing a fixed right atrial pressure estimate, PCWPecho was estimated as 10 or 20 mmHg using age-related mitral E/A cut-offs and cardiac output from left ventricular outflow. In the derivation cohort, both PAMPecho and PCWPecho estimates demonstrated excellent agreement with catheterization measurements. PVRecho was highly feasible, demonstrated negligible bias and excellent agreement with PVRRHC (Bias = -0.58, SD 2.2 mmHg) and outperformed the Abbas method to identify PVRRHC > 3WU (AUC = 0.85 vs. 0.70; p = 0.02). In the validation cohort, PVRecho preserved good invasive agreement with negligible bias, displayed strong diagnostic performance (AUC = 0.84) and significant ability to distinguish isolated post-capillary from combined post- and pre-capillary pulmonary hypertension (PH) subgroups (AUC = 0.77). Conclusion: PVRecho based on Ohm's law employing pragmatic estimates of PCWPecho demonstrates excellent agreement with invasive reference standard measurements and strong diagnostic ability to identify elevated PVRRHC. This novel approach may be useful during therapy selection to distinguish PH hemodynamic subgroups.

RWT/SaVR-A Simple and Highly Accurate Measure Screening for Transthyretin Cardiac Amyloidosis.

Background: Cardiac amyloidosis is an underdiagnosed condition and simple methods for accurate diagnosis are warranted. We aimed to validate a novel, dual-modality approach to identify transthyretin cardiac amyloidosis (ATTR-CA), employing echocardiographic relative wall thickness (RWT), and ECG S-wave from aVR (SaVR), and compare its accuracy with conventional echocardiographic approaches. Material and methods: We investigated 102 patients with ATTR-CA and 65 patients with left ventricular hypertrophy (LVH), all with septal thickness > 14 mm. We validated the accuracy of echocardiographic measures, including RWT, RWT/SaVR, posterior wall thickness (PWT), LV mass index (LVMI), left atrial volume index (LAVI), global longitudinal strain (GLS), and relative apical sparing (RELAPS) to identify ATTR-CA diagnosed using DPD-scintigraphy or abdominal fat biopsy. Results: PWT, RWT, RELAPS, troponin, and RWT/SaVR were significantly higher in ATTR-CA compared to LVH. RWT/SaVR > 0.7 was the most accurate parameter to identify ATTR-CA (sensitivity 97%, specificity 90% and accuracy 91%). RELAPS was found to have much less accuracy (sensitivity 74%, specificity 76% and accuracy 73%). Conclusion: We can confirm the very strong diagnostic accuracy of RWT/SaVR to identify ATTR-CA in patients with septal thickness > 14 mm. Given its high sensitivity and specificity, RWT/SaVR > 0.7 has the potential to implement as a non-invasive, simple, and widely available diagnostic tool when screening for ATTR-CA.

Echocardiographic Biventricular Coupling Index to Predict Precapillary Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a frequent and detrimental condition. Right heart catheterization (RHC) is the gold standard to identify PH subtype (precapillary from postcapillary PH) and is key for treatment allocation. In this study, the novel echocardiographic biventricular coupling index (BCI), based on the ratio between right ventricular stroke work index and left ventricular E/E' ratio, was tested for the discrimination of PH subtype using RHC as the comparator. METHODS: BCI was derived in 334 consecutive patients who underwent transthoracic echocardiography and RHC for all indications. BCI was then tested in a validation cohort of 1,349 patients. RESULTS: The accuracy of BCI to identify precapillary PH was high in the derivation cohort (area under the curve, 0.82; 95% CI, 0.78-0.88; P < .001; optimal cut point, 1.9). BCI identified patients with precapillary PH with high accuracy also in the validation cohort (area under the curve, 0.87 [95% CI, 0.85-0.89; P < .001]; subgroup with PH: area under the curve, 0.91 [95% CI, 0.89-0.93; P < .001]; cut point, 1.9; sensitivity, 82%; specificity, 89%; positive predictive value, 77%; negative predictive value, 92%). BCI outperformed both the D'Alto score (Z = 3.56; difference between areas = 0.05; 95% CI, 0.02-0.07; P < .001) and the echocardiographic pulmonary-to-left atrial ratio index (Z = 2.88; difference between areas = 0.02; 95% CI, 0.01-0.04; P = .004). CONCLUSIONS: BCI is a novel, noninvasive index based on routinely available echocardiographic parameters that identifies with high accuracy patients with precapillary PH. BCI may be of value in the screening workup of patients with PH.

Left atrial reservoir strain improves diagnostic accuracy of the 2016 ASE/EACVI diastolic algorithm in patients with preserved left ventricular ejection fraction: insights from the KARUM haemodynamic database.

AIMS: This study aimed to investigate the incremental value offered by left atrial reservoir strain (LASr) to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) diastolic algorithm to identify elevated left ventricular (LV) filling pressure in patients with preserved ejection fraction (EF). METHODS AND RESULTS: Near-simultaneous echocardiography and right heart catheterization were performed in 210 patients with EF ≥50% in a large, dual-centre study. Elevated filling pressure was defined as invasive pulmonary capillary wedge pressure (PCWP) ≥15 mmHg. LASr was evaluated using speckle-tracking echocardiography. Diagnostic performance of the ASE/EACVI diastolic algorithm was validated against invasive reference and compared with modified algorithms incorporating LASr. Modest correlation was observed between E/e', E/A ratio, and LA volume index with PCWP (r = 0.46, 0.46, and 0.36, respectively; P < 0.001 for all). Mitral e' and TR peak velocity showed no association. The ASE/EACVI algorithm (89% feasibility, 71% sensitivity, 68% specificity) demonstrated reasonable ability (AUC = 0.69) and 68% accuracy to identify elevated LV filling pressure. LASr displayed strong ability to identify elevated PCWP (AUC = 0.76). Substituting TR peak velocity for LASr in the algorithm (69% sensitivity, 84% specificity) resulted in 91% feasibility, 81% accuracy, and stronger agreement with invasive measurements. Employing LASr as per expert consensus (71% sensitivity, 70% specificity) and adding LASr to conventional parameters (67% sensitivity, 84% specificity) also demonstrated greater feasibility (98% and 90%, respectively) and overall accuracy (70% and 80%, respectively) to estimate elevated PCWP. CONCLUSIONS: LASr improves feasibility and overall accuracy of the ASE/EACVI algorithm to discern elevated filling pressures in patients with preserved EF.

Eligibility of patients with heart failure with preserved ejection fraction for sacubitril/valsartan according to the PARAGON-HF trial.

AIMS: In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON-HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios. METHODS AND RESULTS: Eligibility was assessed in the Karolinska-Rennes study (acute HFpEF, LVEF ≥ 45%, and N-terminal pro-B-type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (<54% in women and <52% in men); and (iv) LVEF below mean of normal range (<64% in women and <62% in men). Among 425 patients [age 78 (72-83) years, 57% women, 28% LVEF ≤ 57% (median in PARAGON-HF), the trial scenario, identified 34% as eligible. Left atrial enlargement and/or left ventricular hypertrophy were present in 99%. Inclusion criteria not met were diuretic treatment and New York Heart Association class. Important exclusion criteria were estimated glomerular filtration rate <30 mL/min/1.73 m2 , haemoglobin <10 g/day, and cancer. In the pragmatic scenario, 63% were eligible. In LVEF below lower limit of normal range, 5.4% were eligible, and in LVEF below mean of normal range, 41% were eligible. In patients with LVEF ≤ 57%, eligibility was 42%, 69%, 21%, and 91% according to the trial scenario, pragmatic scenario, LVEF below lower limit of normal range, and LVEF below mean of normal range, respectively. CONCLUSIONS: In real-world HFpEF (LVEF ≥ 45%) with N-terminal pro-B-type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON-HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria.

Accuracy and diagnostic performance of doppler echocardiography to estimate mean pulmonary artery pressure in heart failure.

BACKGROUND: Multiple echocardiographic algorithms have been proposed to estimate mean pulmonary artery pressure (PAPM ) and assess pulmonary hypertension (PH) likelihood. We assessed the accuracy of four echocardiographic approaches to estimate PAPM in heart failure (HF) patients undergoing near-simultaneous right heart catheterization (RHC), and compared diagnostic performance to identify PH with recommendation-advised tricuspid regurgitation peak velocity (TRVmax ). METHODS: We employed four validated echocardiographic algorithms incorporating tricuspid regurgitation peak or mean gradient, pulmonary regurgitation peak gradient, and right ventricular outflow tract acceleration time to estimate PAPM . Echocardiographic estimates of right atrial pressure were incorporated in all algorithms but one. Association and agreement with invasive PAPM were assessed. Diagnostic performance of all algorithms to identify PH was evaluated and compared with the recommended TRVmax cut-off. RESULTS: In 112 HF patients, all echocardiographic algorithms demonstrated reasonable association (r = .41-.65; p < 0.001) and good agreement with invasive PAPM , with relatively lower mean bias and higher precision observed in algorithms that incorporated tricuspid regurgitation peak or mean gradient. All methods demonstrated strong ability to identify PH (AUC = .70-.80; p < 0.001) but did not outperform TRVmax (AUC = .84; p < 0.001). Echocardiographic estimates of right atrial pressure were falsely elevated in 30% of patients. CONCLUSIONS: Echocardiographic estimates demonstrate reasonable association with invasive PAPM and strong ability to identify PH in HF. However, none of the algorithms outperformed recommendation-advised TRVmax . The incremental value of echocardiographic estimates of right atrial pressure may need to be re-evaluated.

Predictors of long-term outcome in heart failure with preserved ejection fraction: a follow-up from the KaRen study.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) has poor long-term prognosis. We assessed rates and predictors of outcome 10 years after an acute episode of HF. METHODS AND RESULTS: The Karolinska-Rennes (KaRen) study enrolled HFpEF patients with acute HF, ejection fraction ≥ 45%, and N-terminal pro-brain natriuretic peptide > 300 ng/L in 2007-11. Clinical data were collected at enrolment and after 4-8 weeks including detailed echocardiography. Follow-up data were collected 10 years after study initiation, starting from 6 months after enrolment until 2018 assessed by telephone. Independent predictors of primary (all-cause mortality or HF hospitalization) and secondary (all-cause mortality) outcomes were assessed by multivariable Cox regression. Of 539 patients, long-term follow-up data were available for 397 patients [52% female; median (interquartile range) age 79 (73, 84) years]. Over a follow-up of 5.44 (2.06-7.89) years, 1, 3, 5, and 10 year mortality rates were 15%, 31%, 47%, and 74%, respectively, with an incidence rate of 130/1000 patient-years. The primary outcome was met in 84% of the population, with an incidence rate of 227/1000 patient-years. The independent predictors of the primary outcome were tricuspid regurgitation peak velocity (m/s) [hazard ratio 1.87 (1.34-2.62)], diabetes mellitus [1.75 (1.11-2.74)], and cancer [1.75 (1.01-3.03)] while female sex was associated with reduced risk [0.64 (0.41-0.98)]. CONCLUSIONS: In HFpEF, 1, 3, 5, and 10 year mortality was 15%, 31%, 47%, and 74% and mortality or first HF hospitalization was 35%, 54%, 67%, and 84%, respectively. Independent predictors of mortality or HF hospitalization were tricuspid regurgitation peak velocity, diabetes mellitus, cancer, and male sex. In clinical management of HFpEF, attention should be paid to both cardiac and non-cardiac conditions.

Accuracy of echocardiographic estimates of pulmonary artery pressures in pulmonary hypertension: insights from the KARUM hemodynamic database.

Accurate assessment of pulmonary artery (PA) pressures is integral to diagnosis, follow-up and therapy selection in pulmonary hypertension (PH). Despite wide utilization, the accuracy of echocardiography to estimate PA pressures has been debated. We aimed to evaluate echocardiographic accuracy to estimate right heart catheterization (RHC) based PA pressures in a large, dual-centre hemodynamic database. Consecutive PH referrals that underwent comprehensive echocardiography within 3 h of clinically indicated right heart catheterization were enrolled. Subjects with absent or severe, free-flowing tricuspid regurgitation (TR) were excluded. Accuracy was defined as mean bias between echocardiographic and invasive measurements on Bland-Altman analysis for the cohort and estimate difference within ± 10 mmHg of invasive measurements for individual diagnosis. In 419 subjects, echocardiographic PA systolic and mean pressures demonstrated minimal bias with invasive measurements (+ 2.4 and + 1.9 mmHg respectively) but displayed wide limits of agreement (- 20 to + 25 and - 14 to + 18 mmHg respectively) and frequently misclassified subjects. Recommendation-based right atrial pressure (RAP) demonstrated poor precision and was falsely elevated in 32% of individual cases. Applying a fixed, median RAP to echocardiographic estimates resulted in relatively lower bias between modalities when assessing PA systolic (+ 1.4 mmHg; 95% limits of agreement + 25 to - 22 mmHg) and PA mean pressures (+ 1.4 mmHg; 95% limits of agreement + 19 to - 16 mmHg). Echocardiography accurately represents invasive PA pressures for population studies but may be misleading for individual diagnosis owing to modest precision and frequent misclassification. Recommendation-based estimates of RAPmean may not necessarily contribute to greater accuracy of PA pressure estimates.

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study.

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF.

BACKGROUND: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers. METHODS AND RESULTS: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis. CONCLUSIONS: Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.

Cardiovascular Autonomic Function Changes and Predictors During a 2-Year Physical Activity Program in Rheumatoid Arthritis: A PARA 2010 Substudy.

Background: Chronic inflammation leads to autonomic dysfunction, which may contribute to the increased risk of cardiovascular diseases (CVD) in patients with rheumatoid arthritis (RA). Exercise is known to restore autonomic nervous system (ANS) activity and particularly its parasympathetic component. A practical clinical tool to assess autonomic function, and in particular parasympathetic tone, is heart rate recovery (HRR). The aim of this substudy from the prospective PARA 2010 study was to determine changes in HRR post-maximal exercise electrocardiogram (ECG) after a 2-year physical activity program and to determine the main predictive factors associated with effects on HRR in RA. Methods: Twenty-five participants performed physiotherapist-guided aerobic and muscle-strengthening exercises for 1 year and were instructed to continue the unsupervised physical activity program autonomously in the next year. All participants were examined at baseline and at years 1 and 2 with a maximal exercise ECG on a cycle ergometer. HRR was measured at 1, 2, 3, 4, and 5 min following peak heart rate during exercise. Machine-learning algorithms with the elastic net linear regression models were performed to predict changes in HRR1 and HRR2 at 1 year and 2 years of the PARA program. Results: Mean age was 60 years, range of 41-73 years (88% women). Both HRR1 and HRR2 increased significantly from baseline to year 1 with guided physical activity and decreased significantly from year 1 to year 2 with unsupervised physical activity. Blood pressure response to exercise, low BMI, and muscular strength were the best predictors of HRR1/HRR2 increase during the first year and HRR1/HRR2 decrease during the second year of the PARA program. Conclusion: ANS activity in RA assessed by HRR was improved by guided physical activity, and machine learning allowed to identify predictors of the HRR response at the different time points. HRR could be a relevant marker of the effectiveness of physical activity recommended in patients with RA at high risk of CVD. Very inactive and/or high CVD risk RA patients may get substantial benefits from a physical activity program.