Association of Reduced Left Atrial Reserve With Exercise Intolerance and Outcome in Hypertension.

BACKGROUND: Hypertensive heart disease (HHD) is a leading contributor to heart failure with preserved ejection fraction (HFpEF). However the mechanisms behind the transition to the symptomatic phase remain unclear. OBJECTIVES: We sought the association of the exercise response of LA mechanical function with functional capacity, symptoms and outcome across the HF spectrum in hypertension. METHODS: Echocardiography (including LA reservoir [PALS] and contractile strain [PACS], and LA stiffness index) were performed at rest and immediately post-exercise in 139 patients with HHD- 35 with stage A, 48 with stage B and 56 with stage C HFpEF. Patients were followed for HF and atrial fibrillation (AF). RESULTS: Exercise capacity was progressively worse from stage A through stage B to stage C, and accompanied by a gradual impairment of changes in PALS and PACS from rest to exercise, whereas LA stiffness reserve remained unchanged until stage C. PALS and PACS reserves were independently associated with exercise capacity(p=0.017 and 0.008, respectively). LA stiffness reserve and E/e' were the strongest associations of symptomatic HF. Over a median of 25 months, 35 patients developed HF and/or AF. PALS and PACS reserves were associated with the study endpoints after adjusting for age, diabetes, NT-proBNP, LA volume index, resting E/e' and resting PALS/PACS. CONCLUSIONS: Impaired exercise reserve of LA strain and stiffness are associated with reduced functional capacity in hypertension, and LA strain reserve is independently associated with outcome. These parameters appear to be determinants of progression to overt HF in HHD, however their contribution may differ depending on HF stage.

Contribution of reduced skeletal muscle perfusion reserve to exercise intolerance in heart failure with preserved ejection fraction.

BACKGROUND: Skeletal muscle (SM)-associated mechanisms of exercise intolerance in HFpEF are insufficiently defined, and inadequate augmentation of SM blood flow during physical effort may be one of the contributors. Therefore, we sought to investigate the association of SM perfusion response to exertion with exercise capacity in this clinical condition. METHODS: Echocardiography and SM microvascular perfusion by contrast-enhanced ultrasound were performed at rest and immediately post-exercise test in 77 HFpEF patients in NYHA class II and III, and in 25 subjects with normal exercise tolerance (stage B). Exercise reserve of cardiac function and SM perfusion was calculated by subtracting resting value from exercise value. RESULTS: In addition to decreased cardiac functional reserve, HFpEF patients demonstrated significantly reduced SM perfusion reserve as compared to HF stage B, with the degree of impairment being greater in the subgroup with more profound left ventricular (LV) diastolic abnormalities (E/e' > 15 and TRV > 2.8 m/s). SM perfusion reserve was significantly associated with exercise capacity (beta = 0.33; SE 0.11; p = 0.003), cardiac output reserve (beta = 0.24; SE 0.12; p = 0.039), resting E/e' (beta = -0.33; SE 0.11; p = 0.006), and patient frailty expressed by the PRISMA 7 score (beta = -0.30; SE 0.11; p = 0.008). In multivariable analysis including clinical, demographic and cardiac functional variables, SM perfusion reserve was in addition to patient frailty, sex and LV longitudinal strain reserve among the independent correlates of exercise capacity. CONCLUSIONS: SM perfusion reserve is impaired in HFpEF, and is associated with reduced exercise capacity independent of clinical, demographic and "central" cardiac factors. This supports the need to consider the SM domain in patient management strategies in HFpEF.

Prognostic Value of the MAGGIC Score, H2FPEF Score, and HFA-PEFF Algorithm in Patients with Exertional Dyspnea and the Incremental Value of Exercise Echocardiography.

BACKGROUND: The strategies for improving outcomes in heart failure with preserved ejection fraction (HFpEF) are insufficiently defined, which affects optimal patient management. The aim of the study was to compare the prognostic value of the previously validated Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score with 2 approaches primarily dedicated to diagnosing HFpEF: the H2FPEF score (heavy, 2 or more hypertensive drugs, atrial fibrillation, pulmonary hypertension [pulmonary artery systolic pressure >35 mm Hg], elder age >60, elevated filling pressures [E/e' > 9]) and the HFA-PEFF algorithm (Heart Failure Association diagnostic algorithm-pretest assessment; echocardiography and natriuretic peptide score; functional testing; final etiology) in patients with exertional dyspnea categorized as HFpEF. METHODS: Clinical and biochemical variables and echocardiographic resting and exercise data from 201 enrollees were retrospectively analyzed. Participants were followed for 48 (24-60) months for HF hospitalization and cardiovascular death. RESULTS: Seventy-four patients (36.8%) met the study outcome. In sequential Cox analysis, the addition of MAGGIC risk score, H2FPEF score, and HFA-PEFF step 2 (including only resting echocardiographic evaluation) and step 3 (including also exercise diastolic data) algorithms to the base model comprising brain natriuretic peptide and peak oxygen uptake improved the predictive power for the study endpoint. Harrell's c statistic showed a greater predictive ability for the HFA-PEFF step 3 algorithm than for each of the other scores (c index 0.715 vs 0.637, 0.644, and 0.638 for MAGGIC, H2FPEF, and HFA-PEFF step 2, respectively; all P < .05). No significant differences were found for other between-score comparisons. CONCLUSION: In patients with exertional dyspnea and a possible HFpEF, the H2FPEF score and HFA-PEFF algorithm limited to resting echocardiography provide prognostic value comparable to the MAGGIC risk score. Extending the HFA-PEFF algorithm with exercise diastolic data is associated with a significant improvement in risk stratification.

Impact of moderately reduced renal function on the diagnostic and prognostic value of galectin-3 in patients with exertional dyspnea.

BACKGROUND: Blood concentration of galectin-3 (Gal-3) - a biomarker of fibrosis useful in diagnostics and prognostication in heart failure (HF) - is known to be elevated in patients with renal impairment, a condition which often accompanies cardiac insufficiency. OBJECTIVES: To investigate the effect of moderately reduced renal function (estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73 m2) on the diagnostic and prognostic utility of circulating Gal-3 in patients with HF with preserved ejection fraction (HFpEF). MATERIAL AND METHODS: Clinical, biochemical and echocardiographic variables were collected at baseline in 154 patients with HFpEF: 101 with normal and 53 with moderately reduced renal function, who were followed up for 48 (24-60) months for HF hospitalization and cardiovascular (CV) death (composite endpoint). RESULTS: Patients with moderately impaired renal function were characterized by higher age, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, Gal-3, B-type natriuretic peptide (BNP) and New York Heart Association (NYHA) class, lower hemoglobin, and more advanced left ventricular diastolic dysfunction. Older age, female sex and deeper impairment of renal performance were determinants of higher Gal-3 blood concentrations. Lower exercise capacity (lower peak VO2) was associated with higher Gal-3 level and more pronounced renal impairment. Multivariable regression analysis demonstrated the significance of renal dysfunction as a determinant of lower exercise capacity and revealed a significant interaction between Gal-3 and eGFR with respect to peak VO2. The addition of Gal-3 to the prognostic models based on clinical data improved their predictive power for the study endpoint. The Kaplan-Meier analysis revealed that the presence of moderately reduced renal function with eGFR 30-60 mL/min/1.73 m2 did not enhance the increased risk of adverse outcome associated with Gal-3 above the median. CONCLUSIONS: In patients with HFpEF, the coexistence of moderate renal dysfunction does not deteriorate the prognostic usefulness of circulating Gal-3. However, renal impairment modifies the association between Gal-3 and exercise capacity, which supports the need to adjust for kidney function when interpreting the contribution of Gal-3 to exercise intolerance in this population.

Incremental Value of Myocardial Work over Global Longitudinal Strain in the Surveillance for Cancer-Treatment-Related Cardiac Dysfunction: A Case-Control Study.

The load dependence of global longitudinal strain (GLS) means that changes in systolic blood pressure (BP) between visits may confound the diagnosis of cancer-treatment-related cardiac dysfunction (CTRCD). We sought to determine whether the estimation of myocardial work, which incorporates SBP, could overcome this limitation. In this case-control study, 44 asymptomatic patients at risk of CTRCD underwent echocardiography at baseline and after oncologic treatment. CTRCD was defined on the basis of the change in the ejection fraction. Those with CTRCD were divided into subsets with and without a follow-up SBP increment >20 mmHg (CTRCD+BP+ and CTRCD+BP-), and matched with patients without CTRCD (CTRCD-BP+ and CTRCD-BP-). The work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were assessed in addition to the GLS. The largest increases in the GWI and GCW at follow-up were found in CTRCD-BP+ patients. The CTRCD+BP- patients demonstrated significantly larger decreases in GWI and GCW than their CTRCD+BP+ and CTRCD-BP- peers. ROC analysis for the discrimination of LV functional changes in response to increased afterload in the absence of cardiotoxicity revealed higher AUCs for GCW (AUC = 0.97) and GWI (AUC = 0.93) than GLS (AUC = 0.73), GWW (AUC = 0.51), or GWE (AUC = 0.63, all p-values < 0.001). GCW (OR: 1.021; 95% CI: 1.001-1.042; p < 0.04) was the only feature independently associated with CTRCD-BP+. Myocardial work is superior to GLS in the serial assessments in patients receiving cardiotoxic chemotherapy. The impairment of GLS in the presence of an increase in GWI and GCW indicates the impact of elevated afterload on LV performance in the absence of actual myocardial impairment.

Association of arterial hemodynamics with left ventricular systolic function in hypertensive patients: A longitudinal study.

BACKGROUND: Left ventricular (LV) systolic impairment, particularly in the longitudinal direction, is considered an early and sensitive marker of hypertensive heart disease and increased cardiovascular risk. The evidence indicates that aortic stiffness and central hemodynamic factors are important determinants of LV performance, mediating the interaction between the heart and vascular load. Despite the existence of cross-sectional analyses linking central blood pressure (BP) parameters with LV mechanics, no longitudinal data are available which include serial measurements in the course of antihypertensive treatment. OBJECTIVES: To investigate the associations between changes in LV longitudinal and circumferential function with alterations in arterial hemodynamics and ventricular-arterial coupling (VAC) in patients with uncomplicated hypertension during a 12-month follow-up. MATERIAL AND METHODS: In this retrospective study, 216 patients (age 64.3 ±7.6 years) underwent echocardiography including left ventricular longitudinal (GLS) and circumferential strain (GCS) analysis, brachial BP measurements, VAC (combining echocardiography and brachial BP), and arterial hemodynamics using radial tonometry at baseline and after 12 months of antihypertensive therapy. Patients were grouped into 2 subsets: with improvement in GLS (n = 103) and with deterioration in GLS (n = 113). RESULTS: No significant differences were observed in the majority of cardiovascular, demographic or clinical characteristics between the groups. The subset with improvement in GLS demonstrated more favorable changes over follow-up in pulse wave velocity (p = 0.03), central augmentation pressure (p = 0.01) and ventricular-arterial coupling (p = 0.04) compared to patients showing deterioration in GLS. In the multivariable analysis, independent determinants of changes in GLS were: GLS at baseline (-0.48; p < 0.001), changes from baseline to follow-up in central augmentation pressure (-0.29; p = 0.002) and ventricular-arterial coupling (-0.25; p = 0.004). Independent determinants of analogous changes in GCS were: GCS at baseline (-0.46; p < 0.001) and changes in central augmentation pressure (-0.22; p = 0.02). CONCLUSIONS: Left ventricular longitudinal and circumferential functional remodeling over time in hypertensive patients is associated with arterial hemodynamics and ventricular-arterial coupling.

Role of skeletal muscle perfusion and insulin resistance in the effect of dietary sodium on heart function in overweight.

AIMS: Weight excess and insulin resistance predispose to heart failure. High sodium consumption may contribute to the development of cardiac impairment in insulin-resistant individuals by promoting inadequate skeletal muscle microvascular perfusion response to insulin. We sought to investigate the association of dietary sodium reduction with muscle perfusion, insulin sensitivity, and cardiac function in overweight/obese insulin-resistant (O-IR) normotensive subjects. METHODS AND RESULTS: Fifty O-IR individuals with higher than recommended sodium intake were randomized to usual or reduced sodium diet for 8 weeks; 25 lean, healthy subjects served as controls for pre-intervention measurements. Echocardiography and muscle perfusion were performed during fasting and under stable euglycaemic-hyperinsulinaemic clamp conditions. O-IR patients demonstrated subclinical cardiac dysfunction as evidenced by lower left ventricular global longitudinal strain (GLS), e' tissue velocity, and left atrial strain and reduced muscle perfusion. The intervention arm showed improvements in insulin resistance [glucose infusion rate (GIR)], GLS, e', atrial strain, and muscle perfusion in fasting conditions, as well as improved responses of GLS and muscle perfusion to insulin during clamp. Significant interactions were found between the allocation to low-salt diet and improvement in muscle perfusion on change in GIR at follow-up (P = 0.030), and between improvement in muscle perfusion and change in GIR on change in GLS response to insulin at follow-up (P = 0.026). Mediation analysis revealed that the relationship between the reduction of sodium intake and improvement in GLS was mediated by improvements in muscle perfusion and GIR (decrease in beta coefficient from -0.29 to -0.16 after the inclusion of mediator variables to the model). CONCLUSIONS: The reduction of dietary sodium in the normotensive O-IR population improves cardiac function, and this effect may be associated with the concomitant improvements in skeletal muscle perfusion and insulin resistance. These findings might contribute to refining heart failure preventive strategies.

Comparison of left ventricular longitudinal systolic function parameters in the prediction of adverse outcome in heart failure with preserved ejection fraction.

AIMS: Several different diagnostic parameters can be used to assess left ventricular (LV) longitudinal systolic function, but no studies comparing their predictive value have been conducted. We sought to compare the prognostic value of LV long-axis function parameters at rest and exercise using the population with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Clinical and biochemical variables were collected at baseline in 201 patients with HFpEF. Echocardiography was performed at rest and immediately after exercise, with measurement of mitral annular plane systolic excursion, systolic tissue velocity (s'), global longitudinal strain (GLS), and global longitudinal strain rate (GLSR). Participants were followed for 48 (24-60) months for heart failure hospitalization and cardiovascular death. Seventy-four patients (36.8%) met the study endpoint. Cox regression analysis revealed that after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score, brain natriuretic peptide (BNP), and peak VO2 , heart failure hospitalization and cardiovascular death were significantly associated with GLS at rest [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.84-0.98; P = 0.016], GLS after exercise (HR 0.84; 95% CI 0.77-0.91; P < 0.001), and GLSR after exercise (HR 0.13; 95% CI 0.04-0.48; P = 0.002). The addition of each of the following: exercise GLS and GLSR and resting GLS to the base model including Meta-Analysis Global Group in Chronic Heart Failure, BNP, and peak VO2 improved predictive power for the study endpoint [net reclassification improvement (NRI) = 49%, P < 0.001; NRI = 42%, P = 0.004; and NRI = 38%, P = 0.009, respectively]. Exercise GLS was the only longitudinal parameter significantly improving c-statistics of the base model (0.68 vs. 0.73; P = 0.047). CONCLUSIONS: Echocardiographic parameters of LV longitudinal function are not equipotential in predicting adverse outcomes in HFpEF. LV deformation indices, especially assessed with exercise, show the highest predictive utility independent from and incremental to clinical data and BNP.

Echocardiography in patients with heart failure: recent advances and future perspectives.

Echocardiography is a relatively inexpensive and widely available technique that has a pivotal role in the assessment and management of patients with heart failure (HF). Advancements in cardiac ultrasound, especially the advent of myocardial deformation imaging, have provided a comprehensive insight into the complexity of cardiac derangements underlying HF, contributing to the better understanding of the disease process. The essential issues that echocardiography can help address include: establishing / confirming diagnosis, categorizing and phenotyping patients, prognosticating, guiding therapeutic decision-making, and monitoring responses to treatment. Novel echocardiographic technologies permit early recognition of preclinical myocardial abnormalities, as well as further tracking of pathologic alterations and therapeutic responses. The predictive utility of a large number of echocardiographic indices, offering an abundance of prognostic information independent of and incremental to clinical data, underpins their use in risk stratification strategies. The evolution of existing modalities, as well as the wider implementation of automation and artificial intelligence, provides the basis for the future development and expanded clinical application of echocardiography.

Prediction of AF in Heart Failure With Preserved Ejection Fraction: Incremental Value of Left Atrial Strain.

OBJECTIVES: This study sought to identify the factors associated with incident atrial fibrillation (AF) in a well-characterized heart failure with preserved ejection fraction (HFpEF) population, with special focus on left atrial (LA) strain. BACKGROUND: AF is associated with HFpEF, with adverse consequences. Effective risk evaluation might allow the initiation of protective strategies. METHODS: Clinical evaluation and echocardiography, including measurements of peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and LA volume index (LAVI), were obtained in 170 patients with symptomatic HFpEF (mean age, 65 ± 8 years), free of baseline AF. AF was identified by standard 12-lead electrocardiogram, review of relevant medical records (including Holter documentation), and surveillance with a portable single-lead electrocardiogram device over 2 weeks. Results were validated in the 103 patients with HFpEF from the Karolinska-Rennes (KaRen) study. RESULTS: Over a median follow-up of 49 months, incident AF was identified in 39 patients (23%). Patients who developed AF were older; had higher clinical risk scores, brain natriuretic peptide, creatinine, LAVI, and LV mass; lower LA strain and exercise capacity; and more impaired LV diastolic function. PACS, PALS, and LAVI were the most predictive parameters for AF (area under receiver-operating characteristic curve: 0.76 for PACS, 0.71 for PALS, and 0.72 for LAVI). Nested Cox regression models showed that the predictive value of PACS and PALS was independent from and incremental to clinical data, LAVI, and E/e' ratio. Classification and regression trees analysis identified PACS ≤12.7%, PALS ≤29.4%, and LAVI >34.3 ml/m2 as discriminatory nodes for AF, with a 33-fold greater hazard of AF (p < 0.001) in patients categorized as high risk. The classification and regression trees algorithm discriminated high and low AF risk in the validation cohort. CONCLUSIONS: PACS and PALS provide incremental predictive information about incident AF in HFpEF. The inclusion of these LA strain components to the diagnostic algorithm may help guide screening and further monitoring for AF risk in this population.

High soluble transferrin receptor in patients with heart failure: a measure of iron deficiency and a strong predictor of mortality.

AIMS: Iron deficiency (ID) is frequent in heart failure (HF), linked with exercise intolerance and poor prognosis. Intravenous iron repletion improves clinical status in HF patients with left ventricular ejection fraction (LVEF) ≤45%. However, uncertainty exists about the accuracy of serum biomarkers in diagnosing ID. The aims of this study were (i) to identify the iron biomarker with the greatest accuracy for the diagnosis of ID in bone marrow in patients with ischaemic HF, and (ii) to establish the prevalence of ID using this biomarker and its prognostic value in HF patients. METHODS AND RESULTS: Bone marrow was stained for iron in 30 patients with ischaemic HF with LVEF ≤45% and 10 healthy controls, and ID was diagnosed for 0-1 grades (Gale scale). A total of 791 patients with HF with LVEF ≤45% were prospectively followed up for 3 years. Serum ferritin, transferrin saturation, soluble transferrin receptor (sTfR) were assessed as iron biomarkers. Most patients with HF (n = 25, 83%) had ID in bone marrow, but none of the controls (P < 0.001). Serum sTfR had the best accuracy in predicting ID in bone marrow (area under the curve 0.920, 95% confidence interval 0.761-0.987, for cut-off 1.25 mg/L sensitivity 84%, specificity 100%). Serum sTfR was ≥1.25 mg/L in 47% of HF patients, in 56% and 46% of anaemics and non-anaemics, respectively (P < 0.05). The reclassification methods revealed that serum sTfR significantly added the prognostic value to the baseline prognostic model, and to the greater extent than plasma N-terminal pro B-type natriuretic peptide. Based on internal derivation and validation procedures, serum sTfR ≥1.41 mg/L was the optimal threshold for predicting 3-year mortality, independent of other established variables. CONCLUSIONS: High serum sTfR accurately reflects depleted iron stores in bone marrow in patients with HF, and identifies those with a high 3-year mortality.

Association of Reduced Apical Untwisting With Incident HF in Asymptomatic Patients With HF Risk Factors.

OBJECTIVES: This study investigated the prognostic utility of left ventricular (LV) untwisting (UT) in the elderly patients at risk of heart failure (HF). BACKGROUND: LV UT mechanics represent a unique combination of LV filling linking ventricular relaxation and suction. The value of this parameter in the prediction of outcomes in patients at risk of HF is unclear. METHODS: A group of 465 asymptomatic subjects ≥65 years of age with ≥1 HF risk factor (hypertension, diabetes, obesity), recruited from the community, underwent clinical evaluation and echocardiography including measurement of LV apical and basal peak UT velocities. Cox regression analysis was used to identify predictors of new-onset HF and cardiovascular death after a mean follow-up of 18.2 ± 7.5 months. RESULTS: A composite of both of the study endpoints occurred in 54 patients (11.6%). Adverse outcome was significantly associated with apical (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96 to 0.99; p = 0.006) UT but not with basal (p = 0.18) UT. The prognostic value of apical UT was independent of and incremental to clinical data, as expressed by the ARIC (Atherosclerosis Risk In Communities) study risk score, left atrial volume index (LAVI), and LV global longitudinal strain (GLS). The addition of apical UT to the model including ARIC risk score, LAVI, and GLS was associated with a 41% improvement in reclassification (p = 0.006). CONCLUSIONS: Echocardiographic assessment of apical UT provides incremental value in predicting adverse outcome in asymptomatic patients with HF risk factors. The inclusion of apical UT to the diagnostic algorithm may improve the prognostication process in this population.

Usefulness of myocardial work measurement in the assessment of left ventricular systolic reserve response to spironolactone in heart failure with preserved ejection fraction.

AIMS: Improvement in left ventricular (LV) systolic reserve, including exertional increase in global longitudinal strain (GLS), may contribute to the clinical benefit from therapeutic interventions in heart failure with preserved ejection fraction (HFpEF). However, GLS is an afterload-dependent parameter, and its measurements may not adequately reflect myocardial contractility recruitment with exercise. The estimation of myocardial work (MW) allows correction of GLS for changing afterload. We sought to investigate the associations of GLS and MW parameters with the response of exercise capacity to spironolactone in HFpEF. METHODS AND RESULTS: We analysed 114 patients (67 ± 8 years) participating in the STRUCTURE study (57 randomized to spironolactone and 57 to placebo). Resting and immediately post-exercise echocardiograms were performed at baseline and at 6-month follow-up. The following indices of MW were assessed: global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency. The amelioration of exercise intolerance at follow-up in the spironolactone group was accompanied by a significant improvement in exertional increase in GCW (P = 0.002) but not in GLS and other MW parameters. Increase in exercise capacity at 6 months was independently correlated with change in exertional increase in GCW from baseline to follow-up (ß = 0.24; P = 0.009) but not with GLS (P = 0.14); however, no significant interaction with the use of spironolactone on peak VO2 was found (P = 0.97). CONCLUSION: GCW as a measure of LV contractile response to exertion is a better determinant of exercise capacity in HFpEF than GLS. Improvement in functional capacity during follow-up is associated with improvement in exertional increment of GCW.

Association of central blood pressure with left atrial structural and functional abnormalities in hypertensive patients: Implications for atrial fibrillation prevention.

AIMS: Functional and structural abnormalities of the left atrium have been demonstrated to be clinically and prognostically significant in a range of cardiovascular disorders, increasing the risk of atrial fibrillation. Among the potential contributors to these aberrations, central arterial factors remain insufficiently defined. Accordingly, we sought to investigate the determinants of left atrium abnormalities in hypertension, with special focus on central haemodynamics. METHODS: In this retrospective, cross-sectional study, 263 patients (age 63.8 ± 8.0 years) with uncomplicated hypertension underwent echocardiography including left atrium strain (LAS) and volume analysis, and central haemodynamics assessment using radial tonometry. RESULTS: Patients were grouped depending on LAS and left atrium volume index (LAVI), using externally validated cutpoints (34.1% for LAS and 34 ml/m2 for LAVI). The subset with lower LAS (n = 124) demonstrated higher central (cPP) and brachial pulse pressure (bPP), ventricular- arterial coupling, left ventricular mass index (LVMI) and LAVI, and lower global left ventricular longitudinal strain and early diastolic tissue velocity (e'). Patients with higher LAVI (n = 119) presented higher systolic blood pressure, cPP, bPP, central augmentation pressure, LVMI and E/e' ratio and lower LAS. In multivariable analysis, cPP was independently associated with both LAS (ß = -0.22; p = 0.002) and LAVI (ß = 0.21; p = 0.003). No independent associations with left atrium parameters were shown for bPP. CONCLUSION: Higher cPP is detrimentally associated with left atrium structural and functional characteristics, thus providing a possible pathophysiological link with the development of substrate for atrial fibrillation. Prophylaxis of atrial fibrillation might be another argument for consideration in the treatment strategy in hypertension targeted measures addressing central blood pressure.

Contribution of Cardiovascular Reserve to Prognostic Categories of Heart Failure With Preserved Ejection Fraction: A Classification Based on Machine Learning.

BACKGROUND: The authors used cluster analysis of data from cardiovascular domains associated with exercise intolerance to help define prognostic phenotypes of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: Resting and postexercise echocardiography was performed in 177 patients with HFpEF and 51 asymptomatic control subjects sharing a common clinical profile. Patterns of features that determine exercise capacity were sought from automated hierarchical clustering of left ventricular (LV) diastolic and systolic function, left atrial function, right ventricular function, ventricular-arterial coupling, chronotropic reserve and myocardial fibrosis. RESULTS: Automated clustering separated a distinct subgroup characterized by a relatively isolated impairment of LV systolic reserve. The clinical factors identified by this process were used to define two phenotypes of patients with symptomatic HFpEF: those with reduced chronotropic and/or diastolic reserve (abnormal CR/DR; n = 137) and those with preserved heart rate reserve and exertional E/e' ratio < 14 (normal CR/DR; n = 40). Change in global LV strain rate from rest to exercise was similar in patients with abnormal CR/DR (0.16 ± 0.18 sec-1) and those with normal CR/DR (0.21 ± 0.17 sec-1) and significantly lower than in asymptomatic subjects (0.54 ± 0.20 sec-1; P < .001 for all). However, although the former group also showed abnormal longitudinal deformation, ventricular-arterial coupling, and cardiac output responses to exercise, the latter group showed only reduced LV systolic reserve. The normal CR/DR group had a lower incidence of cardiovascular hospitalization or death (P = .003) and heart failure hospitalization (P = .002) than the abnormal CR/DR group during 2-year follow-up. CONCLUSIONS: Diminished LV systolic reserve may represent the major identifiable cardiac functional abnormality associated with exercise intolerance in some patients with HFpEF. Despite significant functional limitation, these patients are characterized by a better prognosis than subjects with HFpEF with more physiologic abnormalities.

Comparison of the Diastolic Stress Test With a Combined Resting Echocardiography and Biomarker Approach to Patients With Exertional Dyspnea: Diagnostic and Prognostic Implications.

OBJECTIVES: This study sought to establish the diagnostic and prognostic value of a strategy for prediction of abnormal diastolic response to exercise (AbnDR) using clinical, biochemical, and resting echocardiographic markers in dyspneic patients with mild diastolic dysfunction. BACKGROUND: An AbnDR (increase in left ventricular filling pressure) may indicate heart failure with preserved ejection fraction as the cause of symptoms in dyspneic patients, despite a nonelevated noncardiac at rest. However, exercise testing may be inconclusive in patients with noncardiac limitations to physical activity. METHODS: In 171 dyspneic patients (64 ± 8 years) with suspected heart failure with preserved ejection fraction but resting peak early diastolic mitral inflow velocity/peak early diastolic mitral annular velocity ratio (E/e') <14, a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) and blood assays for biomarkers were performed. Echocardiography following maximal exercise was undertaken to assess AbnDR (exertional E/e' >14). Patients were followed over 26.2 ± 4.6 months for endpoints of cardiovascular hospitalization and death. RESULTS: AbnDR was present in 103 subjects (60%). Independent correlates of AbnDR were resting E/e' (odds ratio [OR]: 8.23; 95% confidence interval [CI]: 3.54 to 9.16; p < 0.001), left ventricular untwisting rate (OR: 0.60; 95% CI: 0.42 to 0.86; p = 0.006), and galectin-3-a marker of fibrosis (OR: 1.80; 95% CI: 1.21 to 2.67; p = 0.004). The use of resting E/e' >11.3 and galectin-3 <1.17 ng/ml to select patients for further diagnostic processing would have allowed exercise testing to be avoided in 65% of subjects, at the cost of misclassification of 13%. The composite outcome of cardiovascular hospitalization or death occurred in 47 patients (27.5%). The predictive value of an AbnDR response and the combined strategy (resting echocardiography and galectin-3 or exercise testing in case of an inconclusive first step) showed similar event prediction (36 vs. 34; p = 0.95). CONCLUSIONS: The implementation of a 2-step algorithm (echocardiographic evaluation of resting E/e' followed by the assessment of galectin-3) may improve the diagnosis and prognostic assessment of individuals with suspected heart failure with preserved ejection fraction who are unable to perform a diagnostic exercise test.

Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response.

OBJECTIVES: This study sought to investigate the association of left ventricular (LV) untwisting rate (UT) and E/e' ratio with the response of exercise capacity to spironolactone in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: In most patients with HFpEF, LV filling abnormalities represent a central component in the development of dyspnea. LV diastolic filling is determined by the interplay of passive (LV stiffness and myocardial collagen content, reflected by E/e' ratio) and active myocardial properties (UT, a precursor to isovolumic pressure decay and contributor to diastolic suction). METHODS: In 194 patients with HFpEF (64 ± 8 years), a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) was performed. Echocardiography following maximal exercise was undertaken to assess LV systolic and diastolic responses to stress. A subset of 105 patients with an exercise-induced increase in estimated LV filling pressure were randomly assigned to spironolactone 25 mg (n = 51) or placebo (n = 54) for 6 months. RESULTS: Baseline peak Vo2 was associated with UT (ß = 0.19; p = 0.01) and E/e' (ß = -0.16; p = 0.03), independent of clinical data and exercise reserve in longitudinal deformation and ventricular-arterial coupling. An increase in peak Vo2 with treatment was independently associated with changes in UT (ß = 0.28; p = 0.003) and exertional increase in E/e' (ß = -0.23; p = 0.01) from baseline to follow-up. A significant interaction with the use of spironolactone on peak Vo2 was found for E/e' (p = 0.02) but not for UT (p = 0.62). CONCLUSIONS: Both active and passive determinants of LV filling, as reflected by UT and E/e', contribute to reduced exercise capacity in HFpEF. Improvement in functional capacity with a 6-month therapy with spironolactone is associated with improvements in both indices. However, the possible mediating effect of this medication is observed only on E/e'.

Determinants of the beneficial effect of mineralocorticoid receptor antagonism on exercise capacity in heart failure with reduced ejection fraction.

BACKGROUND: The determinants of the impact of mineralocorticoid receptor antagonism (MRA) on exercise tolerance in heart failure with reduced ejection fraction (HFrEF) have not been sufficiently characterised. AIM: We sought to investigate the factors associated with improvement in exercise capacity following the introduction of spironolactone to therapy in HFrEF patients, as well as to assess the association between improvement in exercise capacity and changes in cardiac functional characteristics with treatment. METHODS: In 120 patients (age 62 ± 11 years) with stable chronic HFrEF, remaining on optimal pharmacotherapy, spironolactone 25 mg/d was added to treatment. Echocardiographic assessment, including myocardial deformation, and treadmill exercise tests were performed at baseline and at six-month follow-up. RESULTS: According to the functional improvement at follow-up, patients were stratified into two groups: with increase in exercise capacity > 20% (IMPRpos, n = 68) and < 20% (IMPRneg, n = 52) of the baseline value. The IMPRpos subset demonstrated significantly larger improvement in left ventricular systolic and diastolic functions at follow-up, as assessed by global longitudinal deformation (GLS), ejection fraction, and tissue e' velocity. Functional improvement > 20% was independently predicted by diabetes (odds ratio [OR] 5.62, p = 0.011), estimated glomerular filtration rate (OR 0.95, p = 0.008), and B-type natriuretic peptide (BNP) at baseline (OR 0.54, p = 0.027), and associated with increase in GLS at follow-up (OR 1.40, p = 0.019). CONCLUSIONS: In patients with HFrEF, improvement in exercise capacity in response to the addition of spironolactone to treatment is more evident in the presence of diabetes, decreased renal function and lower BNP, and improvement in GLS is a contributor to this beneficial effect of MRA.

Association of Abnormal Left Ventricular Functional Reserve With Outcome in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study sought to determine the prognostic value of abnormal diastolic and systolic responses to exercise (on the basis of exertional E/e' and global longitudinal strain rate [GSR]) in a well-characterized population of patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Impaired cardiovascular functional reserve is believed to contribute to adverse outcomes in HFpEF. However, the exact characteristics of pathophysiological profiles associated with increased clinical risk are still poorly defined. METHODS: A complete echocardiogram (including assessment of myocardial deformation) was performed at rest in 205 patients (64 ± 8 years of age) with symptomatic HFpEF. Echocardiography following maximal exercise was undertaken to assess abnormal diastolic reserve (AbnDR) (exertional E/e' >14) and exercise GSR. Patients were followed over 26 ± 5 months for death and cardiovascular or heart failure (HF) hospitalization. RESULTS: Cardiovascular hospitalization or death occurred in 64 patients (31%), including 51 (25%) with HF hospitalization. The composite endpoint was associated with AbnDR (hazard ratio: 2.69; 95% confidence interval: 1.44 to 5.04; p = 0.002) and reduced exercise GSR (hazard ratio: 0.14; 95% confidence interval: 0.04 to 0.49; p = 0.002). Both exercise parameters showed prognostic value, independent from and incremental to clinical data and B-type natriuretic peptide. The ability of E/e' and GSR measurements to predict outcomes on exertion exceeded their prognostic value at rest, and the presence of reduced exertional GSR in patients with AbnDR was associated with worse prognosis (p = 0.03 for the composite endpoint and p = 0.01 for HF hospitalization). CONCLUSIONS: Both left ventricular systolic and diastolic reserves contribute to risk prediction in HFpEF. The inclusion of the exertional assessment of left ventricular function to diagnostic algorithms may improve the prognostication process in this disease condition.

Identification of the Optimal Protocol for Automated Office Blood Pressure Measurement Among Patients With Treated Hypertension.

BACKGROUND: Automated office blood pressure (AOBP) involving repeated, unobserved blood pressure (BP) readings during one clinic visit is recommended for in-office diagnosis and assessment of hypertension. However, the optimal AOBP protocol to determine BP control in the least amount of time with the fewest BP readings is yet to be determined and was the aim of this study. METHODS: One hundred and eighty-nine patients (mean age 62.8 ± 12.1 years; 50.3% female) with treated hypertension referred to specialist clinics at 2 sites underwent AOBP in a quiet room alone. Eight BP measurements were taken starting immediately after sitting and then at 2-minute intervals (15 minutes total). The optimal AOBP protocol was defined by the smallest mean difference and highest intraclass correlation coefficient (ICC) compared with daytime ambulatory BP (ABP). The same BP device (Mobil-o-graph, IEM) was used for both AOBP and daytime ABP. RESULTS: Average 15-minute AOBP and daytime ABP were 134 ± 22/82 ± 13 and 137 ± 17/83 ± 11 mm Hg, respectively. The optimal AOBP protocol was derived within a total duration of 6 minutes from the average of 2 measures started after 2 and 4 minutes of seated rest (systolic BP: mean difference (95% confidence interval) 0.004(-2.21, 2.21) mm Hg, P = 1.0; ICC = 0.81; diastolic BP: mean difference 0.37(-0.90, 1.63) mm Hg, P = 0.57; ICC = 0.86). AOBP measures taken after 8 minutes tended to underestimate daytime ABP (whether as a single BP or the average of more than 1 BP reading). CONCLUSIONS: Only 2 AOBP readings taken over 6 minutes (excluding an initial reading immediately after sitting) may be needed to be comparable with daytime ABP.