Increased High Mobility Group Box-1 Protein Levels are Associated With Impaired Cardiopulmonary and Echocardiographic Findings After Acute Myocardial Infarction

BackgroundSeveral markers of systemic inflammation seem to play an active role in the pathophysiology of acute coronary syndrome and its evolution. High mobility group box-1 (HMGB-1), a ubiquitous nuclear protein constitutively expressed in quiescent cells, was recently recognized as a newer critical mediator of inflammatory diseases. The present study aimed to evaluate the possible association between HMGB-1 levels and structural and functional indices of cardiovascular performance such as cardiopulmonary and Doppler-echocardiography indices in patients after acute myocardial infarction (MI).Methods and ResultsFifty-four consecutive patients (mean age 58.3 years, 83% males) recovering from acute MI were included in the study protocol. All patients underwent Doppler-echocardiography, cardiopulmonary exercise, and HMGB-1 assay. HMGB-1 levels in acute MI patients were significantly higher compared with age- and body mass index–matched controls (14.8 ± 6.8 vs. 2.3 ± 1.0 ng/mL, P < .0001, respectively). Postinfarction patients showed oxygen consumption at peak exercise (VO_2peak) = 14.4 ± 4.2 mL·kg·min and a slope of increase in ventilation over carbon dioxide output (VE/VCO_2slope) = 32.1 ± 6.2, whereas Doppler-echocardiography values were: left ventricular end-diastolic volume (LVEDV) = 53.4 ± 8.2 mL/m²; left ventricular ejection fraction (LVEF) = 41.7 ± 7.0%. Multiple linear regression analysis (stepwise method) showed that VO_2peak (β = –0.276, P = .012), VE/VCO_2slope (β = 0.244, P = .005), LVEDV (β = 0.267, P = .018), peak creatine kinase-MB (β = 0.339, P = .004), peak Troponin I (β = 0.244, P = .002), and LVEF (β = –0.312, P = .021) were significantly associated with HMGB-1 levels.ConclusionsThe present study demonstrated that in postinfarction patients, HMGB-1 levels were significantly higher compared with controls, and significantly correlated with cardiopulmonary and Doppler-echocardiography parameters.     

Cognition,Physical Function,and Quality of Life in Older Patients With Acute Decompensated Heart Failure

BackgroundOlder adults with acute decompensated heart failure have persistently poor clinical outcomes. Cognitive impairment (CI) may be a contributing factor. However, the prevalence of CI and the relationship of cognition with other patient-centered factors such a physical function and quality of life (QOL) that also may contribute to poor outcomes are incompletely understood.Methods and ResultsOlder (≥60 years) hospitalized patients with acute decompensated heart failure were assessed for cognition (Montreal Cognitive Assessment [MoCA]), physical function (Short Physical Performance Battery [SPPB], 6-minute walk distance [6MWD]), and QOL (Kansas City Cardiomyopathy Questionnaire, Short Form-12). Among patients (N = 198, 72.1 ± 7.6 years), 78% screened positive for CI (MoCA of <26) despite rare medical record documentation (2%). Participants also had severely diminished physical function (SPPB 6.0 ± 2.5 units, 6MWD 186 ± 100 m) and QOL (scores of <50). MoCA positively related to SPPB (ß = 0.47, P < .001), 6MWD ß = 0.01, P = .006) and inversely related to Kansas City Cardiomyopathy Questionnaire Overall Score (ß = –0.05, P < .002) and Short Form-12 Physical Component Score (ß = –0.09, P = .006). MoCA was a small but significant predictor of the results on the SPPB, 6MWD, and Kansas City Cardiomyopathy Questionnaire.ConclusionsAmong older hospitalized patients with acute decompensated heart failure, CI is highly prevalent, is underrecognized clinically, and is associated with severe physical dysfunction and poor QOL. Formal screening may reduce adverse events by identifying patients who may require more tailored care.     

Biomarker Profile of Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction: Insights From the RELAX Trial

BackgroundAlthough left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear.Methods and ResultsWe evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10%–22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P < .05 for all). At baseline, higher levels of endothelin-1, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and troponin I were independently associated with lower LA reservoir and contractile strain (P_adjusted < .05 for all comparisons). Higher LA reservoir strain (β coefficient per 1-unit increase: −21.2, 95% CI: −38.8, −3.7; P = .02) was independently associated with reduction in NT-proBNP at 24 weeks.ConclusionIn HFpEF, LA myopathy is characterized by elevation in biomarkers of neurohormonal activation and myocardial necrosis. Lower LA function is associated with continued elevation in NT-proBNP over time, suggesting that LA myopathy is associated with persistent congestion in HFpEF.     

Moderate Continuous and Modified High-Intensity Interval Training in Patients With Left Ventricular Assist Devices: The Prospective Train-the-LVAD Trial

BackgroundHigh-intensity interval training (HIIT) of 4 minutes at 80%–90% of peak oxygen consumption (VO_2peak) has been shown to be feasible in patients with left ventricular assist devices (LVADs). The effect of shorter bouts of HIIT, which reduce the anaerobic burden, has not been investigated compared to moderate continuous training (MCT).Methods and ResultsWe conducted a prospective, monocentric study (NCT05121077) randomizing patients with LVADs into 20 minutes of MCT (n = 10) or short bouts (≤ 90 seconds) of HIIT (n = 10) following cardiopulmonary exercise testing at 50%–60% and 80%–90% of VO_2peak. Each of the 18 supervised sessions (3×/week, t_0–t₁) included 10 minutes of strengthening training. The primary outcome was the increase of VO_2peak in the 2 groups between t₀ and t₁. Secondary outcomes were changes in the 12-item Kansas City Cardiomyopathy Questionnaire, the 6-minute walk distance and the percentage of VO_2peak at the first ventilatory threshold. VO_2peak significantly increased with HIIT (13.0 ± 4.6mL/kg/min vs 14.6 ± 4.3mL/kg/min; P = 0.037), but not with MCT (11.8 ± 3.3mL/kg/min vs 13.1 ± 3.3mL/kg/min; P = 0.322), without between-group differences (P = 0.853). Secondary outcomes improved from t_0–t₁ in MCT and HIIT, without differences between the groups.ConclusionsShort bouts of HIIT are feasible, and they improved VO_2peak and functional parameters in patients in this pilot prospective study.     

Renal Dysfunction in Heart Failure With Preserved Ejection Fraction: Insights From the RELAX Trial

BackgroundPatients with heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) represent a high-risk phenotype. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial enrolled a high proportion of CKD participants, allowing investigation into differences in HFpEF by CKD status.Methods and ResultsAmong 212 participants, we investigated the associations of CKD with biomarkers, cardiac structure, and exercise capacity, and identified predictors of change in estimated glomerular filtration rate (eGFR) over trial follow-up. CKD participants (eGFR ≤60 mL/min/1.73m²) were older, had more comorbidities, and had worse diastolic function. Lower eGFR was associated with higher levels of endothelin-1, N-terminal pro–B-type natriuretic peptide, aldosterone, uric acid, and biomarkers of fibrosis (P < .05 for all). Whereas lower eGFR was associated with worse peak oxygen consumption (VO₂) after adjustment for demographics, clinical comorbidities, exercise modality, ejection fraction, and chronotropic index (β coefficient per 1 SD decrease in eGFR: −0.61, 95% CI: −1.01, −0.22, P = .002), this association was attenuated after further adjustment for hemoglobin (β coefficient: −0.26, 95% CI: −0.68, 0.16, P = .22). Hemoglobin mediated 35% of the association between eGFR and peak VO₂. Sildenafil therapy was independently associated with worsening eGFR over the trial (β coefficient: −2.79, 95% CI: −5.34, −0.24, P = .03).ConclusionRenal dysfunction in HFpEF is characterized by echocardiographic and biomarker profiles indicative of more advanced disease, and reduced hemoglobin is a strong mediator of the association between renal dysfunction and low exercise capacity. Sildenafil therapy was associated with worsening of renal function in RELAX.     

Exercise Ventilatory Efficiency in Older and Younger Heart Failure Patients With Preserved Ejection Fraction

Background

Patients with heart failure with preserved ejection fraction (HFpEF) exhibit pulmonary abnormalities, but the studies to date have reported wide variability in the ventilatory equivalent for carbon dioxide (V?_E/V?CO₂) slope. It is possible that aging may contribute to that variability. We sought to compare ventilatory efficiency and its components in older and younger HFpEF patients during exercise.

The Effects of Race on Peak Oxygen Consumption and Survival in Patients With Systolic Dysfunction

BackgroundThe relationship of peak exercise oxygen consumption (VO₂) to survival in black heart failure (HF) patients is not well established. We examined the effects of race on peak VO₂ values and survival in HF patients with systolic dysfunction.Methods and ResultsThis study evaluated consecutive ambulatory HF patients who underwent symptom-limited stress tests with breath-by-breath expired gas analyses using ramped treadmill protocols. The relationship between cardiopulmonary exercise parameters and patient transplant-free survival was assessed by race. This study included 580 HF patients (mean age 52 ± 12 years; 28% females; 22% blacks; mean left ventricular ejection fraction 26 ± 12%; mean body mass index 28.7 ± 5.4; 73% on β-blocker). Black patients had a significantly lower peak VO₂ than white patients (14.2 ± 5.2 versus 16.4 ± 7.0; P < .0001), despite adjusting for identified covariates. However, there was no significant difference in the 1-year transplant-free survival between black and white HF patients (87% versus 85%; P = NS). Peak VO₂ was significantly associated with survival in both racial groups.ConclusionsBlack HF patients had significantly lower peak VO₂, but yet had equivalent survival rates at 1 year. Further study is warranted to clarify the impact of these racial differences on the timing of cardiac transplantation black HF patients.     

Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure

BackgroundSkeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF.Methods and ResultsFifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO₂), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO₂ after adjustment for age, gender, body mass index, and QMT: β-coefficient = −11.80, 95%CI (−20.73, −2.86), P= .011.ConclusionEnhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.     

Recumbent Ergometer vs Treadmill Cardiopulmonary Exercise Test in HFpEF: Implications for Chronotropic Response and Exercise Capacity

BackgroundCardiopulmonary exercise testing (CPET) can identify mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF), but exercise modalities with differing body positions (eg, recumbent ergometer, treadmill) are broadly used. In this study, we aimed to determine whether body position affects CPET parameters in patients with HFpEF.MethodsSubjects with stable HFpEF (n = 23) underwent noninvasive treadmill CPET, followed by an invasive recumbent-cycle ergometer CPET within 3 months. A comparison group undergoing similar studies included healthy subjects (n = 5) and subjects with pulmonary arterial hypertension (n = 6).ResultsThe peak oxygen consumption (VO₂peak) and peak heart rate were significantly lower in the recumbent vs the upright position (10.1 vs 13.1 mL/kg/min [Δ–3 mL/kg/min]; P < 0.001; and 95 vs 113 bpm [Δ–18 bpm]; P < 0.001, respectively). No significant differences were found in the minute ventilation to carbon dioxide production ratio, end-tidal pressure of carbon dioxide or respiratory exchange ratio. A similar pattern was observed in the comparison groups.ConclusionsCompared to recumbent ergometer, treadmill CPET revealed higher VO₂peak and peak heart rate response. When determining chronotropic incompetence to adjust beta-blocker administration in HFpEF, body position should be taken into account.     

Association of functional and health status measures in heart failure

BackgroundA wide variety of instruments have been used to assess the functional capabilities and health status of patients with chronic heart failure (HF), but it is not known how well these tests are correlated with one another, nor which one has the best association with measured exercise capacity.Methods and ResultsForty-one patients with HF were assessed with commonly used functional, health status, and quality of life measures, including maximal cardiopulmonary exercise testing, the Duke Activity Status Index (DASI), the Veterans Specific Activity Questionnaire (VSAQ), the Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk distance. Pretest clinical variables, including age, resting pulmonary function tests (forced expiratory volume in 1 s and forced vital capacity), and ejection fraction (EF) were also considered. The association between performance on these functional tools, clinical variables, and exercise test responses including peak VO₂ and the VO₂ at the ventilatory threshold, was determined. Peak oxygen uptake (VO₂) was significantly related to VO₂ at the ventilatory threshold (r = 0.76, P < .001) and estimated METs from treadmill speed and grade (r = 0.72, P < .001), but had only a modest association with 6-minute walk performance (r = 0.49, P < .01). The functional questionnaires had modest associations with peak VO₂ (r = 0.37, P < .05 and r = 0.26, NS for the VSAQ and DASI, respectively). Of the components of the KCCQ, peak VO₂ was significantly related only to quality of life score (r = 0.46, P < .05). Six-minute walk performance was significantly related to KCCQ physical limitation (r = 0.53, P < .01) and clinical summary (r = 0.44, P < .05) scores. Among pretest variables, only age and EF were significantly related to peak VO₂ (r = −0.58, and 0.46, respectively, P < .01). Multivariately, age and KCCQ quality of life score were the only significant predictors of peak VO₂, accounting for 72% of the variance in peak VO₂.ConclusionCommonly used functional measures, symptom tools, and quality of life assessments for patients with HF are poorly correlated with one another and are only modestly associated with exercise test responses. These findings suggest that exercise test responses, non-exercise test estimates of physical function, and quality of life indices reflect different facets of health status in HF and one should not be considered a surrogate for another.     

Prognostic Implications of Left Atrial Stiffness Index in Heart Failure Patients With Preserved Ejection Fraction

BackgroundThe left atrium (LA) plays an important role in the pathophysiology and disease progression of heart failure with preserved ejection fraction (HFpEF).ObjectivesThis study sought to assess the prognostic potential of LA stiffness index in patients who have HFpEF.MethodsThis study retrospectively screened patients with elevated left ventricular end-diastolic pressure (≥16 mm Hg) and preserved ejection fraction (≥50%) between January 1, 2004, and December 31, 2019. All patients underwent left heart catheterization to measure left ventricular end-diastolic pressure. Among these, 307 patients who had suitable image quality for left peak atrial longitudinal strain (PALS) measurement were analyzed. The study population was classified into low LA stiffness (n = 178, early diastolic transmitral inflow velocity/mitral annulus early diastolic velocity [E/e′]/PALS ≤0.26) and high LA stiffness (n = 129, E/e′/PALS >0.26) according to the best LA stiffness index (E/e′/PALS) cutoff value. The primary outcome was a composite of mortality or hospitalization caused by heart failure during follow-up.ResultsLA stiffness index showed good correlations with E/e′ (r = 0.737; P < 0.001), LA volume index (r = 0.529; P < 0.001), right ventricular systolic pressure (r = 0.404; P < 0.001), and log N-terminal pro–B-type natriuretic peptide (r = 0.540; P < 0.001). LA stiffness index demonstrated better predictive performance than echocardiographic diastolic parameters did (P < 0.001). Patients with low LA stiffness had better clinical outcomes than those with high LA stiffness during a median follow-up of 6 years did (P < 0.001). In multivariable analysis, LA stiffness index was independently associated with increased risk of the composite endpoint of death or heart failure hospitalization (HR: 1.59 [95% CI: 1.01-2.51]; P = 0.044).ConclusionsIncreased LA stiffness was associated with increased risk for all-cause mortality and hospitalization caused by heart failure in patients who have HFpEF, and its prognostic role was more pronounced than that of indexes of left ventricular filling pressure.     

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Arterial Stiffness and Abnormal Left Ventricular Hemodynamic Responses During Exercise

BackgroundArterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise.Methods and ResultsA total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (?PCWP/?CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ?PCWP/?CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52–3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption.ConclusionsExercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular–vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.     

Short-term Changes in Hemoglobin and Changes in Functional Status,Quality of Life and Natriuretic Peptides After Initiation of Dapagliflozin in Heart Failure With Reduced Ejection Fraction

BackgroundWe aimed to evaluate the effect of dapagliflozin on short-term changes in hemoglobin in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effect of dapagliflozin on functional capacity, quality of life and NT-proBNP levels.MethodsThis is an exploratory analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly allocated to dapagliflozin or placebo to evaluate short-term changes in peak oxygen consumption (peak VO₂) (NCT04197635). This substudy evaluated 1- and 3-month changes in hemoglobin levels and whether these changes mediated the effects of dapagliflozin on peak VO₂, Minnesota Living-With-Heart-Failure test (MLHFQ) and NT-proBNP levels.ResultsAt baseline, mean hemoglobin levels were 14.3 ± 1.7 g/dL. Hemoglobin levels significantly increased in those taking dapagliflozin (1 month: + 0.45 g/dL (P = 0.037) and 3 months:+ 0.55 g/dL (P = 0.012)]. Changes in hemoglobin levels positively mediated the changes in peak VO₂ at 3 months (59.5%; P < 0.001). Changes in hemoglobin levels significantly mediated the effect of dapagliflozin in the MLHFQ at 3 months (-53.2% and -48.7%; P = 0.017) and NT-proBNP levels at 1 and 3 months (-68.0%; P = 0.048 and -62.7%; P = 0.029, respectively).ConclusionsIn patients with stable HFrEF, dapagliflozin caused a short-term increase in hemoglobin levels, identifying patients with greater improvements in maximal functional capacity, quality of life and reduction of NT-proBNP levels.     

Reduction in Circulating Testosterone Relates to Exercise Capacity in Men With Chronic Heart Failure

BackgroundWe investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF.Methods and ResultsWe studied 205 men with CHF (age 60 ± 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 ± 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO₂), peak O₂ pulse, and ventilatory response to exercise (VE-VCO₂ slope). In multivariable models, reduced peak VO₂ (and reduced peak O₂ pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO₂ slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 ± 0.4 years, a reduction in peak VO₂ (and peak O₂ pulse) was accompanied by a decrease in TT (P < .01) and eFT (P ≤ .01). Increase in VE-VCO₂ slope was related only to an increase in plasma NT-proBNP (P < .05).ConclusionsIn men with CHF, low circulating testosterone independently relates to exercise intolerance. The greater the reduction of serum TT in the course of disease, the more severe the progression of exercise intolerance. Whether testosterone supplementation would improve exercise capacity in hypogonadal men with CHF requires further studies.     

Circuit resistance training in chronic heart failure improves skeletal muscle mitochondrial ATP production rate--a randomized controlled trial

BackgroundWe aimed to determine the role of skeletal muscle mitochondrial ATP production rate (MAPR) in relation to exercise tolerance after resistance training (RT) in chronic heart failure (CHF).Methods and ResultsThirteen CHF patients (New York Heart Association functional class 2.3 ± 0.5; Left ventricular ejection fraction 26 ± 8%; age 70 ± 8 years) underwent testing for peak total body oxygen consumption (VO_2peak), and resting vastus lateralis muscle biopsy. Patients were then randomly allocated to 11 weeks of RT (n = 7), or continuance of usual care (C; n = 6), after which testing was repeated. Muscle samples were analyzed for MAPR, metabolic enzyme activity, and capillary density. VO_2peak and MAPR in the presence of the pyruvate and malate (P+M) substrate combination, representing carbohydrate metabolism, increased in RT (P < .05) and decreased in C (P < .05), with a significant difference between groups (VO_2peak, P = .005; MAPR, P = .03). There was a strong correlation between the change in MAPR and the change in peak total body oxygen consumption (VO_2peak) over the study (r = 0.875; P < .0001), the change in MAPR accounting for 70% of the change in VO_2peak.ConclusionsThese findings suggest that mitochondrial ATP production is a major determinant of aerobic capacity in CHF patients and can be favorably altered by muscle strengthening exercise.     

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction

BackgroundPatients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown.Methods and ResultsWe administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QT_F) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QT_Fvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QT_F interval exposure. Maximum QT_F (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QT_F from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different.ConclusionsHFpEF is associated with enhanced response to drug-induced QT interval lengthening.     

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea

BackgroundIron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.Methods and ResultsConsecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO₂), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO₂ (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV–pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm² vs 2.58 ± 1.14 mm Hg/cm²; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO₂/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.ConclusionsIn patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.     

Determinants of exercise capacity in patients with heart failure without left ventricular hypertrophy

BackgroundDeterminants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated.MethodsCardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO₂). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s′) and early diastolic mitral annular velocities (e′), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s′) were measured at rest and exercise. E/e′ and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively.ResultsDuring exercise, CO, LV-s′, RV-s′, e′, and SPAP were significantly increased (p < 0.05 for all), whereas E/e′ remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO₂. In univariable analyses, LV-s′ (R = 0.35, p = 0.022), SPAP (R = ?0.40, p = 0.008), RV-s′ (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO₂. In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO₂ even after the adjustment for clinically relevant parameters.ConclusionsIn HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure.     

El consumo máximo de oxígeno predice los ingresos recurrentes por insuficiencia cardiaca con fracción de eyección conservada

Introduction and objectives

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with an elevated risk of morbidity and mortality. To date, there is scarce evidence on the role of peak exercise oxygen uptake (peak VO₂) for predicting the morbidity burden in HFpEF. We sought to evaluate the association between peak VO₂ and the risk of recurrent hospitalizations in patients with HFpEF.

Ventricular-Arterial Coupling Derived From Proximal Aortic Stiffness and Aerobic Capacity Across the Heart Failure Spectrum

BackgroundVentricular-arterial coupling (VAC) can be evaluated as the ratio between arterial stiffness (pulsed wave velocity [PWV]) and myocardial deformation (global longitudinal strain [GLS]).ObjectivesThis study aimed to evaluate VAC across the spectrum of heart failure (HF).MethodsThe authors introduced a Doppler-derived, single-beat technique to estimate aortic arch PWV (aa-PWV) in addition to tonometry-derived carotid-femoral PWV (cf-PWV). They measured PWVs and GLS in 155 healthy controls, 75 subjects at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 236 patients in stage C heart failure with preserved ejection fraction (HFpEF) (n = 104) or heart failure with reduced ejection fraction (HFrEF) (n = 132). They evaluated peak oxygen consumption and peripheral extraction using combined cardiopulmonary-echocardiography exercise stress.Resultsaa-PWV was obtainable in all subjects and significantly lower than cf-PWV in all subgroups (P < 0.01). PWVs were directly related and increased with age (all P < 0.0001). cf-PWV/GLS was similarly compromised in HFrEF (1.09 ± 0.35) and HFpEF (1.05 ± 0.21), whereas aa-PWV/GLS was more impaired in HFpEF (0.70 ± 0.10) than HFrEF (0.61 ± 0.14; P < 0.01). Stage A-B had values of cf-PWV/GLS and aa-PWV/GLS (0.67 ± 0.27 and 0.48 ± 0.14, respectively) higher than controls (0.46 ± 0.11 and 0.39 ± 0.10, respectively) but lower than stage C (all P < 0.01). Peak arteriovenous oxygen difference (AVO₂diff) was inversely related with cf-PWV/GLS and aa-PWV/GLS (all P < 0.01). Although cf-PWV/GLS and aa-PWV/GLS independently predicted peak VO₂ in the overall population (adjusted R² = 0.33 and R²= 0.36; all P < 0.0001), only aa-PWV/GLS was independently associated with flow reserve during exercise (R² = 0.52; P < 0.0001).ConclusionsAbnormal VAC is directly correlated with greater severity of HF and worse functional capacity. HFpEF shows a worse VAC than HFrEF when expressed by aa-PWV/GLS.