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Michinari Hieda Last modified date：2023.07.05

Assistant Professor / Department of Basic Medicine / Faculty of Medical Sciences


Papers
1. McKenna ZJ, Moralez G, Romero SA, Hieda M, Huang M, Cramer MN, Sarma S, MacNamara JP, Jaffery MF, Atkins WC, Foster J, Crandall CG., Cardiac Remodeling in Well-Healed Burn Survivors after Six Months of Unsupervised Progressive Exercise Training., Journal of applied physiology (Bethesda, Md. : 1985), 10.1152/japplphysiol.00630.2022, 2023.01, Aerobic exercise is important in the rehabilitation of individuals with prior burn injuries, but no studies have examined whether adult burn survivors demonstrate cardiac remodeling to long-term aerobic exercise training. In this study we tested the hypothesis that 6-months of progressive exercise training improves cardiac magnetic resonance imaging-based measures of cardiac structure and function in well-healed burn survivors. Secondary analyses explored relations between burn surface area and changes in cardiac structure in the cohort of burn survivors. V̇O2peak assessments and cardiac magnetic resonance imaging were performed at baseline and following 6-months of progressive exercise training from nineteen well-healed burn survivors and ten non-burned control participants. V̇O2peak increased following 6-months of training in both groups (Control: Δ5.5±5.8 ml/kg/min; Burn Survivors: Δ3.2±3.6 mL/kg/min, main effect of training p
2. Maruyama T, Hieda M, Eiraku K, Uozumi Y, Nomura H, Constipation and heart failure: An overlooked but important linkage., Geriatrics & gerontology international, 10.1111/ggi.14545, 2023.01.
3. Moriyama S, Hieda M, Kisanuki M, Kawano S, Yokoyama T, Fukata M, Kusaba H, Maruyama T, Baba E, and Akashi K, Fukuda H, Both New-Onset and Pre-Existing Hypertension Indicate Favorable Clinical Outcomes in Patients Treated With Anti-Vascular Endothelial Growth Factor Therapy., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-22-0628, 2022.12, BACKGROUND: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.Methods and Results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133-567) and 170 (72-358) days, respectively, compared with 146 (70-309) days in the non-hypertensive group (P
4. Moriyama S, Hieda M, Kisanuki M, Kawano S, Yokoyama T, Fukata M, Kusaba H, Maruyama T, Baba E, and Akashi K, Fukuda H, Effect of renin-angiotensin system inhibitors in patients with cancer treated with anti-VEGF therapy., Open heart, 10.1136/openhrt-2022-002135, 9, 2, 2022.12, BACKGROUND: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown. OBJECTIVES: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension. METHOD: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint. RESULTS: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584). CONCLUSIONS: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive..
5. Sato T, Hieda M, Futami S, Fukata M, Shiose A, Evaluation of coronary flow is useful in patients with left coronary cusp thrombus formation after left ventricular assist device implantation, European Heart Journal - Case Reports, 10.1093/ehjcr/ytad025, 2022.12.
6. Eiraku K, Uozumi Y, Hieda M, Maruyama T, Nomura H, A senile case of heart failure associated with hypermagnesemia induced by magnesium-containing laxative agent., Geriatrics & gerontology international, 10.1111/ggi.14478, 22, 10, 897-899, 2022.10.
7. Fischer M, Moralez G, Sarma S, MacNamara J, Cramer M, Huang M, Romero S, Hieda M, Shibasaki M, Ogoh S, and Crandall C, Altered cardiac β1 responsiveness in hyperthermic older adults., American journal of physiology. Regulatory, integrative and comparative physiology, 10.1152/ajpregu.00040.2022, 323, 4, R581-R588, 2022.10, Compared with younger adults, passive heating induced increases in cardiac output are attenuated by ∼50% in older adults. This attenuated response may be associated with older individuals' inability to maintain stroke volume through ionotropic mechanisms and/or through altered chronotropic mechanisms. The purpose of this study was to identify the interactive effect of age and hyperthermia on cardiac responsiveness to dobutamine-induced cardiac stimulation. Eleven young (26 ± 4 yr) and 8 older (68 ± 5 yr) participants underwent a normothermic and a hyperthermic (baseline core temperature +1.2°C) trial on the same day. In both thermal conditions, after baseline measurements, intravenous dobutamine was administered for 12 min at 5 µg/kg/min, followed by 12 min at 15 µg/kg/min. Primary measurements included echocardiography-based assessments of cardiac function, gastrointestinal and skin temperatures, heart rate, and mean arterial pressure. Heart rate responses to dobutamine were similar between groups in both thermal conditions (P > 0.05). The peak systolic mitral annular velocity (S'), i.e., an index of left ventricular longitudinal systolic function, was similar between groups for both thermal conditions at baseline. While normothermic, the increase in S' between groups was similar with dobutamine administration. However, while hyperthermic, the increase in S' was attenuated in the older participants with dobutamine (P
8. Kusaba H, Moriyama S, Hieda M, Ito M, Ohmura H, Isobe T, Tsuchihashi K, Fukata M, Ariyama H, Baba E, IMPROVE bleeding score predicts major bleeding in advanced gastrointestinal cancer patients with venous thromboembolism., Jpn J Clin Oncol, 10.1093/jjco/hyac103, 52, 10, 1183-1190, 2022.10, BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism..
9. MacNamara J, Dias K, Hearon C, Hieda M, Turer A, Link M, Sarma S, Levine B, Limits to submaximal and maximal exercise in patients with hypertrophic cardiomyopathy., Journal of applied physiology (Bethesda, Md. : 1985), 10.1152/japplphysiol.00566.2021, 133, 4, 787-797, 2022.10, Patients with hypertrophic cardiomyopathy (HCM) often have reduced exercise capacity, and it is unclear whether cardiovascular regulation during exercise is intact in these patients. We aimed to determine the relationship between cardiac output (Q̇c) and oxygen uptake (V̇o2), and stroke volume (SV) reserve in HCM compared with healthy participants and participants with left ventricular hypertrophy (LVH) but not HCM. Sixteen patients with HCM (48 ± 7 yr, 44% female), 16 participants with LVH (49 ± 5 yr, 44% female), and 61 healthy controls (CON: 52 ± 5 yr, 52% female) completed submaximal steady-state treadmill exercise followed by a maximal exercise test. V̇o2, Q̇c, SV, and arteriovenous oxygen difference were measured during rest and exercise, and Q̇c/V̇o2 slopes were constructed, The Q̇c/V̇o2 slope was blunted in HCM compared with CON and LVH [HCM 4.9 ± 0.7 vs. CON 5.5 ± 1.0 (P = 0.027) vs. LVH 6.0 ± 1.0 AU (P = 0.002)] and participants with HCM had a lower SV reserve (HCM 53 ± 33%, controls 83 ± 33%, LVH 82 ± 22%; HCM vs. controls P = 0.002; HCM vs. LVH P = 0.015). Despite a blunted Q̇c/V̇o2 slope, 75% of patients with HCM achieved ≥80% predicted V̇o2max by augmenting a-vo2 difference at maximal exercise (16.0 ± 0.8 mL/100 mL vs. 13.8 ± 2.7 mL/100 mL, P = 0.021). Patients with HCM do not appropriately match Q̇c to metabolic demand, primarily due to inadequate stroke volume augmentation. Despite this central limitation, many patients achieve normal exercise capacities by significantly increasing peripheral oxygen extraction.NEW & NOTEWORTHY Through state-of-the-art hemodynamic and oxygen uptake methodologies, this study found the cardiac output response to increasing metabolic demand is blunted among patients with hypertrophic cardiomyopathy (HCM), primarily due to a reduced stroke volume reserve. Many patients with HCM augment their peripheral oxygen extraction during maximal exercise to achieve normal exercise capacity and overcome ineffective matching of cardiac output. Peripheral adaptations that compensate for cardiac limitations may contribute to the heterogeneity of functional limitations observed within this patient population..
10. Moriyama S, Fukata M, Hieda M, Yokoyama T, Yoshimoto G, Kusaba H, Nakashima Y, Miyamoto T, Maruyama T, Akashi K, Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation., Open heart, 10.1136/openhrt-2022-002007, 9, 1, 2022.05, OBJECTIVE: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients. METHODS: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT. RESULTS: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type. CONCLUSIONS: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies..
11. Fukudome Y, Hieda M, Masui S, Yokoyama T, Futami S, Moriyama S, Irie K, Fukata M, Ushijima T, Shiose A, Akashi K, Case Report: Bronchogenic Cyst in the Right Atrium of a Young Woman., Frontiers in cardiovascular medicine, 10.3389/fcvm.2022.915876, 9, 915876-915876, 2022.05, A 31-year-old woman was referred to our hospital for evaluation of a cardiac mass in the right atrium. Cardiac magnetic resonance imaging indicated a cystic mass filled with fluid accumulation in the right atrium. The mass was identified as a cardiac cyst and was surgically removed. Pathological examination revealed an extremely rare bronchogenic cyst. Bronchogenic cysts are benign congenital abnormalities of primitive foregut origins that form in the mediastinum during embryonic development. There is unusual clinical dilemmas surrounding the treatment plan for cardiac surgery or biopsy of cardiac masses, especially in patients with rare cardiac cysts. The anatomical location of the cyst can be related to various clinical symptoms and complications. In cases of indeterminate cardiac cysts, direct cyst removal without prior biopsy is of utmost importance..
12. Hearon CM Jr, Dias KA, MacNamara JP, Hieda M, Mantha Y, Harada R, Samels M, Morris M, Szczepaniak LS, Levine BD, Sarma S, 1 Year HIIT and Omega-3 Fatty Acids to Improve Cardiometabolic Risk in Stage-A Heart Failure., JACC. Heart failure, 10.1016/j.jchf.2022.01.004, 10, 4, 238-249, 2022.04, OBJECTIVES: This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A). BACKGROUND: It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors. METHODS: High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide >40 pg/mL or high-sensitivity cardiac troponin T >0.6 pg/mL; visceral fat >2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.O2), left ventricular (LV) mass, LV volume, myocardial triglyceride content (magnetic resonance spectroscopy), arterial stiffness/function (central pulsed-wave velocity; augmentation index), and body composition (dual x-ray absorptiometry scan). RESULTS: Fifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.O2: 4.46 mL/kg per minute, 95% CI: 3.18 to 5.56; P 
13. Hieda M, Levine BD, Response by Hieda and Levine to Letter Regarding Article, "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction"., Circulation, 10.1161/CIRCULATIONAHA.122.058733, 145, 9, e644, 2022.03.
14. Hatakeyama K, Hieda M, Semba Y, Moriyama S, Wang Y, Maeda T, Kato K, Miyamoto T, Akashi K, Kikushige Y, TET2 Clonal Hematopoiesis Is Associated With Anthracycline-Induced Cardiotoxicity in Patients With Lymphoma., JACC. CardioOncology, 10.1016/j.jaccao.2022.01.098, 4, 1, 141-143, 2022.03.
15. Maruyama T, Hieda M, Koyama T, Kawa T, Fujino T, Estimation of Red Cell Filterability Using Two-Step Nickel Mesh Filtration System: A Feasibility Study of Tandem Filtration, 50, 1, 119-125, 2022.02.
16. Maruyama T, Hieda M, Mawatari S, Fujino T, Rheological Abnormalities in Human Erythrocytes Subjected to Oxidative Inflammation., Frontiers in physiology, 10.3389/fphys.2022.837926, 13, 837926-837926, 2022.02, Erythrocytes are oxygen carriers and exposed to redox cycle in oxygenation and deoxygenation of hemoglobin. This indicates that circulating erythrocytes are vulnerable to the oxidative injury occurring under the imbalance of redox homeostasis. In this review article, two topics are presented concerning the human erythrocytes exposed to the oxidative inflammation including septic and sterile conditions. First, we demonstrate rheological derangement of erythrocytes subjected to acute oxidative injury caused by exogenous generators of reactive oxygen species (ROS). Erythrocyte filterability as whole-cell deformability has been estimated by the gravity-based nickel mesh filtration technique in our laboratory and was dramatically impaired in a time-dependent manner after starting exposure to the ROS generators, that is associated with concurrent progression of membrane protein degradation, phospholipid peroxidation, erythrocyte swelling, methemoglobin formation, and oxidative hemolysis. Second, we introduce an impairment of erythrocyte filterability confirmed quantitatively in diabetes mellitus and hypertension of animal models and patients under treatment. Among the cell geometry, internal viscosity, and membrane property as the three major determinants of erythrocyte deformability, erythrocyte membrane alteration is supposed to be the primary cause of this impairment in these lifestyle-related diseases associated with persistent oxidative inflammation. Excessive ROS trigger the inflammatory responses and reduce the erythrocyte membrane fluidity. Oxidative inflammation increasing erythrocyte membrane rigidity underlies the impaired systemic microcirculation, which is observed in diabetic and/or hypertensive patients. On the other hand, elevated internal viscosity caused by sickle hemoglobin polymerization is a primary cause of impaired erythrocyte filterability in sickle cell disease (SCD). However, oxidative inflammation is also involved in the pathophysiology of SCD. The physiologic level of ROS acts as signaling molecules for adaptation to oxidative environment, but the pathological level of ROS induces suicidal erythrocyte death (eryptosis). These findings provide further insight into the ROS-related pathophysiology of many clinical conditions..
17. Yogamaya Mantha, Shutaro Futami, Shohei Moriyama, Michinari Hieda, Valvulo-Arterial Impedance and Dimensionless Index for Risk Stratifying Patients With Severe Aortic Stenosis., Frontiers in cardiovascular medicine, 10.3389/fcvm.2021.742297, 8, 742297-742297, 2021.12, The hemodynamic effects of aortic stenosis (AS) consist of increased left ventricular (LV) afterload, reduced myocardial compliance, and increased myocardial workload. The LV in AS patients faces a double load: valvular and arterial loads. As such, the presence of symptoms and occurrence of adverse events in AS should better correlate with calculating the global burden faced by the LV in addition to the transvalvular gradient and aortic valve area (AVA). The valvulo-arterial impedance (Zva) is a useful parameter providing an estimate of the global LV hemodynamic load that results from the summation of the valvular and vascular loads. In addition to calculating the global LV afterload, it is paramount to estimate the stenosis severity accurately. In clinical practice, the management of low-flow low-gradient (LF-LG) severe AS with preserved LV ejection fraction requires careful confirmation of stenosis severity. In addition to the Zva, the dimensionless index (DI) is a very useful parameter to express the size of the effective valvular area as a proportion of the cross-section area of the left ventricular outlet tract velocity-time integral (LVOT-VTI) to that of the aortic valve jet (dimensionless velocity ratio). The DI is calculated by a ratio of the sub-valvular velocity obtained by pulsed-wave Doppler (LVOT-VTI) divided by the maximum velocity obtained by continuous-wave Doppler across the aortic valve (AV-VTI). In contrast to AVA measurement, the DI does not require the calculation of LVOT cross-sectional area, a major cause of erroneous assessment and underestimation of AVA. Hence, among patients with LG severe AS and preserved LV ejection fraction, calculation of DI in routine echocardiographic practice may be useful to identify a subgroup of patients at higher risk of mortality who may derive benefit from aortic valve replacement. This article aims to elucidate the Zva and DI in different clinical situations, correlate with the standard indexes of AS severity, LV geometry, and function, and thus prove to improve risk stratification and clinical decision making in patients with severe AS..
18. Toru Maruyama, Michinari Hieda, Erythrocyte damage observed in patients with heart valve replacement: Investigation by morphological, biochemical and hemorheological techniques, Journal of Biorheology, 10.17106/jbr.35.57, 35, 2, 57-61, 2021.10, Current sophisticated open heart surgical technologies have improved the prognosis of patients undergoing heart valve repair and replacement. Optimal antithrombotic strategy is now established using antiplatelet and anticoagulant agents, whereas subclinical erythrocyte damage caused by prosthetic heart valves is drawing less attention. Therefore, the aim of this study is to investigate the erythrocyte damage in prosthetic heart valve recipients from several viewpoints of serum biochemistry, erythrocyte morphology, and clinical hemorheology. Serum lactate dehydrogenase level was elevated significantly (p = 0.007) in patients with metallic heart valves (n = 6) but not in those with bioprosthetic heart valves (n = 8) as compared with healthy controls (n = 8). In the microscopic examination, teardrop cells, fragmented cells, and erythrocyte with local membrane protrusion (so-called budding) were observed in some patients with metallic heart valve replacement but not in the other two groups. Erythrocyte filterability estimated by our specific gravity filtration technique showed significant intergroup difference at low filtration pressure (50 cmH2O) (p
19. Hieda M, Sarma S, Hearon CM Jr, MacNamara JP, Dias KA, Samels M, Palmer D, Livingston S, Morris M, Levine BD. , One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction, Circulation, 10.1161/CIRCULATIONAHA.121.054117, 144, 12, 934-946, 2021.09.
20. Tran T, Muralidhar A, Hunter K, Buchanan C, Coe G, Hieda M, Tompkins C, Zipse M, Spotts MJ, Laing SG, Fosmark K, Hoffman J, Ambardekar AV, Wolfel EE, Lawley J, Levine B, Kohrt WM, Pal J, Cornwell WK 3rd., Right ventricular function and cardiopulmonary performance among patients with heart failure supported by durable mechanical circulatory support devices., J Heart Lung Transplant, 10.1016/j.healun.2020.11.009, 40, 2, 128-137, 2021.02, BACKGROUND
Patients with continuous-flow left ventricular assist devices (CF-LVADs) experience limitations in functional capacity and frequently, right ventricular (RV) dysfunction. We sought to characterize RV function in the context of global cardiopulmonary performance during exercise in this population.

METHODS
A total of 26 patients with CF-LVAD (aged 58 ± 11 years, 23 males) completed a hemodynamic assessment with either conductance catheters (Group 1, n = 13) inserted into the right ventricle to generate RV pressure‒volume loops or traditional Swan‒Ganz catheters (Group 2, n = 13) during invasive cardiopulmonary exercise testing. Hemodynamics were collected at rest, 2 sub-maximal levels of exercise, and peak effort. Breath-by-breath gas exchange parameters were collected by indirect calorimetry. Group 1 participants also completed an invasive ramp test during supine rest to determine the impact of varying levels of CF-LVAD support on RV function.

RESULTS
In Group 1, pump speed modulations minimally influenced RV function. During upright exercise, there were modest increases in RV contractility during sub-maximal exercise, but there were no appreciable increases at peak effort. Ventricular‒arterial coupling was preserved throughout the exercise. In Group 2, there were large increases in pulmonary arterial, left-sided filling, and right-sided filling pressures during sub-maximal and peak exercises. Among all participants, the cardiac output‒oxygen uptake relationship was preserved at 5.8:1. Ventilatory efficiency was severely abnormal at 42.3 ± 11.6.

CONCLUSIONS
Patients with CF-LVAD suffer from limited RV contractile reserve; marked elevations in pulmonary, left-sided filling, and right-sided filling pressures during exercise; and severe ventilatory inefficiency. These findings explain mechanisms for persistent reductions in functional capacity in this patient population..
21. Hardin EA, Stoller D, Lawley J, Howden EJ, Hieda M, Pawelczyk J, Jarvis S, Prisk K, Sarma S, Levine BD, Noninvasive Assessment of Cardiac Output: Accuracy and Precision of the Closed-Circuit Acetylene Rebreathing Technique for Cardiac Output Measurement., J Am Heart Assoc, 10.1161/JAHA.120.015794, 9, 17, e015794-e015794, 2020.09.
22. Cramer MN, Hieda M, Huang M, Moralez G, Crandall CG, Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress., Exp Physiol., 10.1113/EP088834, 2020, 1-12, 2020.08.
23. Mantha Y, Harada R, Hieda M, Assaf A, Tatiraju U, Feldman M and Kawalsky D, Masson Tumor in the Left Atrial Appendage Presenting as Cardioembolic Cerebral Infarction., JACC: Case Reports, 10.1016/j.jaccas.2020.05.044, 1-5, 2020.07.
24. Hieda M, Esposito G, Bossone E, Novel Clinical and Pathophysiologic Concepts in Cardiovascular Emergencies., Heart Fail Clin., 10.1016/j.hfc.2020.04.001, 16, 3, XI-XII, 2020.07.
25. Rao P, Katz D, Hieda M, Sabe M, How to Manage Temporary Mechanical Circulatory Support Devices in the Critical Care Setting: Translating Physiology to the Bedside., Heart Fail Clin., 10.1016/j.hfc.2020.03.001, 16, 3, 283-293, 2020.07.
26. Hieda M, Noninvasive Positive Pressure Ventilation for Acute Decompensated Heart Failure., Heart Fail Clin., 10.1016/j.hfc.2020.02.005, 16, 3, 271-282, 2020.07.
27. Hieda M, Goto Y, Cardiac Mechanoenergetics in Patients with Acute Myocardial Infarction: From Pressure-Volume Loop Diagram Related to Cardiac Oxygen Consumption., Heart Fail Clin., 10.1016/j.hfc.2020.02.002, 16, 3, 255-269, 2020.07.
28. Moghadam N, Hieda M, Ramey L, Levine BD, Guilliod R., Hyperbaric Oxygen Therapy in Sports Musculoskeletal Injuries., Med Sci Sports Exerc, 10.1249/MSS.0000000000002257, 52, 6, 1420-1426, 2020.06.
29. Maruyama T, Arita T, Yokoyama T, Hieda M, Fukata M, Fujino T, Mawatari S, Akashi K, Impaired deformability and association with density distribution of erythrocytes in patients with type 2 diabetes mellitus under treatment., Clin Hemorheol Microcirc, 10.3233/CH-200873, 1-11, 2020.05.
30. Hieda M, Esposito G, Bossone E, The Latest Clinical Understandings and Theory of the Cardiovascular Systems for Cardiovascular Emergencies and Their Management., Heart Fail Clin, 10.1016/j.hfc.2020.01.001, 16, 2, Ⅸ-Ⅹ, 2020.04.
31. Mantha Y, Harada R, Hieda M, Management of Common Cardiovascular Emergencies in Critically Ill Patients., Heart Fail Clin, 10.1016/j.hfc.2020.01.001, 16, 2, 153-166, 2020.04.
32. Harada R, Mantha Y, Hieda M, Back to Basics: Key Physical Examinations and Theories in Patients with Heart Failure., Heart Fail Clin, 10.1016/j.hfc.2020.01.001, 16, 2, 139-151, 2020.04.
33. Mantha Y, Feldman M, Assaf A, Harada R, Musselman D, Hieda M, Kawalsky D, Anomalous Origin of Right Coronary Artery from Pulmonary Artery (ARCAPA) in a Middle- Aged Woman., JACC case report, 10.1016/j.jaccas.2020.01.008, 2, 3, 464-467, 2020.03.
34. Mada PK, Malus EM, Parvathaneni A, Chen B, Castano B, Adley B, Moore M, Hieda M, Impact of Treatment with Direct Acting Antiviral Drugs on Glycemic Control in Patients with Hepatitis C and Diabetes Mellitus., Clin Hemorheol Microcirc, 10.1155/2020/6438753., 2020, e1-e6, 2020.01.
35. Hieda M, Satyam S, Hearon Jr. C, Dias K, Martinez J, Samels M, Everding B, Palmer D, Livingston S, Morris M, Howden E, Levine BD, Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection., Circulation, 10.1161/CIRCULATIONAHA.119.040332, 141, 2, 115-123, 2019.12.
36. Hearon Jr. C, Ph.D; Sarma S, Dias K, Hieda M, Levine DB, Impaired oxygen uptake kinetics in heart failure with preserved ejection fraction., Heart, 10.1136/heartjnl-2019-314797, 105, 20, 1552-1558, 2019.10.
37. Aiad N, Hearon C, Hieda M, Dias K; Levine DB, and Sarma S, Mechanisms of Left Atrial Enlargement in Obesity - The Influence of Left Ventricular Remodeling., American Journal of Cardiology, 10.1016/j.amjcard.2019.04.043, 124, 3, 442-447, 2019.08.
38. Hieda M, Yoo JK, Badrov BM, Parker SR, Anderson HE, Wiblin LJ, Kawalsky J, North SC, Suris A, and Fu Q, Reduced Left Ventricular Diastolic Function in Women with Post-Traumatic Stress Disorder., American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 10.1152/ajpregu.00002.2019, 317, 1, 108-112, 2019.07.
39. McNamara DA, Aiad N, Howden E, Hieda M, Link MS, Everding B, Palmer D, Samels M, Ng J, Adams-Huet B, Mildred O, Sarma S, and Levine BD, Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults., Circulation, 10.1161/CIRCULATIONAHA.118.037615, 139, 12, 1507-1516, 2019.03.
40. Samuel TJ, Nelson MD, Nasirian A, Jaffery M, Moralez G, Romero SA, Cramer MN, Huang M, Kouda K, Hieda M, Sarma S and Crandall CG, Cardiac Structure and Function in Well-Healed Burn Survivors., Journal of Burn Care & Research, 10.1093/jbcr/irz008, 40, 2, 235-241, 2019.02.
41. Badrov BM, Park S, Yoo JK, Hieda M, Okada Y, Jarvis SS, Stickford AS, Best SA, Nelson DB, and Fu Q, MD, Role of Corin in blood pressure regulation in normotensive and hypertensive pregnancy: a prospective study., Hypertension, 10.1161/HYPERTENSIONAHA.118.12137, 73, 2, 432-439, 2019.02.
42. Hieda M, Howden E, Sarma S, Cornwell W, Lawley J, Tarumi T, Palmer D, Samels M, Everding B, Livingston S, Fu Q, Zhang R, and Levine BD, The Impact of 2-Years of High Intensity Exercise Training on a Model of Integrated Cardiovascular Regulation., Journal of Physiology, 10.1113/JP276676, 597, 2, 419-429, 2019.01, KEY POINTS: Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non-neural control mechanisms may contribute to changes in heart rate variability. We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high-intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. The dynamic Starling mechanism gain and arterial-cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34-fold larger than that in the control group after the intervention. In these previously sedentary, otherwise healthy, middle-aged adults, 2 years of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity. ABSTRACT: Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel-group, randomized controlled study, we examined the effect of 2 years of high-intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. Sixty-one healthy participants (48% male, aged 53 years, range 52-54 years) were randomized to either 2 years of exercise training (exercise group: n = 34) or control/yoga group (controls: n = 27). Before and after 2 years, subjects underwent a 6 min recording of beat-by-beat pulmonary artery diastolic pressure (PAD), stroke volume index (SV index), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2 Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function were calculated by transfer function gain between PAD and SV index; SV index and sBP; and sBP and RR interval, respectively. Fifty-three participants (controls: n = 25; exercise group: n = 28) completed the intervention. After 2 years, the dynamic Starling mechanism gain (Group × Time interaction: P = 0.008) and the arterial-cardiac baroreflex gain (P = 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34-fold, whereas there was no change in the controls (P = 0.02). In these previously sedentary, otherwise healthy middle-aged adults, a 2 year programme of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity, without changing dynamic arterial elastance..
43. Hieda M, Howden E, Shibata S, Fujimoto N, Bhella PS, Hastings JL, Tarumi T, Satyam S, Fu Q, Zhang R, Levine BD, Impact of Lifelong Exercise Training Dose on Ventricular-Arterial Coupling., Circulation, 10.1161/CIRCULATIONAHA.118.035116, 138, 23, 2638-2647, 2018.12, BACKGROUND: The dynamic Starling mechanism, as assessed by beat-by-beat changes in stroke volume and left ventricular end-diastolic pressure, reflects ventricular-arterial coupling. It deteriorates with age, and is preserved in highly trained masters athletes. Currently, it remains unclear how much exercise over a lifetime is necessary to preserve efficient ventricular-arterial coupling. The purpose of this study was to assess the dose-dependent relationship between lifelong exercise training and the dynamic Starling mechanism in healthy seniors. METHODS: One hundred two seniors were recruited and stratified into 4 groups based on 25 years of exercise training history: sedentary subjects (n=27,
44. Hieda M, Yoo JK, Sun D, Okada Y, Parker R, Roberts-Reeves M, Adams-Huet B, Nelson D, Levine DB, and Fu Q, Time Course of Changes in Maternal Left Ventricular Function during Subsequent Pregnancy in Women with a History of Gestational Hypertensive Disorders., American Journal of Physiology-Regulatory, Integrativeand and Comparative Physiology, 10.1152/ajpregu.00040.2018, 315, 4, 587-594, 2018.10.
45. Opondo MA, Aiad N, Cain MA, Sarma S, Howden E, Stoller DA, Ng J, van Rijckevorsel P, Hieda M, Tarumi T, Palmer MD, Levine BD, Does High Intensity Endurance Training Increase the Risk of Atrial Fibrillation? A Longitudinal Study of Left Atrial Structure and Function., Circulation: Arrhythmia and Electrophysiology, 10.1161/CIRCEP.117.005598., 11, 5, e005598, 2018.05, BACKGROUND: Exercise mitigates many cardiovascular risk factors associated with atrial fibrillation. Endurance training has been associated with atrial structural changes which can increase the risk for atrial fibrillation. The dose of exercise training required for these changes is uncertain. We sought to evaluate the impact of exercise on left atrial (LA) mechanical and electrical function in healthy, sedentary, middle-aged adults. METHODS: Sixty-one adults (52±5 years) were randomized to either 10 months of high-intensity exercise training or yoga. At baseline and post-training, all participants underwent maximal exercise stress testing to assess cardiorespiratory fitness, P-wave signal-averaged electrocardiography for filtered P-wave duration and atrial late potentials (root mean square voltage of the last 20 ms), and echocardiography for LA volume, left ventricular end-diastolic volume, and mitral inflow for assessment of LA active emptying. Post-training data were compared with 14 healthy age-matched Masters athletes. RESULTS: LA volume, Vo2 max, and left ventricular end-diastolic volume increased in the exercise group (15%, 17%, and 16%, respectively) with no change in control (P
46. Yoo JK, Okada Y, Best SA, Parker RS, Hieda M, Levine BD, Fu Q, Left ventricular remodeling and arterial afterload in older women with uncontrolled and controlled hypertension., Menopause, 10.1097/GME.0000000000001046, 25, 5, 554-562, 2018.05.
47. Hieda M, Parker J, Rajabi T, Fujimoto N, Bhella PS, Prasad A, Hastings JL, Sarma S, Levine BD, Left Ventricular Volume-Time Relation in Patients With Heart Failure With Preserved Ejection Fraction., Am J Cardiol, 10.1016/j.amjcard.2017.11.033, 121, 5, 609-614, 2018.03.
48. Howden E, Carrick-Ranson G, Sarma S, Hieda M, Fujimoto N, Benjamin D. Levine, Effect of Sedentary Aging and Lifelong Exercise on Left Ventricular Systolic Function., Medicine & Science in Sports & Exercise, 10.1249/MSS.0000000000001464, 50, 3, 494-501, 2018.03.
49. Hieda M; Howden E; Shibata S; Tarumi T; Lawley J; Hearon C Jr.; Palmer D; Fu Q; Zhang R; Sarma S; Benjamin D. Levine, Pre-load Corrected Dynamic Starling Mechanism in Patients with Heart Failure with Preserved Ejection Fraction., Journal of Applied Physiology, 10.1152/japplphysiol.00718.2017, 124, 1, 76-82, 2018.01, The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume (SV) because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. The purpose of this study was to test whether the LVEDP-SV relationship remained impaired in heart failure with preserved ejection fraction (HFpEF) patients after normalization of LVEDP. Right heart catheterization and model-flow analysis of the arterial pressure waveform were performed while preload was manipulated using lower-body negative pressure to alter LVEDP. The DSM was compared at similar levels of LVEDP between HFpEF patients ( n = 10) and age-matched healthy controls ( n = 12) (HFpEF vs. CONTROLS: 10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m-2·mmHg-1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction..
50. Ogoh S, Moralez G, Washio T, Sarma S, Hieda M, Romero S, Cramer M, Shibasaki M, and Crandall C, Effect of increases in cardiac contractility on cerebral blood flow in humans., American Journal of Physiology Heart and Circulatory Physiology, 10.1152/ajpheart.00287.2017, 313, 6, H1155-H1161, 2017.12, The effect of acute increases in cardiac contractility on cerebral blood flow (CBF) remains unknown. We hypothesized that the external carotid artery (ECA) downstream vasculature modifies the direct influence of acute increases in heart rate and cardiac function on CBF regulation. Twelve healthy subjects received two infusions of dobutamine [first a low dose (5 μg·kg−1·min−1) and then a high dose (15 μg·kg−1·min−1)] for 12 min each. Cardiac output, blood flow through the internal carotid artery (ICA) and ECA, and echocardiographic measurements were performed during dobutamine infusions. Despite increases in cardiac contractility, cardiac output, and arterial pressure with dobutamine, ICA blood flow and conductance slightly decreased from resting baseline during both low- and high-dose infusions. In contrast, ECA blood flow and conductance increased appreciably during both low- and high-dose infusions. Greater ECA vascular conductance and corresponding increases in blood flow may protect overperfusion of intracranial cerebral arteries during enhanced cardiac contractility and associated increases in cardiac output and perfusion pressure. Importantly, these findings suggest that the acute increase of blood perfusion attributable to dobutamine administration does not cause cerebral overperfusion or an associated risk of cerebral vascular damage.

NEW & NOTEWORTHY A dobutamine-induced increase in cardiac contractility did not increase internal carotid artery blood flow despite an increase in cardiac output and arterial blood pressure. In contrast, external carotid artery blood flow and conductance increased. This external cerebral blood flow response may assist with protecting from overperfusion of intracranial blood flow..
51. Watanabe T, Seguchi O, Nishimura K, Fujita T, Murata Y, Yanase M, Sato T, Sunami H, Nakajima S, Hisamatsu E, Sato T, Kuroda K, Hieda M, Wada K, Hata H, Ishibashi-Ueda H, Miyamoto Y, Fukushima N, Kobayashi J, Nakatani T, Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients., Int J Cardiol, 10.1016/j.ijcard.2015.10.082, 203, 307-314, 2016.06.
52. Hieda M, Seguchi O, Mutara Y, Sunami H, Sato T, Yanase M, Hiroki H, Fujita T, Nakatani T, Acute response test to adaptive servo-ventilation, a possible modality to assessing the reversibility of pulmonary vascular resistance., J Artif Organs, 10.1007/s10047-015-0833-1, 18, 3, 280-283, 2015.09.
53. Hieda M, Sata M, Nakatani T, The Importance of the Management of Infectious Complications for Patients with Left Ventricular Assist Device., Healthcare, 10.3390/healthcare3030750, 3, 3, 750-756, 2015.08.
54. Sato T, Seguchi O, Iwashima Y, Yanase M, Nakajima S, Hieda M, Watanabe T, Sunami H, Murata Y, Hata H, Fujita T, Kobayashi J, Nakatani T, Serum Brain Natriuretic Peptide Concentration 60 Days after Surgery as a Predictor of Long-term Prognosis in Patients Implanted with a Left Ventricular Assist Device., ASAIO J, 10.1097/MAT.0000000000000237, 61, 4, 373-378, 2015.07.
55. Nakajima S, Seguchi O, Murata Y, Fujita T, Hata H, Yamane T, Hieda ;, Watanabe T, Sato T, Sunami H, Yanase M, Kobayashi J, Nakatani T, Left coronary artery occlusion caused by a large thrombus on the left coronary cusp in a patient with a continuous-flow ventricular assist device., J Artif Organs, 10.1007/s10047-014-0758-0, 17, 2, 197-201, 2014.06.
56. Hieda M, Sata M, Seguchi O, Yanase M, Murata Y, Sato T, Sunami H, Nakajima S, Watanabe T, Hori Y, Wada K, Hata H, Fujita T, Kobayashi J, Nakatani T, Importance of Early Appropriate Intervention including Antibiotics and Wound care for Device-related Infection in Patients with Left Ventricular Assist Device., Transplant Proc, 10.1016/j.transproceed.2013.11.106, 46, 3, 907-910, 2014.04.
57. Suwa H, Seguchi O, Fujita T, Murata Y, Hieda M, Watanabe T, Sato T, Sunami H, Yanase M, Hata H, Nakatani T, Paracorporeal ventricular assist device as a bridge to transplant candidacy in the era of implantable continuous-flow ventricular assist device., J Artif Organs, 10.1007/s10047-013-0731-3, 17, 1, 16-22, 2014.03.
58. Sato T, Seguchi O, Morikawa N, Hieda M, Watanabe T, Sunami H, Murata Y, Yanase M, Hata H, Fujita T, Nakatani T, A heart transplant candidate with severe pulmonary hypertension and extremely high pulmonary vascular resistance., J Artif Organs, 10.1007/s10047-013-0695-3, 16, 2, 253-257, 2013.06.
59. Kongphanich A, Hieda M, Kurokawa K, Murata T, Kobayashi N, Overcoming the blockade at the upstream of caspase cascade in Fas-resistant HTLV-I-infected T cells by cycloheximide., Biochem Biophys Res Commun, 10.1016/S0006-291X(02)00531-4, 294, 3, 714-718, 2002.06.


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