Serological Screening of Immunoglobulin G against SARS-CoV-2 Nucleocapsid and Spike Protein before and after Two Vaccine Doses among Healthcare Workers in Japan.

This study sought to evaluate the effects of two vaccine doses and the extent of SARS-CoV-2 infection among healthcare workers. We measured immunoglobulin G antibody titers against SARS-CoV-2 nucleocapsid and spike protein among healthcare workers at Gunma University Hospital. In March 2021, prior to BNT-162b2 vaccination, two of 771 participants were seropositive for nucleocapsid and spike protein, whereas 768 were seronegative. The remaining one participant was seropositive for nucleocapsid protein but seronegative for spike protein. A total of 769 participants were seropositive for spike protein after two vaccination doses. The two seropositive participants prior to vaccination showed the highest antibody titers after the second vaccination. They were probably infected with SARS-CoV-2 without clinical symptoms before March 2021. Four weeks after the second vaccination, a younger age was associated with higher antibody titers against SARS-CoV-2 spike protein. Thirty-two weeks after the second vaccination, blood samples were collected from 342 of 769 participants. Antibody titers at 32 weeks after the second vaccination significantly decreased compared with those at 4 weeks after the second vaccination among all age groups. The rate of decrease in antibody titers between 4 and 32 weeks after the second vaccination was greater in the female participants. No sex differences were observed in the antibody titers within each age group. BNT-162b2 vaccination thus induced seroconversion in an age-dependent manner. Serological screening could further establish the likelihood of subclinical SARS-CoV-2 infection.

Impact of Right Atrial Remodeling in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Few studies have investigated right atrial (RA) remodeling in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to characterize the RA remodeling in HFpEF and to determine its prognostic significance. METHODS AND RESULTS: Patients with HFpEF were classified based on the presence of RA enlargement (RA volume index >39 mL/m2 in men and >33 mL/m2 in women). Compared with patients with normal RA size (n = 234), patients with RA dilation (n = 67) showed a higher prevalence of atrial fibrillation (AF), worse right ventricular systolic function, more severe pulmonary hypertension, and a greater prevalence of mild tricuspid regurgitation, as well as impaired RA reservoir function, with increased hepatobiliary enzyme levels. AF was strongly associated with the presence of RA dilation (odds ratio [OR] 10.2, 95% confidence interval [CI] 4.00-26.1 in current AF vs no AF and odds ratio 3.38, 95% CI 1.26-9.07, earlier AF vs no AF). Patients with RA dilation had more than a two-fold increased risk of composite outcomes of all-cause mortality or HF hospitalization (adjusted hazard ratio 2.01, 95% CI 1.09-3.70, P = .02). The presence of RA dilation also displayed an additive prognostic value over left atrial dilation alone. CONCLUSIONS: These data demonstrate that HFpEF with RA remodeling is associated with distinct echocardiographic features characterizing advanced right heart dysfunction with an increased risk of adverse outcomes.

Pulmonary Vascular Alterations on Computed Tomography Imaging and Outcomes in Heart Failure With Preserved Ejection Fraction: a Preliminary Data.

BACKGROUND: Pulmonary vascular disease may play an important role in the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, no study has demonstrated noninvasive quantification of pulmonary vascular alterations in HFpEF. This study sought to determine the association between pulmonary vascular alterations quantified by chest computed tomography scan and clinical outcomes in HFpEF. METHODS AND RESULTS: Pulmonary vascular alterations were quantified in 151 patients with HFpEF who underwent noncontrast chest computed tomography scan by measuring the percentage of total cross-sectional area (CSA) of pulmonary vessels less than 5 mm2 to the total lung area (%CSA<5). We divided the patients by the median value of %CSA<5 (=1.45%) and examined the association between %CSA<5 and a composite outcome of all-cause mortality or HF hospitalization. During a median follow-up of 17.3 months, there were 44 (29%) composite outcomes. Event rates were significantly higher in patients with higher %CSA<5 than those with lower %CSA<5 (log-rank P = .02). %CSA<5 was associated with an increased risk of the outcome (hazard ratio per 1.0% increment, 1.46; 95% confidence interval 1.06-1.98; P = .02) in an unadjusted Cox model, and was independently and incrementally associated with the outcome over age, the presence of atrial fibrillation, E/e' ratio, and estimated pulmonary artery systolic pressure (global χ2 17.3 vs 11.5, P = .02). CONCLUSIONS: A higher %CSA<5 was associated with an increased risk of all-cause mortality or HF hospitalization in patients with HFpEF, with an incremental prognostic value over age, atrial fibrillation, E/e' ratio, and pulmonary artery systolic pressure.

Association between lung ultrasound B-lines and exercise-induced pulmonary hypertension in patients with connective tissue disease.

BACKGROUND: Identification of elevation in pulmonary pressures during exercise may provide prognostic and therapeutic implications in patients with connective tissue disease (CTD). Interstitial lung disease (ILD) is common in CTD patients and subtle interstitial abnormalities detected by lung ultrasound could predict exercise-induced pulmonary hypertension (PH). METHODS AND RESULTS: Echocardiography and lung ultrasound were performed at rest and bicycle exercise in CTD patients (n = 41) and control subjects without CTD (n = 24). Ultrasound B-lines were quantified by scanning four intercostal spaces in the right hemithorax. We examined the association between total B-lines at rest and the development of exercise-induced PH during ergometry exercise. Compared to controls, the number of total B-lines at rest was higher in CTD patients (0 [0, 0] vs 2 [0, 9], P < .0001) and was correlated with radiological severity of ILD assessed by computed tomography (fibrosis score, r = .70, P < .0001). Pulmonary artery systolic pressure (PASP) was increased with ergometry exercise in CTD compared to controls (48 ± 14 vs 35 ± 13 mm Hg, P = .0006). The number of total B-lines at rest was highly correlated with higher PASP (r = .52, P < .0001) and poor right ventricular pulmonary artery coupling (tricuspid annular plane systolic excursion/PASP ratio, r = -.31, P = .01) during peak exercise. The number of resting B-lines predicted the development of exercise-induced PH with an area under the curve .79 (P = .0003). CONCLUSIONS: These data may suggest the value of a simple resting assessment of lung ultrasound as a potential tool for assessing the risk of exercise-induced PH in CTD patients.

Pathophysiologic and prognostic importance of cardiac power output reserve in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by multiple cardiac reserve limitations during exercise. Cardiac power output (CPO) is an index of global cardiac performance and can be estimated non-invasively by echocardiography. We hypothesized that CPO reserve during exercise would be associated with impaired cardiovascular reserve, exercise intolerance, and adverse outcomes in HFpEF. METHODS AND RESULTS: Exercise stress echocardiography was performed in 425 dyspnoeic patients [217 HFpEF and 208 non-heart failure (HF) controls] to estimate CPO at rest and during exercise. We classified patients with HFpEF based on the median value of changes in CPO from rest to peak exercise (ΔCPO >0.49 W/100 g). Patients with HFpEF and a lower CPO reserve had poorer biventricular systolic function, impaired chronotropic response during exercise, and worse aerobic capacity than controls and those with a higher CPO reserve. During a median follow-up of 358 days, a composite outcome of all-cause mortality or HF events occurred in 30 patients. Patients with a lower CPO reserve had four-fold and nearly 10-fold increased risks of the outcomes compared with those with a higher CPO reserve and controls, respectively [hazard ratio (HR) 4.05, 95% confidence interval (CI) 1.16-10.1, P = 0.003 and HR 9.61, 95% CI 3.58-25.8, P < 0.0001]. We further found that a lower CPO reserve had an incremental prognostic value over the H2FPEF score and exercise duration. In contrast, resting CPO did not predict clinical outcomes in patients with HFpEF. CONCLUSION: A lower CPO reserve was associated with biventricular systolic dysfunction, chronotropic incompetence, exercise intolerance, and adverse outcomes in patients with HFpEF.

Characterization and prognostic importance of chronotropic incompetence in heart failure with preserved ejection fraction.

BACKGROUND: Exercise intolerance is the primary symptom of patients with heart failure with preserved ejection fraction (HFpEF). Chronotropic incompetence has been considered to be common and contribute to poor exercise capacity in HFpEF. However, clinical characteristics, pathophysiology, and outcomes of chronotropic incompetence in HFpEF remain poorly understood. METHODS: Patients with HFpEF (n = 246) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. The patients were divided into two groups based on the presence of chronotropic incompetence, which was defined by heart rate reserve <0.80. RESULTS: Chronotropic incompetence was common in HFpEF (n = 112, 41 %). Compared to HFpEF patients with a normal chronotropic response (n = 134), those with chronotropic incompetence had higher body mass index, a higher prevalence of diabetes, more frequent ß-blocker use, and worse New York Heart Association class. During peak exercise, patients with chronotropic incompetence demonstrated less increase in cardiac output and arterial oxygen delivery (cardiac output × saturation × hemoglobin × 1.34 × 10), higher metabolic work (peak oxygen consumption [VO2]/watt), an inability to increase arteriovenous oxygen difference, and poorer exercise capacity (lower peak VO2) than those without. Chronotropic incompetence was associated with higher rates of a composite of all-cause mortality or worsening HF events (hazard ratio, 2.66, 95 % confidence intervals, 1.16-6.09, p = 0.02). CONCLUSION: Chronotropic incompetence is common in HFpEF, and is associated with unique pathophysiologic characteristics during exercise and clinical outcomes.

Prognostic utility of cardiopulmonary exercise testing with simultaneous exercise echocardiography in heart failure with preserved ejection fraction.

AIMS: Cardiopulmonary exercise testing (CPET) combined with exercise echocardiography (CPETecho) allows simultaneous assessments of cardiac, pulmonary, and ventilation in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to determine whether simultaneous assessment of CPET variables could provide additive predictive value over exercise stress echocardiography in patients with dyspnoea. METHODS AND RESULTS: CPETecho was performed in 443 patients with suspected HFpEF (240 HFpEF and 203 controls without HF). Patients with HFpEF were divided based on peak oxygen consumption (VO2, ≥10 or <10 ml/min/kg) or the slope of minute ventilation to carbon dioxide production (VE vs. VCO2 slope ≥45.0 or <45.0). The primary endpoint was defined as a composite of all-cause mortality, HF hospitalization, unplanned hospital visits requiring intravenous diuretics, or intensification of oral diuretics. During a median follow-up of 399 days, the composite outcome occurred in 57 patients. E/e' ratio during peak exercise was associated with adverse outcomes. Patients with HFpEF and lower peak VO2 had increased risks of the composite event (hazard ratio [HR] 5.05, 95% confidence interval [CI] 2.65-9.62, p < 0.0001 vs. controls; HR 3.14, 95% CI 1.69-5.84, p = 0.0003 vs. HFpEF with higher peak VO2). Elevated VE versus VCO2 slope was also associated with adverse events in HFpEF. The addition of either the presence of abnormal peak VO2 or VE versus VCO2 slope increased the predictive ability over the model based on age, sex, atrial fibrillation, left atrial volume index, and exercise E/e' (p < 0.05). CONCLUSION: These data provide new insights into the role of CPETecho in patients with HFpEF.

Exercise Stress Echocardiography-Based Phenotyping of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring improved phenotypic classification. Previous studies have identified subphenotypes of HFpEF, but the lack of exercise assessment is a major limitation. The aim of this study was to identify distinct pathophysiologic clusters of HFpEF based on clinical characteristics, and resting and exercise assessments. METHODS: A total of 265 patients with HFpEF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Cluster analysis was performed by the K-prototype method with 21 variables (10 clinical and resting echocardiographic variables and 11 exercise echocardiographic parameters). Pathophysiologic features, exercise tolerance, and prognosis were compared among phenogroups. RESULTS: Three distinct phenogroups were identified. Phenogroup 1 (n = 112 [42%]) was characterized by preserved biventricular systolic reserve and cardiac output augmentation. Phenogroup 2 (n = 58 [22%]) was characterized by a high prevalence of atrial fibrillation, increased pulmonary arterial and right atrial pressures, depressed right ventricular systolic functional reserve, and impaired right ventricular-pulmonary artery coupling during exercise. Phenogroup 3 (n = 95 [36%]) was characterized by the smallest body mass index, ventricular and vascular stiffening, impaired left ventricular diastolic reserve, and worse exercise capacity. Phenogroups 2 and 3 had higher rates of composite outcomes of all-cause mortality or heart failure events than phenogroup 1 (log-rank P = .02). CONCLUSION: Exercise echocardiography-based cluster analysis identified three distinct phenogroups of HFpEF, with unique exercise pathophysiologic features, exercise capacity, and clinical outcomes.

Adiposity and clinical outcomes in East Asian patients with heart failure and preserved ejection fraction.

Background: Despite the obesity paradox, visceral adiposity is associated with poor clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unclear whether a relationship between visceral fat and clinical outcomes exists in Asian patients with HFpEF, in whom obesity is rare. Methods: Visceral and subcutaneous adipose tissue (VAT and SAT) volume and area were measured using computed tomography (CT) in 196 HFpEF patients. The primary endpoint was a composite of all-cause mortality or HF hospitalization. Results: Participants had a normal body mass index (BMI) (22.5 ± 4.4 kg/m2), and obesity (BMI > 30 kg/m2) was rare (4.6 %). The primary outcome was observed in 64 patients during a median follow-up of 11.6 months. Lower VAT and SAT volumes were associated with underweight and malnutrition. Composite outcomes increased as body weight, BMI, and height-indexed SAT volume and area decreased. Lower height-indexed VAT volume and area were also associated with the outcomes. The height-indexed SAT area provided independent and incremental prognostic value over age, BMI, blood pressure, and creatinine and albumin levels. Conclusions: In lean East Asian patients with HFpEF, a lower VAT volume was associated with poorer clinical outcomes. CT-based assessments of adiposity may provide incremental prognostic value over simple anthropometric indices in lean HFpEF patients.

Effects of Mineralocorticoid Receptor Antagonists in Early-Stage Heart Failure With Preserved Ejection Fraction.

Background: Hospitalization with a first episode of heart failure (HF) is a serious event associated with poor clinical outcomes in HF with preserved ejection fraction (HFpEF). Identification of HFpEF via detection of elevated left ventricular filling pressure at rest or during exercise may allow early intervention. Benefits of treatment with mineralocorticoid receptor antagonists (MRAs) in established HFpEF have been reported, but use of MRAs is not well studied in early HFpEF without prior HF hospitalization. Methods: We retrospectively studied 197 patients with HFpEF who did not have prior hospitalization but had been diagnosed by exercise stress echocardiography or catheterization. We examined changes in natriuretic peptide levels and echocardiographic parameters reflecting diastolic function following MRA initiation. Results: Of the 197 patients with HFpEF, MRA treatment was initiated for 47 patients. After a median 3-month follow-up, reduction in N-terminal pro-B-type natriuretic peptide levels from baseline to follow-up was greater in patients treated with MRA than in those who were not (median, -200 pg/mL [interquartile range, -544 to -31] vs 67 pg/mL [interquartile range, -95 to 456], P < 0.0001 in 50 patients with paired data). Similar results were observed for the changes in B-type natriuretic peptide levels. Reduction in the left atrial volume index was also greater in the MRA-treated group than in the non-MRA-treated group after a median 7-month follow-up (77 patients with paired echocardiographic data). Patients with lower left ventricular global longitudinal strain experienced a greater reduction in N-terminal pro-B-type natriuretic peptide levels following MRA treatment. In the safety assessment, MRA modestly decreased renal function but did not change potassium levels. Conclusions: Our results suggest that MRA treatment has potential benefits for early-stage HFpEF.

Contexte: L'hospitalisation consécutive à un premier épisode d'insuffisance cardiaque (IC) est un événement grave associé à des résultats cliniques médiocres dans l'IC à fraction d'éjection préservée (ICFEP). Or, la détection d'une pression de remplissage ventriculaire gauche élevée au repos ou à l'effort peut permettre de déceler une ICFEP et d'intervenir de façon précoce. Par ailleurs, le recours à des antagonistes des récepteurs minéralocorticoïdes (ARM) serait bénéfique dans les cas d'ICFEP, mais leur utilisation n'a pas été bien étudiée dans l'ICFEP précoce sans hospitalisation préalable pour cause d'insuffisance cardiaque. Méthodologie: Nous avons étudié rétrospectivement 197 patients atteints d'ICFEP qui n'avaient pas été hospitalisés auparavant, mais dont la maladie avait été diagnostiquée par une échocardiographie de stress ou un cathétérisme. Après l'instauration des ARM, nous avons examiné les variations des taux de peptides natriurétiques et des paramètres échocardiographiques reflétant la fonction diastolique. Résultats: Sur les 197 patients atteints d'ICFEP, 47 ont entamé un traitement par des ARM. Après un suivi médian de trois mois, la réduction des taux de propeptides natriurétiques de type B N-terminal (NT-proBNP) entre la valeur initiale et le suivi était plus importante chez les patients traités par des ARM que chez ceux qui ne l'étaient pas (médiane : -200 pg/ml [écart interquartile : -544 à -31] contre 67 pg/ml [écart interquartile : -95 à 456], p < 0,0001 chez 50 patients ayant des données appariées). Des résultats similaires ont été observés pour la variation des taux de peptides natriurétiques de type B. La réduction du volume de l'oreillette gauche était également plus importante dans le groupe traité par des ARM que dans le groupe témoin après un suivi médian de sept mois (données échocardiographiques appariées pour 77 patients). Les patients présentant une déformation longitudinale globale du ventricule gauche plus faible ont connu une réduction plus importante des taux de NT-proBNP après le traitement par des ARM. Enfin, lors de l'évaluation de l'innocuité, les ARM ont légèrement altéré la fonction rénale, mais sans modifier les taux de potassium. Conclusions: Ces résultats semblent indiquer que le traitement par des ARM présente des avantages potentiels dans les cas d'ICFEP au stade précoce.

Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction.

AIMS: Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnoea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF. METHODS AND RESULTS: Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non-heart failure controls (non-cardiac dyspnoea [NCD]) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA-PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle-tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (area under the curve 0.87, p < 0.0001), with a superior diagnostic ability to exercise E/e' ratio (DeLong p = 0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ2 212.4 vs. 166.2, p < 0.0001). These findings were confirmed in Protocol 2. CONCLUSION: Left atrial compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnoea.

Diagnostic value of expired gas analysis in heart failure with preserved ejection fraction.

Cardiopulmonary exercise testing (CPET) may potentially differentiate heart failure (HF) with preserved ejection fraction (HFpEF) from noncardiac causes of dyspnea (NCD). While contemporary guidelines for HF recommend using CPET for identifying causes of unexplained dyspnea, data supporting this practice are limited. This study aimed to determine the diagnostic value of expired gas analysis to distinguish HFpEF from NCD. Exercise stress echocardiography with simultaneous expired gas analysis was performed in patients with HFpEF (n = 116) and those with NCD (n = 112). Participants without dyspnea symptoms were also enrolled as controls (n = 26). Exercise capacity was impaired in patients with HFpEF than in controls and those with NCD, evidenced by lower oxygen consumption (VO2), but there was a substantial overlap between HFpEF and NCD. Receiver operating characteristic curve analyses showed modest diagnostic abilities of expired gas analysis data in differentiating individuals with HFpEF from the controls; however, none of these variables clearly differentiated between HFpEF and NCD (all areas under the curve < 0.61). Expired gas analysis provided objective assessments of exercise capacity; however, its diagnostic value in identifying HFpEF among patients with symptoms of exertional dyspnea was modest.

Disproportionate exercise-induced pulmonary hypertension in relation to cardiac output in heart failure with preserved ejection fraction: a non-invasive echocardiographic study.

AIMS: Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non-invasively by the mean pulmonary artery pressure-cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise-induced PH in relation to CO (DEi-PH) and its prognostic impact in patients with HFpEF. METHODS AND RESULTS: A total of 345 patients (166 HFpEF and 179 controls) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. DEi-PH was defined as the mPAP/CO slope >5.2 mmHg/L/min (median value). At rest, there were no differences in right ventricular (RV) function and severity of PH between HFpEF patients with and without DEi-PH. Compared with controls (n = 179) and HFpEF without DEi-PH (n = 83), HFpEF with DEi-PH (n = 83) demonstrated worse exercise capacity (lower peak oxygen consumption), depressed RV systolic function, impaired RV-pulmonary artery coupling, limitation in CO augmentation, more right-sided congestion, and worse ventilatory efficiency (higher minute ventilation vs. carbon dioxide volume) during peak exercise. Kaplan-Meier analyses showed that HFpEF patients with DEi-PH had higher rates of composite outcomes of all-cause mortality or heart failure events than those without (log-rank p = 0.0002). CONCLUSION: Patients with HFpEF and DEi-PH demonstrated distinct pathophysiologic features that become apparent only during exercise. These data suggest that DEi-PH is a pathophysiologic phenotype of HFpEF and reinforce the importance of exercise stress echocardiography for detailed characterization of HFpEF.

Incremental diagnostic value of post-exercise lung congestion in heart failure with preserved ejection fraction.

AIMS: Lung ultrasound (LUS) may unmask occult heart failure with preserved ejection fraction (HFpEF) by demonstrating an increase in extravascular lung water (EVLW) during exercise. Here, we sought to examine the dynamic changes in ultrasound B-lines during exercise to identify the optimal timeframe for HFpEF diagnosis. METHODS AND RESULTS: Patients with HFpEF (n = 134) and those without HF (controls, n = 121) underwent a combination of exercise stress echocardiography and LUS with simultaneous expired gas analysis to identify exercise EVLW. Exercise EVLW was defined by B-lines that were newly developed or increased during exercise. The E/e' ratio peaked during maximal exercise and immediately decreased during the recovery period in patients with HFpEF. Exercise EVLW was most prominent during the recovery period in patients with HFpEF, while its prevalence did not increase from peak exercise to the recovery period in controls. Exercise EVLW was associated with a higher E/e' ratio and pulmonary artery pressure, lower right ventricular systolic function, and elevated minute ventilation to carbon dioxide production (VE vs. VCO2) slope during peak exercise. Increases in B-lines from rest to the recovery period provided an incremental diagnostic value to identify HFpEF over the H2FPEF score and resting left atrial reservoir strain. CONCLUSION: Exercise EVLW was most prominent early during the recovery period; this may be the optimal timeframe for imaging ultrasound B-lines. Exercise stress echocardiography with assessments of recovery EVLW may enhance the diagnosis of HFpEF.

Contributions of anemia to exercise intolerance in heart failure with preserved ejection fraction-An exercise stress echocardiographic study.

Aims: Anemia is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with exercise intolerance. However, there are limited data on how anemia contributes to reduced exercise capacity in patients with HFpEF. We aimed to characterize exercise capacity, cardiovascular and ventilatory reserve, and the oxygen (O2) pathway in anemic patients with HFpEF. Methods: A total of 238 patients with HFpEF and 248 dyspneic patients without HF underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. Patients with HFpEF were classified into two groups based on the presence of anemia (hemoglobin < 13.0 g/dL in men and < 12.0 g/dL in women). Results: Anemic HFpEF patients (n = 112) had worse nutritional status and renal function, lower iron levels, and greater left ventricular (LV) remodeling and plasma volume expansion than those without anemia (n = 126). Exercise capacity, assessed by peak oxygen consumption, exercise intensity, and exercise duration, was lower in the anemic HFpEF group than in the other groups. Despite a similar cardiac output during exercise, anemic patients with HFpEF demonstrated limitations in arterial O2 delivery, lower arteriovenous O2 content difference, and ventilatory inefficiency (higher minute ventilation vs. carbon dioxide production slope) during peak exercise. Conclusion: Anemic HFpEF patients demonstrated unique pathophysiological features with greater LV remodeling and plasma volume expansion, limitations in arterial O2 delivery and peripheral O2 extraction, and ventilatory inefficiency, which may contribute to reduced exercise capacity. Further studies are needed to develop an optimal approach for treating anemia in patients with HFpEF.

Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder mostly caused by desmosome gene mutations. Recent comprehensive desmosome mutation analyses of Caucasian ARVC patients have revealed the presence of not only a single heterozygous mutation, but also compound and digenic heterozygosity. However, the genetic basis of Japanese ARVC remains poorly elucidated. METHODS AND RESULTS: The subjects were 7 definite and 1 possible ARVC probands (6 males, 16-76 years of age), and their family members. Genetic screening for major ARVC-causing genes (junction plakoglobin, desmoplakin, plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2) was performed. We identified 3 cases of compound heterozygosities (Case 1: DSG2 S194L and DSG2 R292C; Case 2: PKP2 2489+1G>A and PKP2 D812N; Case 3: PKP2 M565R and PKP2 D812N) and 1 of digenic heterozygosity (Case 4: PKP2 1728_1729insGATG and DSG2 R292C) among the definite ARVC patients. All family members we investigated have remained asymptomatic. They carried, if any, only a single variant, indicating that the probands carry in trans compound heterozygosity. These results suggest that each of these variants alone may not be sufficient and second variants may be required to manifest overt ARVC in Japanese patients. CONCLUSIONS: Our comprehensive genetic analysis of desmosome genes identified 3 cases of compound heterozygosities in trans and 1 of digenic heterozygosity among 7 definite Japanese ARVC patients, providing novel insights into the genetic basis of Japanese ARVC.

Echocardiography in the diagnostic evaluation and phenotyping of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest unmet needs in modern cardiology given its diagnostic difficulty and limited therapeutic options. Echocardiography provides valuable information on cardiac structure, function, and hemodynamics and plays a central role in the evaluation of HFpEF. Echocardiography is crucial in identifying HFpEF among patients with dyspnea, especially when overt congestion is absent. The combination of echocardiographic indices of diastolic function, clinical characteristics, and natriuretic peptide tests has been proposed in the diagnostic evaluation of patients with suspected HFpEF. Echocardiography also provides valuable insight into the pathophysiology and underlying phenotypes of HFpEF. Exercise stress echocardiography can also detect abnormalities that develop only during exercise. This may enhance the diagnosis of HFpEF by demonstrating elevation in the left ventricular filling pressure and may have potential for better pathophysiological characterization. This review focuses on the role of echocardiography in the diagnostic evaluation and phenotyping of HFpEF. We also discuss the potential role of exercise stress echocardiography for the diagnosis and disease phenotyping of HFpEF.

The roles of global longitudinal strain imaging in contemporary clinical cardiology.

Myocardial deformation imaging is now readily available during routine echocardiography and plays an important role in the advanced care of cardiovascular diseases. Its clinical value in detecting subtle myocardial dysfunction, by helping diagnose disease and allowing prediction of disease progression and earlier pharmacological intervention, has been demonstrated. Strain imaging has been the most studied and clinically used technique in the field of cardio-oncology. A relative percent reduction in left ventricular (LV) global longitudinal strain > 15% from baseline is considered a marker of early subclinical LV dysfunction and may have the potential to guide early initiation of cardioprotective therapy. The role of strain imaging is expanding to other fields, such as cardiac amyloidosis, other cardiomyopathies, valvular heart diseases, pulmonary hypertension, and heart failure with preserved ejection fraction. It is also used for the evaluation of the right ventricle and atria. This review aims to provide a current understanding of the roles of strain imaging in the evaluation and management of patients with cardiovascular diseases in clinical practice.

Exercise Stress Echocardiography in the Diagnostic Evaluation of Heart Failure with Preserved Ejection Fraction.

More than half of patients with heart failure have a preserved ejection fraction (HFpEF). The prevalence of HFpEF has been increasing worldwide and is expected to increase further, making it an important health-care problem. The diagnosis of HFpEF is straightforward in the presence of obvious objective signs of congestion; however, it is challenging in patients presenting with a low degree of congestion because abnormal elevation in intracardiac pressures may occur only during physiological stress conditions, such as during exercise. On the basis of this hemodynamic background, current consensus guidelines have emphasized the importance of exercise stress testing to reveal abnormalities during exercise, and exercise stress echocardiography (i.e., diastolic stress echocardiography) may be used as an initial diagnostic approach to HFpEF owing to its noninvasive nature and wide availability. However, evidence supporting the use of this method remains limited and many knowledge gaps exist with respect to diastolic stress echocardiography. This review summarizes the current understanding of the use of diastolic stress echocardiography in the diagnostic evaluation of HFpEF and discusses its strengths and limitations to encourage future studies on this subject.

Diastolic Filling Time, Chronotropic Response, and Exercise Capacity in Heart Failure and Preserved Ejection Fraction With Sinus Rhythm.

Background Exercise-induced high heart rate may impair exercise tolerance by reducing diastolic filling time and ventricular filling in heart failure with preserved ejection fraction (HFpEF). Given the importance of chronotropic response, we hypothesized that reduction in diastolic filling time because of exercise-induced increased heart rate would not impair cardiac output reserve and exercise capacity. We sought to determine the association between heart rate, diastolic filling time, hemodynamics, and exercise capacity in HFpEF. Methods and Results Patients with HFpEF (n=66) and controls without HF (n=107) underwent bicycle exercise echocardiography with simultaneous expired gas analysis to measure oxygen consumption. Diastolic filling time was assessed by the overlap time between mitral E- and A-waves (longer overlap time indicates shorter diastolic filling duration). Overlap time increased (ie, diastolic filling time shortened) in HFpEF and controls as heart rate increased with exercise, and the relationship was similar between the groups. Greater heart rate response correlated with higher cardiac output (r=0.51, P<0.0001) and oxygen consumption (r=0.50, P<0.0001) during peak exercise. Shorter diastolic filling time, as assessed by longer overlap time, was correlated with higher cardiac output (r=0.47, P<0.0001) and peak oxygen consumption (r=0.38, P=0.007), not with E/e' or right ventricular-pulmonary artery uncoupling. Longer overlap time was associated with mitral A velocity (r=0.53, P<0.0001) and left atrial booster pump strain (r=0.42, P<0.0001). Conclusions Shortening of diastolic filling interval in tandem with increased heart rate during exercise does not limit cardiac output reserve or exercise capacity in HFpEF.