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Positive Airway Pressure in HFpEF Patients With Sleep-Disordered Breathing
The 20th Annual Scientific Meeting
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JHFS
S161
Panel Discussion PD1-6
PD3-2
Positive Airway Pressure in HFpEF Patients With Sleep-Disordered Breathing Akiomi Yoshihisa, Tetsuro Yokokawa, Satoshi Suzuki, Yasuchika Takeisi; The Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
The Role of AMP Deaminase in Diabetic Cardiomyopathy and Its Regulatory Mechanisms: A Potential Novel Therapeutic Target Masaya Tanno, Hidemichi Kouzu, Yuki Tatekoshi, Tetsuji Miura; Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Backgrounds: Since effective pharmacotherapy for HFpEF is still unclear, management of co-morbidities such as sleep disordered breathing (SDB) may have the impact in HFpEF. We aimed to clarify whether SDB treatment using positive airway pressure (PAP) improves right heart function, pulmonary function, exercise capacity and prognosis in HFpEF patients. Methods and Results: Consecutive 116 patients with HFpEF and moderate–severe SDB (apnea hypopnea index >15/h) were divided into two groups: 36 patients with PAP (PAP group) and 80 patients without PAP (nonPAP group). Right ventricular fractional area change (RV-FAC), tricuspid valve regurgitation pressure gradient (TR-PG), tricuspid E/e, forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), percentage of vital capacity, and peak VO2 were determined before and 6 months later, and all-cause mortality was followed up for 902 days. All parameters improved in the PAP group (RV-FAC: 37.2 to 45.2%; TR-PG: 32.0 to 21.2 mmHg; tricuspid E/e: 8.2 to 5.1; FEV1/FVC: 84.0 to 89.6%; percentage of vital capacity: 84.1 to 88.6%; and peak VO2: 16.8 to 19.3 ml/kg/min; P < .05, respectively), but not in the non-PAP group. Importantly, all-cause mortality was significantly lower in the PAP group than in the non-PAP group (5.6% vs 15.0%, log-rank P = .032). Conclusion: PAP improved right heart function, pulmonary function and exercise capacity and reduced all-cause mortality in patients with HFpEF and SDB.
PD2-2 Quantitative Assessments of Fluid Accumulation in Patients With Acute Decompensated Heart Failure Taiki Sakaguchi1, Tomohito Ohtani1, Yasushi Sakata1, Yoshio Yasumura2; 1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan; 2Cardiovascular Division, Osaka Police Hospital, Osaka, Japan Introduction: Fluid volume overload is generally considered to be a representative condition of right heart failure, and accurately quantifying the body fluid status is of critical importance in assessing whether adequate decongestion has been achieved. We have previously reported a method to quantify the degree of extracellular fluid volume (ECV) accumulation using bioelectrical impedance analysis and its prognostic implications in patients with acute decompensated heart failure (ADHF). Central venous pressure (CVP) is also used as a surrogate measure of venous congestion and body fluid status. Purpose: To assess the relationship between these quantitative assessments of fluid accumulation in ADHF patients. Methods and Results: We measured ECV and CVP in 100 ADHF patients. Although a positive correlation was observed between CVP and ECV status among new-onset patients, this relationship was not observed among repeater patients. Conclusions: CVP in patients with repeat ADHF hospitalizations was not solely determined by the degree of fluid accumulation. It should be determined by not only whole body fluid volume and volume distribution in the blood vessels, but also right ventricular function. Our findings suggest that body fluid management that is guided by CVP alone is inadequate for repeater ADHF patients.
PD2-5 Impact of Right Heart Failure on Liver—Is It a Functional or Organic Change? Tomohito Ohtani1, Kei Nakamoto1, Yoshiki Sakata2, Yasushi Sakata1; 1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 2 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan Hepatic congestion due to elevated right-sided cardiac pressure is often observed in patients with advanced heart failure (HF). They also have liver dysfunction represented as liver function test abnormalities. However, it is difficult to assess whether these abnormalities are based on reversible or irreversible organ change. To examine the reversibility of liver, we analyzed laboratory data in 44 patients with advanced HF before and after (3 month) the implantation of left ventricular assist device (LVAD), which can improve hemodynamics, and assessed pathological findings in 7 autopsy cases with advanced HF (duration of HF 8.6 ± 4.2 years). Total bilirubin (T-bil) level were improved after LVAD implantation (from 1.2 ± 1.0 to 0.9 ± 0.5 mg/dL). Even in the patients with T-bil more than 1.5 mg/dL (1.6–5.5 mg/dL) before LVAD implantation, T-bil level decreased to less than 1.5 mg/dL (0.5–1.1 mg/dL) after LVAD support. Although increased T-bil level in autopsy cases was associated with the increased liver weight, severe fibrotic change was not observed. These data suggested that liver damage due to right heart failure is likely to be reversible to some extent even in advanced HF.
AMP deaminase (AMPD) depletes nucleotide pool and ATP by catalyzing conversion of AMP to IMP. ATP depletion may preferably induce diastolic dysfunction rather than systolic dysfunction because energy demand for SERCA is higher than that for actomyosin ATPase. We recently demonstrated that AMPD activity was increased and ATP was subsequently depleted in a rat model of diabetes. In the diabetic hearts, pressurevolume loop analysis showed that impaired relaxation was manifested by pressure overloading. ATP level was negatively correlated with Tau and LVEDP, indicating that ATP depletion is responsible for the diastolic dysfunction. Thus, AMPD is a promising therapeutic target for diabetic cardiomyopathy and this notion led us to investigate underlying mechanisms of the increased activity of AMPD. Metabolomic analysis showed that fructose 1,6-diphosphate (F1,6P) level was decreased in diabetic hearts due to decreased phosphofructokinase 1 (PFK1) activity. In vitro addition of F1,6P to LV tissue lysates reduced AMPD activity, veryfing that AMPD activity depends on the F1,6P level. Two-dimensional gel electrophoresis using anti-AMPD immunoprecipitates of LV tissue and MALDI-TOF/MS analysis revealed that interaction of phosphoglucomutase-1 (PGM1) with AMPD were significantly reduced in diabetic hearts. Here, we will discuss the mechanisms by which reduced AMPD-PGM1 interaction modifies activity of PFK1 and AMPD, to gain insight into how AMPD could be targeted for treatment of diabetic cardiomyopathy.
•
JHFS
S161
Panel Discussion PD1-6
PD3-2
Positive Airway Pressure in HFpEF Patients With Sleep-Disordered Breathing Akiomi Yoshihisa, Tetsuro Yokokawa, Satoshi Suzuki, Yasuchika Takeisi; The Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
The Role of AMP Deaminase in Diabetic Cardiomyopathy and Its Regulatory Mechanisms: A Potential Novel Therapeutic Target Masaya Tanno, Hidemichi Kouzu, Yuki Tatekoshi, Tetsuji Miura; Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Backgrounds: Since effective pharmacotherapy for HFpEF is still unclear, management of co-morbidities such as sleep disordered breathing (SDB) may have the impact in HFpEF. We aimed to clarify whether SDB treatment using positive airway pressure (PAP) improves right heart function, pulmonary function, exercise capacity and prognosis in HFpEF patients. Methods and Results: Consecutive 116 patients with HFpEF and moderate–severe SDB (apnea hypopnea index >15/h) were divided into two groups: 36 patients with PAP (PAP group) and 80 patients without PAP (nonPAP group). Right ventricular fractional area change (RV-FAC), tricuspid valve regurgitation pressure gradient (TR-PG), tricuspid E/e, forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), percentage of vital capacity, and peak VO2 were determined before and 6 months later, and all-cause mortality was followed up for 902 days. All parameters improved in the PAP group (RV-FAC: 37.2 to 45.2%; TR-PG: 32.0 to 21.2 mmHg; tricuspid E/e: 8.2 to 5.1; FEV1/FVC: 84.0 to 89.6%; percentage of vital capacity: 84.1 to 88.6%; and peak VO2: 16.8 to 19.3 ml/kg/min; P < .05, respectively), but not in the non-PAP group. Importantly, all-cause mortality was significantly lower in the PAP group than in the non-PAP group (5.6% vs 15.0%, log-rank P = .032). Conclusion: PAP improved right heart function, pulmonary function and exercise capacity and reduced all-cause mortality in patients with HFpEF and SDB.
PD2-2 Quantitative Assessments of Fluid Accumulation in Patients With Acute Decompensated Heart Failure Taiki Sakaguchi1, Tomohito Ohtani1, Yasushi Sakata1, Yoshio Yasumura2; 1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan; 2Cardiovascular Division, Osaka Police Hospital, Osaka, Japan Introduction: Fluid volume overload is generally considered to be a representative condition of right heart failure, and accurately quantifying the body fluid status is of critical importance in assessing whether adequate decongestion has been achieved. We have previously reported a method to quantify the degree of extracellular fluid volume (ECV) accumulation using bioelectrical impedance analysis and its prognostic implications in patients with acute decompensated heart failure (ADHF). Central venous pressure (CVP) is also used as a surrogate measure of venous congestion and body fluid status. Purpose: To assess the relationship between these quantitative assessments of fluid accumulation in ADHF patients. Methods and Results: We measured ECV and CVP in 100 ADHF patients. Although a positive correlation was observed between CVP and ECV status among new-onset patients, this relationship was not observed among repeater patients. Conclusions: CVP in patients with repeat ADHF hospitalizations was not solely determined by the degree of fluid accumulation. It should be determined by not only whole body fluid volume and volume distribution in the blood vessels, but also right ventricular function. Our findings suggest that body fluid management that is guided by CVP alone is inadequate for repeater ADHF patients.
PD2-5 Impact of Right Heart Failure on Liver—Is It a Functional or Organic Change? Tomohito Ohtani1, Kei Nakamoto1, Yoshiki Sakata2, Yasushi Sakata1; 1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 2 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan Hepatic congestion due to elevated right-sided cardiac pressure is often observed in patients with advanced heart failure (HF). They also have liver dysfunction represented as liver function test abnormalities. However, it is difficult to assess whether these abnormalities are based on reversible or irreversible organ change. To examine the reversibility of liver, we analyzed laboratory data in 44 patients with advanced HF before and after (3 month) the implantation of left ventricular assist device (LVAD), which can improve hemodynamics, and assessed pathological findings in 7 autopsy cases with advanced HF (duration of HF 8.6 ± 4.2 years). Total bilirubin (T-bil) level were improved after LVAD implantation (from 1.2 ± 1.0 to 0.9 ± 0.5 mg/dL). Even in the patients with T-bil more than 1.5 mg/dL (1.6–5.5 mg/dL) before LVAD implantation, T-bil level decreased to less than 1.5 mg/dL (0.5–1.1 mg/dL) after LVAD support. Although increased T-bil level in autopsy cases was associated with the increased liver weight, severe fibrotic change was not observed. These data suggested that liver damage due to right heart failure is likely to be reversible to some extent even in advanced HF.
AMP deaminase (AMPD) depletes nucleotide pool and ATP by catalyzing conversion of AMP to IMP. ATP depletion may preferably induce diastolic dysfunction rather than systolic dysfunction because energy demand for SERCA is higher than that for actomyosin ATPase. We recently demonstrated that AMPD activity was increased and ATP was subsequently depleted in a rat model of diabetes. In the diabetic hearts, pressurevolume loop analysis showed that impaired relaxation was manifested by pressure overloading. ATP level was negatively correlated with Tau and LVEDP, indicating that ATP depletion is responsible for the diastolic dysfunction. Thus, AMPD is a promising therapeutic target for diabetic cardiomyopathy and this notion led us to investigate underlying mechanisms of the increased activity of AMPD. Metabolomic analysis showed that fructose 1,6-diphosphate (F1,6P) level was decreased in diabetic hearts due to decreased phosphofructokinase 1 (PFK1) activity. In vitro addition of F1,6P to LV tissue lysates reduced AMPD activity, veryfing that AMPD activity depends on the F1,6P level. Two-dimensional gel electrophoresis using anti-AMPD immunoprecipitates of LV tissue and MALDI-TOF/MS analysis revealed that interaction of phosphoglucomutase-1 (PGM1) with AMPD were significantly reduced in diabetic hearts. Here, we will discuss the mechanisms by which reduced AMPD-PGM1 interaction modifies activity of PFK1 and AMPD, to gain insight into how AMPD could be targeted for treatment of diabetic cardiomyopathy.