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.

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.

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.

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.

Pathophysiologic Contributions of Visceral Adiposity to Left Ventricular Diastolic Dysfunction.

BACKGROUND: Visceral fat produces inflammatory cytokines and may play a major role in heart failure with preserved ejection fraction (HFpEF). However, little data exist regarding how qualitative and quantitative abnormalities of visceral fat would contribute to left ventricular diastolic dysfunction (LVDD). METHODS: We studied 77 participants who underwent open abdominal surgery for intra-abdominal tumors (LVDD, n = 44; controls without LVDD, n = 33). Visceral fat samples were obtained during the surgery, and mRNA levels of inflammatory cytokines were measured. Visceral and subcutaneous fat areas were measured using abdominal computed tomography. RESULTS: Patients with significant LVDD had greater LV remodeling and worse LVDD than controls. While body weight, body mass index, and subcutaneous fat area were similar in patients with LVDD and controls, the visceral fat area was larger in patients with LVDD than in controls. The visceral fat area was correlated with BNP levels, LV mass index, mitral e' velocity, and E/e' ratio. There were no significant differences in the mRNA expressions of visceral adipose tissue cytokines (IL-2, -6, -8, and -1ß, TNFα, CRP, TGFß, IFNγ, leptin, and adiponectin) between the groups. CONCLUSIONS: Our data may suggest the pathophysiological contribution of visceral adiposity to LVDD.

Epidemiology, Pathophysiology, Diagnosis, and Therapy of Heart Failure With Preserved Ejection Fraction in Japan.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a global health care problem, with diagnostic difficulty, limited treatment options and high morbidity and mortality rates. The prevalence of HFpEF is increasing because of the aging population and the increasing burden of cardiac and metabolic comorbidities, such as systemic hypertension, diabetes, chronic kidney disease, and obesity. The knowledge base is derived primarily from the United States and Europe, and data from Asian countries, including Japan, remain limited. Given that phenotypic differences may exist between Japanese and Western patients with HFpEF, careful characterization may hold promise to deliver new therapy specific to the Japanese population. In this review, we summarize the current knowledge regarding the epidemiology, pathophysiology and diagnosis of and the potential therapies for HFpEF in Japan.

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.

Reactive Oxygen Species in the Aorta and Perivascular Adipose Tissue Precedes Endothelial Dysfunction in the Aorta of Mice with a High-Fat High-Sucrose Diet and Additional Factors.

Metabolic syndrome (Mets) is the major contributor to the onset of metabolic complications, such as hypertension, type 2 diabetes mellitus (DM), dyslipidemia, and non-alcoholic fatty liver disease, resulting in cardiovascular diseases. C57BL/6 mice on a high-fat and high-sucrose diet (HFHSD) are a well-established model of Mets but have minor endothelial dysfunction in isolated aortas without perivascular adipose tissue (PVAT). The purpose of this study was to evaluate the effects of additional factors such as DM, dyslipidemia, and steatohepatitis on endothelial dysfunction in aortas without PVAT. Here, we employed eight-week-old male C57BL/6 mice fed with a normal diet (ND), HFHSD, steatohepatitis choline-deficient HFHSD (HFHSD-SH), and HFHSD containing 1% cholesterol and 0.1% deoxycholic acid (HFHSD-Chol) for 16 weeks. At week 20, some HFHSD-fed mice were treated with streptozocin to develop diabetes (HFHSD-DM). In PVAT-free aortas, the endothelial-dependent relaxation (EDR) did not differ between ND and HFHSD (p = 0.25), but in aortas with PVAT, the EDR of HFHSD-fed mice was impaired compared with ND-fed mice (p = 0.005). HFHSD-DM, HFHSD-SH, and HFHSD-Chol impaired the EDR in aortas without PVAT (p < 0.001, p = 0.019, and p = 0.009 vs. ND, respectively). Furthermore, tempol rescued the EDR in those models. In the Mets model, the EDR is compromised by PVAT, but with the addition of DM, dyslipidemia, and SH, the vessels themselves may result in impaired EDR.

Prognostic benefit of early diagnosis with exercise stress testing in heart failure with preserved ejection fraction.

BACKGROUND: Delayed diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) can lead to poor clinical outcomes. Exercise stress testing, especially exercise stress echocardiography, plays a primary role in the early detection of HFpEF among dyspnoeic patients, but its prognostic significance is unknown, as is whether initiation of guideline-directed therapy could improve clinical outcomes in such early-stage HFpEF. METHODS AND RESULTS: Ergometry exercise stress echocardiography was performed in 368 patients with exertional dyspnoea. Heart failure with preserved ejection fraction was diagnosed by a total score of HFA-PEFF algorithm Step 2 (resting assessments) and Step 3 (exercise testing) ≥ 5 or elevated pulmonary capillary wedge pressure at rest or during exercise. The primary endpoint comprised all-cause mortality and worsening HF events. Heart failure with preserved ejection fraction was diagnosed in 182 patients, while 186 had non-cardiac dyspnoea (controls). Patients diagnosed with HFpEF had a seven-fold increased risk of composite events than that of controls [hazard ratio (HR) 7.52; 95% confidential interval (CI), 2.24-25.2; P = 0.001]. Patients with an HFA-PEFF Step 2 < 5 points but had an HFA-PEFF ≥ 5 after exercise stress testing (Steps 2-3) had a higher risk of composite events than controls. Guideline-recommended therapies were initiated in 90 patients diagnosed with HFpEF after index exercise testing. Patients with early treatment experienced lower rates of composite outcomes than those without (HR 0.33; 95% CI, 0.12-0.91; P = 0.03). CONCLUSION: Identification of HFpEF by exercise stress testing may allow risk stratification in dyspnoeic patients. Furthermore, initiation of guideline-directed therapy may be associated with improved clinical outcomes in patients with early-stage HFpEF. LAY SUMMARY: Delayed diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) can lead to poor clinical outcomes. Exercise stress testing, especially exercise stress echocardiography, plays a primary role in the early identification of HFpEF among dyspnoeic patients, but its prognostic significance is unknown, as is whether initiation of guideline-directed therapy could improve clinical outcomes in such early-stage HFpEF. In the current study, ergometry exercise stress echocardiography was performed in 368 patients with exertional dyspnoea. Heart failure with preserved ejection fraction was diagnosed by the established algorithm consisting of Step 2 (resting assessments) and Step 3 (exercise echocardiography or exercise right heart catheterization). The primary endpoint comprised all-cause mortality and worsening HF events. Heart failure with preserved ejection fraction was diagnosed in 182 patients and non-cardiac dyspnoea (controls) in 186 patients. Patients newly diagnosed with HFpEF had a seven-fold increased risk of composite events than that of controls. Guideline-recommended therapies were initiated in 90 patients newly diagnosed with HFpEF after index exercise testing. Patients with early treatment experienced lower rates of composite outcomes than those without. In conclusion, identification of HFpEF by exercise stress testing may allow risk stratification in patients with chronic exertional dyspnoea. Furthermore, initiation of guideline-directed therapy may be associated with improved clinical outcomes in patients with early-stage HFpEF.

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.

A Low Arginine/Ornithine Ratio is Associated with Long-Term Cardiovascular Mortality.

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p＜0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.

D-Dimer beyond Diagnosis of Pulmonary Embolism: Its Implication for Long-Term Prognosis in Cardio-Oncology Era.

Venous thromboembolism (VTE) is a common comorbidity of cancer, often referred to as cancer-associated thrombosis (CAT). Even though its prevalence has been increasing, its clinical picture has not been thoroughly investigated. In this single-center retrospective observational study, 259 patients who were treated for pulmonary embolism (PE) between January 2015 and December 2020 were available for analysis. The patients were divided by the presence or absence of concomitant malignancy, and those with malignancy (N = 120, 46%) were further classified into active (N = 40, 15%) and inactive groups according to the treatment status of malignancy. In patients with malignancy, PE was more often diagnosed incidentally by computed tomography or D-dimer testing, and the proportion of massive PE was lower. Although D-dimer levels overall decreased after the initiation of anticoagulation therapy, concomitant malignancy was independently associated with higher D-dimer at discharge despite the lower severity of PE at onset. The patients with malignancy had a poor prognosis during post-discharge follow-up. Active malignancy was independently associated with major adverse cardiovascular events (MACE) and major bleeding. D-dimer at discharge was an independent predictor of mortality even after adjustment for malignancy. This study's findings suggest that CAT-PE patients might have hypercoagulable states, which can potentially lead to a poorer prognosis.

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.

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.

Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.

Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.

Endothelial Extracellular Signal-Regulated Kinase/Thromboxane A2/Prostanoid Receptor Pathway Aggravates Endothelial Dysfunction and Insulin Resistance in a Mouse Model of Metabolic Syndrome.

Background Metabolic syndrome is characterized by insulin resistance, which impairs intracellular signaling pathways and endothelial NO bioactivity, leading to cardiovascular complications. Extracellular signal-regulated kinase (ERK) is a major component of insulin signaling cascades that can be activated by many vasoactive peptides, hormones, and cytokines that are elevated in metabolic syndrome. The aim of this study was to clarify the role of endothelial ERK2 in vivo on NO bioactivity and insulin resistance in a mouse model of metabolic syndrome. Methods and Results Control and endothelial-specific ERK2 knockout mice were fed a high-fat/high-sucrose diet (HFHSD) for 24 weeks. Systolic blood pressure, endothelial function, and glucose metabolism were investigated. Systolic blood pressure was lowered with increased NO products and decreased thromboxane A2/prostanoid (TP) products in HFHSD-fed ERK2 knockout mice, and Nω-nitro-l-arginine methyl ester (L-NAME) increased it to the levels observed in HFHSD-fed controls. Acetylcholine-induced relaxation of aortic rings was increased, and aortic superoxide level was lowered in HFHSD-fed ERK2 knockout mice. S18886, an antagonist of the TP receptor, improved endothelial function and decreased superoxide level only in the rings from HFHSD-fed controls. Glucose intolerance and the impaired insulin sensitivity were blunted in HFHSD-fed ERK2 knockout mice without changes in body weight. In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD-fed controls. Conclusions Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome.

Key Phenotypes of Heart Failure with Preserved Ejection Fraction: Pathophysiologic Mechanisms and Potential Treatment Strategies.

Pathophysiological heterogeneity is considered the primary reason for the limited effective treatment options for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have focused on HFpEF phenotyping that categorizes patients as pathophysiologically homogeneous groups to develop personalized treatment strategies. This approach relies on comorbidities, cardiac structure and function, central hemodynamics at rest and during exercise, or machine learning techniques. Although some phenotypes have been successfully identified, efforts are still ongoing. This review summarizes the current understanding of phenotyping approaches in patients with HFpEF, highlighting its pathophysiology and potential treatment strategies."