PrevAleNce and Associated factors of inappropriaTe dosing of direct Oral anticoaguLants In pAtients with Atrial Fibrillation: the ANATOLIA-AF Study.

PURPOSE: Inappropriate dosing of direct oral anticoagulants is associated with an increased risk of stroke, systemic embolism, major bleeding, cardiovascular hospitalization, and death in patients with atrial fibrillation. The main goal of the study was to determine the prevalence and associated factors of inappropriate dosing of direct oral anticoagulants in real-life settings. METHODS: This study was a multicenter, cross-sectional, observational study that included 2004 patients with atrial fibrillation. The study population was recruited from 41 cardiology outpatient clinics between January and May 2021. The main criteria for inappropriate direct oral anticoagulant dosing were defined according to the recommendations of the European Heart Rhythm Association. RESULTS: The median age of the study population was 72 years and 58% were women. Nine-hundred and eighty-seven patients were prescribed rivaroxaban, 658 apixaban, 239 edoxaban, and 120 dabigatran. A total of 498 patients (24.9%) did not receive the appropriate dose of direct oral anticoagulants. In a logistic regression model, advanced age, presence of chronic kidney disease and permanent atrial fibrillation, prescription of reduced doses of direct oral anticoagulants or edoxaban treatment, concomitant use of amiodarone treatment, and non-use of statin treatment were significantly associated with potentially inappropriate dosing of direct oral anticoagulants. CONCLUSION: The study demonstrated that the prevalence of inappropriate direct oral anticoagulant dosing according to the European Heart Rhythm Association recommendations was 24.9% in patients with atrial fibrillation. Several demographic and clinical factors were associated with the inappropriate prescription of direct oral anticoagulants.

Determinants of reverse dipping blood pressure in normotensive, non-diabetic population with an office measurement below 130/85mmHg.

Objective: The role of dipping blood pressure pattern in normotensives is unclear. The study aims to search the circadian blood pressure rhythm and the clinical determinants related to reverse dipping pattern in a strictly selected, normotensive population.Methods: The study population was divided into three groups depending on the nocturnal dipping pattern as dipping, non-dipping, and reverse dipping. Basal clinical characteristics, anthropometric measurements, and spot urine samples from the first-morning void were collected. Clinical determinants related to the presence of reverse dipping pattern were tested by the Multiple Binary Logistic Regression analysis.Results: A total of 233 participants were involved in the study population (median age 45 years [40-50]). Dipping pattern was detected in 55.4%, non-dipping pattern in 33.0%, and reverse dipping pattern in 11.6% of the study population. There was no difference between the groups in terms of basal clinical features. Albumin-to-creatinine ratio (ACR) (p < .001) and hs-CRP levels (p = .006) were also statistically significant across the groups. ACR (HR: 1.195, 95% CI: 1.067-1.338, p = .002) and hs-CRP (HR: 2.438, 95% CI: 1.023-5.808, p = .044) were found to be related to the presence of reverse dipping blood pressure pattern.Conclusions: The absence of nocturnal physiological dipping is seen at a remarkable rate in the normotensive Turkish population. ACR and hs-CRP are the clinical determinants related to the presence of reverse dipping blood pressure pattern.

Which is responsible for target organ damage in masked hypertension? Is it an increase in blood pressure or a disruption of the circadian rhythm?

OBJECTIVE: Masked hypertension (MH) and non-dipping pattern are conditions associated with target organ damage and cardiovascular risk, which are frequently observed together. We aimed to show the relationship between the target organ damage observed in MH and the deterioration in the dipping pattern. METHODS: Patients who underwent ambulatory blood pressure monitoring (ABPM) and office blood pressure (BP) <140/90 mmHg were retrospectively screened. In ABPM data, those with daytime BP ≥135/85 mmHg and night BP ≥120/70 mmHg were included in the MH group, while the others were included in the normotensive group. The patients were grouped as dipper, non-dipper and reverse-dipper according to ABPM results. Left ventricular mass index (LVMI), glomerular filtration rate (GFR) and serum creatinine levels were used to determine target organ damage. RESULTS: 289 patients [mean age 46.6 ± 12.4 years, 136 (47.1%) males], 154 (53.3%) of whom had MH were included in our study. GFR value was found to be significantly lower, serum creatinine levels and LVMI were significantly higher in patients with MH compared to normotensives (p < .05, for all). When the subgroups were examined, it was found that this difference was associated with the disruption in the dipping pattern. In patients with MH, dipping pattern disruption without change in systolic BP was independently associated with an increase in LVMI (p < .05, for both). CONCLUSION: Target organ damage seen in MH may be due to the deterioration of the dipping pattern.

Heart rate variability and heart rate turbulence in patients with vasovagal syncope.

Aim    The autonomic nervous system plays an important role in the pathogenesis of vasovagal syncope, but studies on the effect of basal autonomic tone have found confusing results. The aim of this study was to investigate the effect of basal autonomic functions, as assessed by heart rate variability (HRV) and heart rate turbulence (HRT), in patients with vasovagal syncope.Material and methods    Patients who underwent head-up tilt test (HUTT) due to unexplained syncope and who had a 24 hr Holter ECG recording in the same period were retrospectively analyzed. Patients with diabetes, a history of myocardial infarction, heart failure, orthostatic hypotension, atrial fibrillation, or use of vasoactive drugs, such as beta blockers, were excluded from the study. 161 patients who met these criteria were included in the study. Time domain HRV parameters from Holter ECG recordings and HRT parameters from patients with sufficient number of ventricular premature contractions were measured.Results    The age of the patients varied from 16 to 75 yrs (mean: 44.8±18.5 yrs). HUTT results of 60 (37.2 %) patients were evaluated as positive. There were no significant differences in the basal demographic, clinical, or laboratory findings of the tilt-positive and tilt-negative patient groups. Likewise, there were no significant differences between the time domain HRV parameters and HRT parameters of both groups.Conclusion    HRV and HRT parameters reflecting basal autonomic function were not different between HUTT positive and HUTT negative patient groups. These findings suggest that basal autonomic functions have no effect on vasovagal syncope pathogenesis.

Severe upper gastrointestinal bleeding from aortoenteric fistula: a late complication of esophagojejunostomy.

Aortoenteric fistula is an uncommon cause of upper gastrointestinal bleeding, which is life-threatening if not treated. This complication may occur even months to years after surgery [Mitchel 1995]. It is commonly observed in patients who have undergone previous aortic surgery and rarely occurs in patients with a history of gastrointestinal tract surgery [Brock 1953]. The diagnosis of aortoenteric fistula depends on a high level of clinical suspicion. Herein, we report a case of a 53-year-old man who underwent surgical treatment because of new-onset severe gastrointestinal bleeding that was related to an aortoenteric fistula.

The Effects of Niacin on Inflammation in Patients with Non-ST Elevated Acute Coronary Syndrome.

BACKGROUND: In this study, we aimed to evaluate the effects of niacin on high sensitivity C reactive protein (hs-CRP) and cholesterol levels in non-ST elevated acute coronary syndrome (NSTE-ACS) patients. METHODS: In this prospective, open label study, 48 NSTE-ACS were randomized to niacin or control group. Patients continued their optimal medical therapy in the control group. In the niacin group patients were assigned to receive extended-release niacin 500 mg/day. Patients were contacted 1 month later to assess compliance and side effects. Blood samples for hs-CRP were obtained upon admittance to the coronary care unit, in the third day and in the first month of the treatment. Fasting blood samples for cholesterol levels were obtained before and 30 days after the treatment. The primary end point of the study was to evaluate changes in hs-CRP, cholesterol levels, short-term cardiovascular events, and the safety of niacin in NSTE-ACS. RESULTS: Baseline demographic, clinical and laboratory characteristics were similar between the two groups. Logarithmic transformation of baseline and 3(rd) day hs-CRP levels were similar between the groups; but 1 month later, logarithmic transformation of hs-CRP level was significantly lower in the niacin group (0.43 ± 0.39 to 0.83 ± 0.91, p = 0.04). HDL-C level was significantly increased in the niacin group during follow-up. Drug related side effects were seen in 7 patients in the niacin group but no patients discontinued niacin. CONCLUSIONS: Our findings demonstrate that lower dose extended release niacin can be used safely and decreases hs-CRP and lipid parameters successfully in NSTE-ACS patients. KEY WORDS: Acute coronary syndrome; hs-CRP; Inflammation; Niacin.

Long-Term Prognosis of Patients with Heart Failure: Follow-Up Results of Journey HF-TR Study Population.

BACKGROUND: Despite advances in therapeutic management of patients with heart failure, there is still an increasing morbidity and mortality all over the world. In this study, we aimed to present the 3-year follow-up outcomes of patients included in the Journey HF-TR study in 2016 that has evaluated the clinical characteristics and management of patients with acute heart failure admitted to the hospital and present a national registry data. METHODS: The study was designed retrospectively between November 2016 and December 2019. Patient data included in the previously published Journey HF-TR study were used. Among 1606 patients, 1484 patients were included due to dropout of 122 patients due to inhospital death and due to exclusion of 173 due to incomplete data. The study included 1311 patients. Age, gender, concomitant chronic conditions, precipitating factors, New York Heart Association, and left ventricular ejection fraction factors were adjusted in the Cox regression analysis. RESULTS: During the 3-year follow-up period, the ratio of hospitalization and mortality was 70.5% and 52.1%, respectively. Common causes of mortality were acute decompensation of heart failure and acute coronary syndrome. Angiotensin receptor blockers, betablockers, statin, and sacubitril/valsartan were found to reduce mortality. Hospitalization due to acute decompensated heart failure, acute coronary syndrome, lung diseases, oncological diseases, and cerebrovascular diseases was associated with the increased risk of mortality. Implantation of cardiac devices also reduced the mortality. CONCLUSIONS: Despite advances in therapeutic management of patients with heart failure, our study demonstrated that the long-term mortality still is high. Much more efforts are needed to improve the inhospital and long-term survival of patients with chronic heart failure.

Real-World Evaluation of Anticoagulant Treatment Patterns in Patients with Atrial Fibrillation: Data from Multicenter ROTA Study.

OBJECTIVE: Oral anticoagulant therapy is the cornerstone of atrial fibrillation management to prevent stroke and systemic embolism. However, there is limited real-world information regarding stroke and systemic embolism prevention strategies in patients with atrial fibrillation. The aim of the ROTA study is to obtain the real-world data of anticoagulant treatment patterns in patients with atrial fibrillation. METHODS: The ROTA study is a prospective, multicenter, and observational study that included 2597 patients with atrial fibrillation. The study population was recruited from 41 cardiology outpatient clinics between January 2021 and May 2021. RESULTS: The median age of the study population was 72 years (range: 22-98 years) and 57.4% were female. The median CHA2DS2-VASc and HAS-BLED scores were 4 (range: 0-9) and 1 (range: 0-6), respectively. Vitamin K antagonists and direct oral anticoagulants were used in 15.9% and 79.4% of patients, respectively. The mean time in therapeutic range was 52.9% for patients receiving vitamin K antagonists, and 76% of those patients had an inadequate time in therapeutic range with <70%. The most common prescribed direct oral anticoagulants were rivaroxaban (38.1%), apixaban (25.5%), and edoxaban (11.2%). The rate of overuse of vitamin K antagonists and direct oral anticoagulants was high (76.1%) in patients with low stroke risk, and more than one-fourth of patients on direct oral anticoagulant therapy were receiving a reduced dose of direct oral anticoagulants. Among patients who were on direct oral anticoagulant treatment, patients with apixaban treatment were older, had higher CHA2DS2-VASc and HAS-BLED scores, and had lower creatinine clearance than the patients receiving other direct oral anticoagulants. CONCLUSIONS: The ROTA study provides important real-world information about anticoagulant treatment patterns in patients with atrial fibrillation.time in therapeutic range with <70%.

Association of Morning Surge and Postexercise Heart Rate and Blood Pressure Recovery.

INTRODUCTION: The autonomic nervous system plays an active role in the regulation of early morning blood pressure (BP) and BP/pulse regulation in the treadmill exercise test (TET). AIM: We evaluated the relationship between BP/pulse changes during TET and morning blood pressure surge (MS). METHODS: Patients who underwent ambulatory blood pressure measurement (ABPM) and TET in the same visit between 2017 and 2020 were evaluated retrospectively. Patients with previously diagnosed hypertension and/or using antihypertensives and office BP ≥ 140/90 were excluded from the study.MS values and dipping percentage were calculated from ABPM data. The patients were analyzed by dividing them into two groups according to the MS median, and BP/pulse values during exercise and recovery periods were compared in these groups. RESULTS: 202 patients [median age 45 (39-51), male 134 (66.3%)] were included in the study. MS median was 18.5 (10.75-27) mmHg. TET recovery period 3rd-min systolic blood pressure (RSBP) was higher in the group with high MS (p: 0.017). Systolic and diastolic dipping percentages were higher in the group with higher MS (p: 0.015, p: 0.040, respectively). Peak systolic and diastolic BP, RSBP, and recovery 3rd min diastolic BP were positively correlated with MS (p < 0.05, for all). Additionally, an independent relationship was observed between RSBP and MS (ß: 0.205, p: 0.028). CONCLUSION: We found an independent association between RSBP and MS. Increased RSBP may be associated with target organ damage and cardiovascular events such as MS.

Association of the Atherogenic Index of Plasma with C-Reactive Protein and Urinary Albumin Excretion in a Normotensive Nondiabetic Population.

Background: The atherogenic index of plasma (AIP) is an indicator of atherogenic dyslipidemia and is significantly associated with the development of atherosclerotic cardiovascular disease. Previous studies showing the association of AIP with C-reactive protein (CRP) and microalbuminuria included hypertensive and diabetic patients. We aimed to determine the association of AIP with CRP and albuminuria in a normotensive and nondiabetic population. Methods: The study was conducted retrospectively. Two hundred thirty-three individuals without hypertension, diabetes, cardiovascular disease, malignancy, systemic inflammatory disease, nephrological disease, and active infection were determined and included in the study. Urinary albumin excretion was calculated from the albumin-creatinine ratio in fresh spot urine [urinary albumin-creatinine ratio (UACR)]. AIP risk groups were compared in terms of clinical and laboratory findings, and the correlation between AIP and CRP and UACR was evaluated. Results: A total of 233 people, with a mean age of 45.4 years and 139 (69.7%) of whom were male, were included in the study. One hundred thirty-eight (59.2%) individuals were found to be in the low-risk group, 29 (12.5%) in the medium-risk group, and 66 (28.3%) in the high-risk group, according to the AIP value. CRP and UACR were not different between the AIP risk groups (P: 0.141 and 0.441, respectively). A mild correlation was found between AIP and CRP (r: 0.192; P: 0.003), but no correlation was found between AIP and UACR (r: 0.086; P: 0.193). The stepwise linear regression analysis with model adjusted for possible confounders and AIP revealed that only body mass index was a significant predictor of CRP (ß: 0.308; P < 0.001), while only systolic blood pressure was a significant predictor of UACR (ß: 0.19; P: 0.004), but AIP was not. Conclusions: AIP was not associated with CRP and UACR in normotensive and nondiabetic individuals. This finding suggests that the relationship found in previous studies is related to the presence of hypertension or diabetes rather than the AIP.

In-Hospital Bleeding and Mortality in Acute Coronary Syndrome Patients Treated with Tirofiban and Potent P2Y12 Inhibitors.

OBJECTIVE: In this study, we aimed to determine whether potent agents affect in-hospital bleeding and mortality compared to clopidogrel in patients with the acute coronary syndrome in whom tirofiban and P2Y12 inhibitor are used together. METHODS: Patients who were treated interventionally between 2015 and 2020 and were using tirofiban were retrospectively screened. Clinical, laboratory, and angiographic findings were obtained from the hospital database. Patients were analyzed by dividing them into clopidogrel and prasugrel/ticagrelor groups. RESULTS: Acute coronary syndrome patients (n = 227) who were treated interventionally were included in this retrospective study. Clopidogrel was given to 93 (41%), ticagrelor to 112 (49.3%), and prasugrel to 22 of the patients (9.7%). Compared to the ticagrelor/prasugrel group, the clopidogrel group was older and more were women, and the history of hypertension and previous coronary artery disease was higher (P, respectively: <.001; .001; .008; .0045). The creatinine value was higher, the basal hemoglobin was lower, and the GRACE (Global Registry of Acute Coronary Events) and CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) scores were higher (P, respectively: .026; .002; .002; <.001). The in-hospital bleeding rate was signifi- cantly higher in the clopidogrel group (P < .001). Although the in-hospital mortality rate was higher, it was not statistically significant (P = .07). Regression analysis showed that GRACE score and gender were associated with in-hospital mortality (P < .001; P=.031, respectively), and only age was associated with in-hospital bleeding (P < .001). No relationship was found with P2Y12 inhibitor. CONCLUSION: In our study, we found that the combined use of potent P2Y12 inhibitor with tiro- fiban in acute coronary syndrome patients treated interventionally was not different from the use of clopidogrel in terms of in-hospital bleeding and mortality.

New perspective on fatigue in hemodialysis patients with preserved ejection fraction: diastolic dysfunction : Fatigue and diastolic dysfunction.

The relationship between diastolic dysfunction and fatigue in hemodialysis patients with preserved ejection fraction is unknown. In this context, the objective of this study is to assess fatigue using the relevant scales and to demonstrate its relationship with diastolic dysfunction. The patients who underwent hemodialysis were evaluated prospectively. Patients' fatigue was assessed using the Visual Analogue Scale to Evaluate Fatigue Severity (VAS-F). The echocardiographic works were performed as recommended in the American Society of Echocardiography guidelines. A total of 94 patients [mean age 64.7 ± 13.5 years, 54 males (57.4%)] were included in the study. The median VAS-F score of these patients was 68.5 (33.25-91.25), and they were divided into two groups according to this value. Peak myocardial velocities during early diastole (e') and tricuspid annular plane systolic excursion (TAPSE) values were found to be significantly lower in the group with high VAS-F scores, whereas the early diastolic flow velocities (E)/e' ratio and pulmonary artery peak systolic pressures (PAP) were found to be significantly higher (p < 0.05, for all). E/e' ratio (r 0.311, p 0.002) and PAP (r 0.281, p 0.006) values were found to be positively correlated with the VAS-F score, as opposed to the TAPSE (r - 0.257, p 0.012) and e' (r - 0.303, p 0.003) values, which were found to be negatively correlated with the VAS-F score. High fatigue scores in hemodialysis patients may be associated with diastolic dysfunction. In addition, in our study, we determined the correlation of VAS-F score with E/e' ratio, PAP and TAPSE.

Evaluation of the relationship between para-aortic adipose tissue and ascending aortic diameter using a new method.

BACKGROUND: Para-aortic adipose tissue (PAT) is the local adipose tissue that externally surrounds the aorta. It contributes significantly to aortic atherosclerosis and enlargement. Studies conducted with computed tomography and magnetic resonance have shown that individuals with aortic aneurysm had more PAT than healthy individuals. In this study, we measured PAT using transthoracic echocardiography (TTE). The aim of this study is to investigate the possible relationship of TTE measured PAT with ascending aortic width. METHODS: PAT was defined as the hypoechoic space in front of ascending aortic 2 cm above the sinotubular junction at the end of the systole. Patients were divided into 2 groups according to the presence of dilatation in the ascending aorta using Roman's classification (aortic size index, ASI). ASI of less than 21 was considered no aortic dilation and an ASI of 21 mm/m2 or greater was considered to have aortic dilation. RESULTS: A total of 321 unselected patients were divided into the ascending aortic dilatation (AAD) group (n = 96) and the normal ascending aorta diameter group (n = 225 patients). PAT was significantly higher in the AAD group compared with the non-ADD group (0.9 (0.48) vs. 0.7 (0.91) mm, p < 0.0001). Univariate and multivariate logistic regression analysis revealed that PAT (OR: 3.005, 95%CI (1.445-6.251)) were significantly associated with AAD. CONCLUSIONS: This is the first study which evaluated PAT measured by TTE. We found a significant association between PAT measured by TTE and ascending aorta width.

Evaluation of demographic and clinical characteristics of female patients presenting with MINOCA and differences between male patients: A subgroup analysis of MINOCA-TR registry.

OBJECTIVE: Although the prevalence and rate of myocardial infarction with non-obstructive coronary arteries (MINOCA) are higher in women than in men in previous cohorts, potential demographic and clinical differences between women who are diagnosed with MINOCA versus myocardial infarction with obstructive coronary arteries (MIOCA) have not been studied till date. In this study, we aimed to document these characteristics and to compare them between female patients with MINOCA and MIOCA. METHODS: The study was a subgroup analysis of the MINOCA-TR study. The study was a multi-center, observational cohort study that was conducted in Turkey between March 2018 and October 2018. In this study, 477 (29.3%) female patients who had been diagnosed with acute myocardial infarction were evaluated. RESULTS: Of these women, 49 (10.3%) were diagnosed with MINOCA (mean age 58.9±12.9 years) and 428 (89.7%) had a final diagnosis of MIOCA (mean age 67.4±11.8 years). The prevalence of hypertension, hyperlipidemia, and diabetes mellitus was significantly lower in the MINOCA group than in the MIOCA group. In addition, the MINOCA group had higher rates of recent flu history and non-ST elevation myocardial infarction (NSTEMI) presentation than the MIOCA group. There were significant clinical differences in patients with MINOCA in terms of sex. The female patients were older, had higher systolic blood pressures, and lower hemoglobin levels than male patients. CONCLUSION: The study revealed that the prevalence of traditional coronary artery disease risk factors was lower in female patients with MINOCA than in those who had final diagnosis of MIOCA.

A new and simple parameter for diagnosis pulmonary edema: Expiratory air humidity.

PURPOSE: Acute pulmonary edema is characterized by increased levels of fluid in the interstitial and alveolar space of the lung and requires emergency treatment. In acute pulmonary edema, the amount of fluid in the intra-alveolar, interstitial space, and pleural space vary considerably and this fluid will evaporate in different amounts compared to the physiological fluid. The aim of this study was to compare the humidity rates of expiratory air measured before and after pulmonary edema induced by α-naphthylthiourea (ANTU) in rats. METHODS: The study included twenty healthy adult rats divided equally into a healthy control group and a pulmonary edema group. Pulmonary edema was induced by administering ANTU intraperitoneally in the rats in the study group. Humidity, temperature, lung weight, pleural effusion, and histopathological changes in the respiratory system due to pulmonary edema were examined in the ANTU group. Control measurments were taken before administration of ANTU and again 4 h after administration of ANTU when lung damage was considred to be at maximum levels. RESULTS: Mean expiratory air humidity was 71.22±3.59% before ANTU and 56.28±3.94% after administration of ANTU. The mean humidity difference of -14.94±5.96% was considered statistically different (p = 0.01). CONCLUSION: Humidity rate in expiratory air was significantly lower in rats with acute pulmonary edema compared to healthy rats. This result supports the hypothesis that humidity in expiratory air can be considered an important parameter in patients during clinical are follow-up for pulmonary edema.

The Safety and Tolerability of Nebivolol in Hypertensive Patients with Coronary Artery Disease and Left Ventricular Ejection Fraction ≥ 40%: A Population-Based Cohort Study (Nebivolol-TR Study).

BACKGROUND: This study aimed to assess the safety and tolerability of nebivolol in hypertensive patients with coronary artery disease and left ventricular ejection fraction ≥ 40% in a Turkish cohort. METHODS: A total of 1015 hypertensive patients and coronary artery disease with left ventricular ejection fraction ≥ 40% were analyzed from 29 different centers in Turkey. Primary outcomes were the mean change in blood pressure and heart rate. Secondary outcomes were to assess the rate of reaching targeted blood pressure (<130/80 mmHg) and heart rate (<60 bpm) and the changes in the clinical symptoms (angina and dyspnea). Adverse clinical events and clinical outcomes including cardiovascular mortality, cardiovascular hospital admissions, or acute cardiac event were recorded. RESULTS: The mean age of the study population was 60.3 ± 11.5 years (male: 54.2%). During a mean follow-up of 6 months, the mean change in blood pressure was -11.2 ± 23.5/-5.1 ± 13.5 mmHg, and the resting heart rate was -12.1 ± 3.5 bpm. Target blood pressure and heart rate were achieved in 76.5% and 37.7% of patients. Angina and functional classifications were improved by at least 1 or more categories in 31% and 23.2% of patients. No serious adverse events related to nebivolol were reported. The most common cardiovascular side effect was symptomatic hypotension (4.2%). The discontinuation rate was 1.7%. Cardiovascular hospital admission rate was 5% and hospitalization due to heart failure was 1.9% during 6 months' follow-up. Cardiovascular mortality rate was 0.1%. CONCLUSION: Nebivolol was well tolerated and safe for achieving blood pressure and heart rate control in hypertensive patients with coronary artery disease and heart failure with preserved or mildly reduced ejection fraction.