Factors Associated With Sacubitril/Valsartan Continuation and the Methods of Combining Heart Failure Medications in Patients With Heart Failure.

BACKGROUND: Sacubitril/valsartan (SV) is recommended for patients with heart failure (HF). In addition, a combination of 4 HF medications, including SV, is recommended in patients with HF with reduced ejection fraction (HFrEF). However, evidence on the characteristics of patients who could continue SV and its initiation methods is limited. OBJECTIVE: To investigate the factors associated with SV continuation and methods of combining HF medications. METHODS: This retrospective cohort study included HF patients who initiated with SV at our institution. The endpoint was SV continuation for 6 months after its initiation. Multivariate analysis was used to extract factors associated with SV continuation. The relationship between the methods of combining HF medications (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, or sodium-glucose cotransporter 2 inhibitors), including the number of HF medications, their combination patterns, and the timing of their initiation, and SV continuation was examined in patients with HFrEF. RESULTS: Of 186 eligible patients, 68.8% had HFrEF, and 79.0% continued SV for 6 months. Significant factors associated with SV continuation were albumin ≥ 3.5 g/dL (odds ratio, 4.81; 95% confidence interval, 2.19-10.59), body mass index (BMI) ≥ 18.5 kg/m2 (4.17; 1.10-15.85), and systolic blood pressure (SBP) ≥ 110 mmHg (2.66; 1.12-6.28). In patients with HFrEF, the proportion of HF medications not initiated simultaneously with SV was significantly higher in the continuation group than in the discontinuation group (67.3% vs 33.3%, P = 0.002). The number of HF medications and their combination patterns were not significantly associated with SV continuation. CONCLUSION AND RELEVANCE: Albumin, BMI, and SBP are useful indicators for selecting patients who are likely to continue SV. In addition, initiating only SV without simultaneously initiating other HF medications in patients with HFrEF may lead to SV continuation.

The Prognostic Value of Left Atrial Reservoir Functional Indices Measured by Three-Dimensional Speckle-Tracking Echocardiography for Major Cardiovascular Events.

BACKGROUND: Left atrial (LA) volume and left ventricular longitudinal strain (LVLS) have significant prognostic values for major cardiovascular events (MACEs). Prognostic values of LA reservoir functional indices measured by 3-dimensional (3D) speckle-tracking echocardiography (STE) were evaluated.Methods and Results:A total of 264 patients, who underwent 2-dimensional (2D) echocardiography and 3DSTE for various underlying heart diseases, were followed up to record MACE. After a mean follow up of 547±435 days, 30 patients developed MACE: 7 cardiac deaths, 6 strokes, 1 non-fatal myocardial infarction, and 22 admissions for heart failure (5 of these had cardiac death after discharge, whereas 1 sustained stroke after discharge). Receiver operating characteristic curve analysis was performed to determine the optimal cut-off levels of 4 LA functional indices: LA emptying fraction (LAEmpF), LA longitudinal strain (LALS), LA circumferential strain (LACS), and LA area change ratio (LAAC), using 3DSTE. Among these factors, 2DLVLS, 3DLAEmpF, and 3DLALS demonstrated a higher hazard ratio (>5.0) than other variables. The 3DLAEmpF and 3DLALS had a higher average treatment effect (ATE) and ATE on the treated (ATT), respectively, than the other indices after propensity score matching. Addition of 3DLAEmpF to the base model using clinical variables and LV ejection fraction or 2DLVLS demonstrated higher prognostic power. CONCLUSIONS: LAEmpF calculated using 3DSTE possessed additive prognostic values for the prediction of MACE.

Impact of Exercise-Based Cardiac Rehabilitation on the Mid-Term Outcomes of Patients After Acute Myocardial Infarction Treated With Current Acute-Phase Management and Optimal Medical Therapy.

BACKGROUND: Early reported beneficial effects of cardiac rehabilitation (CR) have recently been disputed. The present study aimed to investigate the clinical impact of CR on the mid-term outcomes of patients following ST-segment elevation myocardial infarction (STEMI) treated with currently available management. METHODS: This study reviewed 145 consecutive patients who underwent primary coronary intervention and were discharged without any disability after STEMI during 2013-2015. RESULTS: Among the patients, 66 (45.5%) completed an outpatient CR program (CR group) and 79 were their non-CR counterparts or patients who dropped out of the program (N-D group). There were no between-group differences in patient demographics and clinical profiles, including door-to-balloon times and prescriptions. A total of 27 patients developed major adverse cardiac and cerebrovascular events (MACCE) during follow-up. The MACCE-free survival rates were 88% and 76% in the CR and N-D groups, respectively (log-rank, p=0.04). Cox proportional analysis demonstrated that inclusion in the N-D group was a significant predictor of MACCEs (HR, 2.36; 95% CI, 1.07-5.74; p=0.03). In the CR group, peak oxygen consumption and ventilatory efficiency determined by cardiopulmonary exercise testing significantly improved after the program (p<0.01). CONCLUSIONS: The impact of CR on the mid-term prognosis of patients with STEMI, even in the current myocardial infarction management era, was beneficial.

Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

The HTML version of this Article contained errors in Supplementary Figure S2 "Flowchart of the lyso-Gb3 screening and gene analysis in female patients", which have been detailed in the associated Correction.

Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

In the above article, we noticed that one female patient in the positive group (plasma lyso-Gb3 7.6 ng/ml, α-galactosidase A activity 4.9 nmol/h/ml) who presented at the neurology clinic was already diagnosed with Fabry disease before the current study. We excluded patients with a confirmed diagnosis of Fabry disease and those with relatives known to have Fabry disease. To accurately describe the information in the current study, we must exclude this patient from the analysis. We have accurately revised this information as follows.

Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.

Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

PURPOSE: Plasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females. METHODS: Between 1 July 2014 and 31 December 2015, we screened 2,359 patients (1,324 males) referred from 168 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively. RESULTS: Of 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml-1) and low α-Gal A activity (≤4.0 nmol h-1 ml-1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 14 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 7 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance). CONCLUSION: Plasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.

Prognostic Value of Left Atrial Size and Functional Indices Measured by 3-Dimensional Speckle-Tracking Analysis.

BACKGROUND: The prognostic value of indices for left atrial volumes (LAV) and reservoir function measured by 3D speckle-tracking analysis (3DSTA) has not been determined. Methods and Results: LA maximal and minimal volume indices (LAVImax, LAVImin), and LA emptying fraction (LAEmpF) were measured via 2D echocardiography (2DE) and 3DSTA in 514 patients (62% male, mean age: 66±15 years) with various cardiovascular diseases. Two cutoff values using normal±2SD (cutoff criterion 1) and receiver-operating characteristic analysis (cutoff criterion 2) were evaluated. During a mean follow-up of 720±383 days, MACE (cardiac death, nonfatal myocardial infarction, stroke and admission for heart failure) occurred in 98 patients. Kaplan-Meier survival analysis showed both cutoff criteria measured by 2DE and 3DSTA had significant predictive power for MACE (P<0.001). For cutoff criterion 1, 3DSTA measurements yielded higher hazard ratios than 2DE by Cox proportional hazard model. Cutoff criterion 2 using 3DSTA had higher average treatment effect values than 2DE by matching propensity scores on the outcome. Further, a regression model that included clinical variables, left ventricular ejection fraction and cutoff criterion 2 using 3DSTA-derived LAEmpF had significantly higher prognostic power than 2DE. CONCLUSIONS: LA indices measured by 3DSTA had greater prognostic power for future MACE than 2DE. In particular, 3DSTA-derived LAEmpF has the potential to be a valuable prognostic tool in clinical settings.

Extended Posterior Leaflet Augmentation for Ischemic Mitral Regurgitation　- Augmented Posterior Leaflet Snuggling up to Anterior Leaflet.

BACKGROUND: The ideal surgical technique for ischemic mitral regurgitation (MR) is controversial. We introduced an extended posterior mitral leaflet (PML) augmentation technique for functional MR with severe tethering, which detached the PML from the annulus almost completely and augmented it with a large 3×6-cm oval pericardial patch. Methods and Results: A total of 17 mitral repairs using the new technique were performed for ischemic MR with no 30-day mortality and 2 hospital deaths. The NYHA class was III in 47% and IV in 13%. The EuroSCORE II was 9.7±4.9. The ring size was 32±1.4 mm. Concomitant coronary bypass was performed in 67% and left ventricular repair in 28%. The mechanism of leaflet closure was evaluated using transthoracic echocardiography in 15 survivors. MR decreased to none or trivial with a significant increase in coaptation length (Pre: 4.6±0.8 mm vs. Post: 9.8±2.5 mm; P<0.001). The PML flexibly moved forward and tightly contacted as if "snuggling up" to the anterior leaflet. There were no late deaths, heart failure readmissions or MR recurrences during follow-up (850±181 days). All patients remained in NYHA I or II. CONCLUSIONS: Extended PML augmentation for ischemic MR showed excellent early results with deep leaflet coaptation through a "snuggling up" phenomenon, which would help prevent late MR recurrence.

Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease.

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

Cardiac Sarcoidosis Mimicking Septal Tumor with Intermittent Complete Atrioventricular Block.

A 52-year-old woman with intermittent complete atrioventricular (AV) block detected on exercise was admitted to the hospital. Echocardiography revealed lesions on the right ventricular side of the interventricular septum and free wall of the basal inferolateral area. Gadolinium-enhanced cardiovascular magnetic resonance (CMR) imaging revealed the mass and wall thickening at the same locations with late gadolinium enhancement (LGE). Focal uptake at the septal lesion was detected using 67Ga scintigraphy. Focal on diffuse intense uptake in the lesions was observed on Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging. Whole-body CT and laboratory evaluations uncovered no signs of malignant tumors in other organs. Ophthalmologic evaluation revealed ophthalmologic sarcoidosis. Although the result of endomyocardial biopsy was negative, the presence of cardiac sarcoidosis was strongly suggested on the basis of the new Japanese guidelines published in 2017. AV conduction disturbance and tracer accumulation on 67Ga scintigraphy completely disappeared after 2 weeks of steroid therapy. The size of mass, inferolateral wall thickness in echocardiography and CMR, and standardized uptake value (SUV) of the masses on 18F-FDG PET also decreased over time.

Predictors of a Good Diuretic Response and Administration Methods for Carperitide in Patients With Acute Heart Failure.

PURPOSE: In Japan, carperitide has been recommended for the treatment of pulmonary congestion in patients with acute heart failure. Identifying useful indicators to support the decision to administer carperitide and the optimal timing of administration may lead to better improvement of pulmonary congestion. Therefore, we investigated the factors associated with good diuretic response to carperitide in patients with acute heart failure and the optimal timing of carperitide administration. METHODS: This retrospective cohort study investigated 293 hospitalized patients who were diagnosed with acute heart failure and treated with carperitide at the Department of Cardiology, Showa University Fujigaoka Hospital. The primary endpoint was the diuretic response to carperitide. Patients with urine output ≥100 mL/h were defined as the good diuretic response group, and those with a urine output <100 mL/h during the first 6 hours of carperitide administration were defined as the poor diuretic response group. Multivariate analysis was used to examine the predictors of good diuretic response. The relationship between the time from intravenous furosemide to carperitide administration and urine output was also investigated. FINDINGS: The patients' median age was 77 (range: 28-99) years, and 75.5% had New York Heart Association stage IV acute heart failure. The median urine output within 6 hours of carperitide administration was 104.5 (range: 6.6-1571.3) mL/h, and 118 patients (53.6%) showed a good diuretic response. Significant predictors of good diuretic response were age < 75 years [odds ratio (OR) 4.186; 95% confidence interval (CI), 2.129-8.230; P < 0.001], no prior use of loop diuretics (OR 2.155; 95% CI, 1.104-4.207; P = 0.024), blood urea nitrogen <20 mg/dL (OR 2.637; 95% CI, 1.340-5.190; P = 0.005), and white blood cell count <8.6 × 109/L (OR 3.162; 95% CI, 1.628-6.140; P = 0.001). The median urine output in the group with <2 hours between intravenous furosemide and carperitide administration was significantly higher than that in the group with an interval >6 hours [127.3; interquartile range (IQR), 77.6-216.2 mL/h vs. 66.2; IQR. 51.8-114.8 mL/h; P = 0.012). IMPLICATIONS: The 4 predictors (age, no prior use of loop diuretics, blood urea nitrogen, and white blood cell count) of good diuretic response are useful indicators to support decision-making for carperitide administration. Additionally, the administration of carperitide within 2 hours of intravenous furosemide may lead to the improvement of pulmonary congestion.

Prognostic value of left atrial reverse remodelling in patients hospitalized with acute decompensated heart failure.

AIMS: Left atrial (LA) volume index (LAVI) in chronic heart failure (HF) predicts cardiovascular outcomes. However, the association between LAVI reduction during acute decompensated HF (ADHF) and its prognostic potential is limited. We hypothesized that LA reverse remodelling (LARR) after ADHF therapy would be associated with better clinical outcomes. METHODS: This retrospective study analysed clinical outcomes and the LAVI reduction rate of 363 out of 861 patients hospitalized for ADHF who underwent two-point echocardiography at admission and discharge between January 2015 and December 2019. The mean age was 74.3 ± 13.6 years, and the mean ejection fraction (EF) was 38.9 ± 15.2%. The follow-up echocardiogram was performed 13.0 [9.5, 20] days after admission. As the median LAVI reduction rate was 7.02%, the LARR was defined as an LAVI reduction rate >7%. RESULTS: During the 34.0 ± 20.2 months of follow-up, 117 patients (32.2%) reached the primary endpoint defined as cardiovascular death and rehospitalization for ADHF. Kaplan-Meier survival analysis showed that patients with LARR had a better prognosis. Multivariate analysis indicated that LARR was an independent predictor of cardiovascular events. Similar findings were observed in the subgroup analyses of patients with persistent/permanent atrial fibrillation and those with non-HF with reduced EF. Among patients who were brain natriuretic peptide (BNP) responders, defined as a relative reduction of >70% in BNP from admission to discharge, non-LARR was observed in 41.6%. BNP responders without LARR experienced worse prognoses. CONCLUSIONS: LARR in the early vulnerable phase after hospitalization for ADHF was associated with better long-term clinical outcomes.

A case of spontaneous coronary artery dissection that later turned out to be Takayasu arteritis.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS), which typically occurs in women at low risk of atherosclerosis. We herein report a case of SCAD in a 57-year-old man who later developed Takayasu arteritis. The patient presented to our hospital complaining of chest pain and was diagnosed with unstable angina. Emergent coronary angiography was performed, and optical coherence tomography revealed that ACS was caused by SCAD. The patient was treated medically without further ballooning or stenting. Because there was a bilateral difference in blood pressure, the systemic artery was screened by contrast-enhanced computed tomography, which showed left subclavian artery occlusion, proximal stenosis of the superior mesenteric artery, right common iliac artery dissection, and left external iliac artery dissection. Based on these results and 18F-fluorodeoxyglucose positron emission tomography findings, we diagnosed Takayasu arteritis. Prednisolone and tocilizumab were selected for medical treatment, and the patient was in a good condition at one year after the diagnosis. Takayasu arteritis can cause dissection of various arteries and should be suspected when atypical SCAD or multiple dissections are present. Early initiation of immunosuppressive therapy can control disease activity. Learning objective: Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome. In this case, we experienced a case of SCAD which turned out to be the first symptom of Takayasu arteritis. Immunosuppressive therapy was effective for both coronary lesion and systemic vasculitis. Not only fibromuscular dysplasia, but also various types of vasculitis should therefore be considered in the differential diagnosis when encountering atypical SCAD cases.

Bleeding risk factors and real-world antithrombotic therapies in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention: a retrospective study.

BACKGROUND: Bleeding risk factors in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) are unclear and data on the use of antithrombotic drugs are lacking. We investigated the bleeding risk factors in elderly patients with atrial fibrillation undergoing PCI to help optimize antithrombotic therapy according to bleeding risk. We also investigated the association between the actual use of antithrombotic therapy and bleeding events. METHODS: A retrospective cohort study was conducted on 134 elderly patients with atrial fibrillation who underwent primary PCI at the Department of Cardiology, Showa University Fujigaoka Hospital. The endpoint was a bleeding event within 1-year. Bleeding risk factors were identified using multivariate analysis. The association between the number of antithrombotics and bleeding events was evaluated using the chi-squared test. RESULTS: The mean age of the patients was 76.0 ± 6.2 years. Bleeding events occurred in 41 (30.6%) patients. Age > 80 years (odds ratio [OR]: 2.54, 95% confidence interval [CI]: 1.10-5.85), multivessel disease (OR: 2.76, 95% CI: 1.22-6.23), and history of surgery (OR: 3.03, 95% CI: 1.14-8.06) were identified as bleeding risk factors. The proportion of patients receiving triple therapy was significantly higher in the bleeding group compared to the non-bleeding group (70.7% vs. 27.5%, p < 0.001). CONCLUSIONS: Age > 80, multivessel disease, and history of surgery were found to be risk factors for bleeding in elderly patients with atrial fibrillation undergoing PCI. In addition, dual therapy after PCI in elderly patients at high risk of bleeding should be considered to avoid bleeding events.

Development of a model predicting cardiac events in heart failure patients with decreased renal function: a retrospective study.

BACKGROUND: Inappropriate and multiple medications affect the prognosis of patients with acute decompensated heart failure (ADHF). However, in ADHF patients with decreased renal function, there have been no reports on prognostic factors, including medication data, or models for predicting cardiac events. AIM: To develop a model including medication data to predict cardiac events in ADHF patients with decreased renal function. METHOD: This retrospective cohort study included 443 first-time admitted ADHF patients with decreased renal function (estimated glomerular filtration rate < 60 mL/min/1.73 m2 at discharge) in the Showa University Fujigaoka Hospital. The primary outcome was cardiac events within one year after discharge, defined as the composite of HF readmission, HF mortality, and cardiovascular mortality. The model for predicting cardiac events was developed using predictive factors extracted by multivariable analysis. The cardiac events curves were visualized using the Kaplan-Meier method and estimated using a log-rank test. RESULTS: The incidence of cardiac events within one year after discharge was 20.1%. By multivariable analysis, we observed that atrial fibrillation, weight loss < 5%, brain natriuretic peptide ≥ 200 pg/mL, polypharmacy, and beta-blockers use below target dosage were significantly associated with an increased risk of cardiac events. The developed model, the cardiac events rate in the high-risk group was significantly higher than in the low-risk group (41.0 vs. 9.2%, p < 0.001). CONCLUSION: The developed model for predicting cardiac events will be useful in decision-making to support appropriate early management of ADHF patients with decreased renal function.

Cardiac Structure and Cardiorespiratory Fitness in Young Male Japanese Rugby Athletes.

Limited data are available on athlete's heart for rugby athletes. This study aimed to investigate cardiac structure and its relationship with cardiorespiratory fitness in young Japanese rugby athletes. A prospective cross-sectional study using echocardiography and cardiopulmonary exercise testing (CPET) was conducted on 114 male collegiate rugby players. There was a higher prevalence of increased left ventricular (LV), atrial, and aortic dimensions in the young athletes than that in previously published reports, whereas the wall thickness was within the normal range. Anthropometry and CPET analyses indicated that the forwards and backs presented muscular and endurance phenotypes, respectively. Indexed LV and aortic dimensions were significantly larger in the backs than in the forwards, and the dimensions significantly correlated with oxygen uptake measured by CPET. On the four-tiered classification for LV hypertrophy, abnormal LV geometry was found in 16% of the athletes. Notably, the resting systolic blood pressure was significantly higher in athletes with concentric abnormal geometry than in the other geometry groups, regardless of their field positions. Japanese young athletes may exhibit unique phenotypes of cardiac remodeling in association with their fitness characteristics. The four-tiered LV geometry classification potentially offers information regarding the subclinical cardiovascular risks of young athletes.

Intraoperative Trifecta Valve Malfunction.

The Trifecta valve has been reported to have valve dysfunction months to years after operation. However there were no reports of intraoperative valve dysfunction. A 73-year-old man with aortic stenosis underwent aortic valve replacement using a 21-mm Trifecta valve with Glide Technology (Trifecta GT; Abbot). Hemodynamics were collapsed after aortic declamp because of severe regurgitation, and we replaced it with another biologic valve. We noticed that the removed valve's mount post was open outwardly more than usual. Despite the progress of the biologic valve, dysfunction like this case can occur during operation, and it is important to reoperate immediately even if there is no obvious tear or deformity.

Potential Association of Circulating MicroRNA-181c and MicroRNA-484 Levels with Cardiorespiratory Fitness after Myocardial Infarction: A Pilot Study.

OBJECTIVES: In the field of exercise physiology, there has been great interest in exploring circulating microRNAs (miRs) as potential biomarkers. However, it remains to be determined whether circulating miRs reflect cardiorespiratory fitness. The aim of this study was to investigate the association between circulating levels of specific miRs and cardiorespiratory fitness evaluated by cardiopulmonary exercise testing (CPET) after acute myocardial infarction (MI). METHODS: Twenty patients who had had an acute MI were included. All patients underwent CPET in the convalescent phase. Quantitative real-time polymerase chain reaction analyses for miR-181 members (a/b/c) and miR-484 were performed to determine the expression levels in the peripheral blood of the included patients and healthy control subjects (n=5). RESULTS: Post-MI patients showed impaired exercise tolerance and ventilatory efficiency in CPET analysis. Compared with controls, circulating levels of miR-181a and 181c were gradually and significantly elevated through the 1st to 7th days after acute MI, whereas miR-181b and miR-484 were not. Circulating miR levels did not correlate with clinical or echocardiographic parameters. However, circulating levels of miR-181c and miR-484 on the 7th day showed significant positive correlations with the anaerobic threshold and peak oxygen consumption from CPET analysis. Moreover, miR-181c levels were inversely associated with the ventilatory inefficiency index. Patients with high exercise capacity after MI showed significantly higher expressions of circulating miR-181c and miR-484 than those with low exercise capacity. CONCLUSIONS: The results of this pilot study suggest that circulating levels of miR-181c and miR-484 after acute MI may be predictive biomarkers of post-MI cardiorespiratory fitness.