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Impact of Heart Failure Etiology on Ventricular Unloading in Patients Supported with Left Ventricular Assist Devices (LVADs)
The 21st Annual Scientific Meeting
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HFSA
S39
Cardiovascular Physiology 097 Decrease Uniplex Activity Rescue Enegetics and Inhibits Apoptosis in the Falling Heart Gerardo García-Rivas1, Yuriana Oropeza-Almazan1, Héctor Chapoy-Villanueva1, Keith A. Youker2, Guillermo Torre-Amione1; 1Tecnologico de Monterrey, Monterrey, Mexico; 2 Methodist Hospital, Houston, Texas Impairment of intracellular Ca2+ homeostasis and bioenergetics are prominent features of heart failure (HF), but the underlying metabolic perturbations are poorly understood. Intramitochondrial Ca2+ is a key factor in high-energy demand conditions, since it can activate energy metabolism. Mitochondria Ca2+ transport is mediated by the Uniplex; however, insight was limited by the complete absence of this molecular understanding. This situation has changed recently, and new perspectives have been opened by the molecular identification of the Uniplex. Along this line, we evaluated the effect of silencing Uniplex with an aim to determine the role of MCU in HF progression. We evaluated the effect of lipid nanovector with siRNA-targeting Uniplex (MCU-subunit) (NV) in mice in vivo to decrease MCU expression in heart. Additionally, we measured the expression of the Uniplex in failing human left ventricular tissue (HF) obtained at the time of orthotopic heart transplantation or left ventricular assist device insertion and compared them to non-failing left ventricular wall samples obtained from explanted hearts of patients with pulmonary hypertension. In the murine model of HF, we determined ventricular function and remodeling, mitochondrial dysfunction, energetics and cell viability using flow cytometry. First, mice treated with NV demonstrated a reduction of Uniplex expression by 30%, which resulted in significant decrease in mitochondrial Ca2+ transport. NV-treated animals showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca2+ overload. Furthermore, after HF MCU silencing decreased necrosis and apoptosis levels was observed. The expression of MCU increased 3,5 times in HF compared with nonfailing left ventricular samples (P = 0,001). In addition, the mitochondrial protein MICU1 which interacts with the uniporter pore-forming subunit Uniplex increased 1,9 times (P = 0,004). The levels of both proteins showed a sustained ratio with positive correlation (r = 0,747 P = 0,003) and this could indicate the existence of a controlled coexpression mechanism during HF. Overexpression of Uniplex could facilitate mitochondrial Ca2+ overload in HF thus making the organelle more sensitive to apoptosis.
098 Mitochondrial Hyperacetylation Contributes with Ventricular Dysfunction as Consequence of SIRT3 Deficiency in Obesity and Metabolic Syndrome Jose Morales, Elena C. Castillo, Christian Silva-Platas, Guillermo Torre-Amione, Keith A. Youker, Gerardo García-Rivas; Tecnologico de Monterrey, Monterrey, Mexico Cyclophilin D (CypD) mediates mitochondrial permeability transition pore (mPTP) opening, which contributes with mitochondrial dysfunction. CypD function is regulated by its acetylation state that depends on GCN5L1 acetyltransferase and SIRT3 deacetylate activity. Since obese rats with obesity and metabolic syndrome (MS) decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular impairment and heart failure. Male rats with obesity and MS showed diastolic dysfunction and a 34% phosphocreatine reduction. Accordingly, mitochondrial from these animals was 2.5-fold prone to mPTP opening compared with controls. SIRT3 mitochondrial expression decreased 22%, concomitantly with hyperacetylated mitochondrial profile including CypD. Additionally, SIRT3 expression from human biopsies for falling hearts showed 70% decrease expression level in obese patients in comparison to non-obese patients. The hyperacetlylation profiles correlates with Body Mass Index, ventricular dysfunction and cardiac remodeling in patients with end-state of HF. Our results indicate that obesity and MS reduces SIRT3 expression and that CypD hyperacetylation increase the mPTP opening, suggesting that activation of SIRT3 might be a potential target for ventricular dysfunction and heart failure.
099 Gender’s Effect on Hemodynamic Unloading and Readmissions in Patients Supported with Left Ventricular Assist Devices (LVADs) David M. Tehrani, Nitasha Sarswat, Daniel Rodgers, Adam Vohra, Sirtaz Adatya, Gene H. Kim, Jayant Raikhelkar, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel; University of Chicago, Chicago, Illinois Purpose: LVADs are a mainstay of therapy for advanced heart failure; however, the physiologic effects of LVADs in gender is unknown. We aim to evaluate the hemodynamic/echocardiographic affects of LVADs and subsequent readmissions after ramp testing in females. Methods: In this prospective study, consecutive patients undergoing hemodynamic/echocardiographic ramp testing were enrolled. Data was collected at baseline and incremental speed changes during ramp testing. Demographics, as well as hemodynamic/echocardiographic characteristics were compared between males and females. Readmission rates were reported per patient years of follow-up and compared with the Wilcoxon Rank Sum test. Additional readmission rate stratification was done based on post-ramp optimal filling pressures (defined as CVP ≤12 and PCWP
≤18 mmHg). Results: Among 65 enrolled patients, 25 females (38.5%) were identified. No significant difference in LVAD type or baseline hemodynamic/echocardiographic characteristics were found. During ramp test, left ventricular end-diastolic diameter (LVEDD) decreased more in the female group, which persisted when limiting to those with HeartMate 2 devices only (N = 43) [LVEDD slope: -0.26 (0.14) vs -0.15 (0.08), P < .01], but significance was lost after adjusting for BSA. All other hemodynamic/ echocardiographic responses to speed change were similar. Over a mean follow-up of 353 ± 168 days, no significant difference was noted for rates of total (2.17 ± 1.82 vs 1.96 ± 2.46 admissions/patient-year, P = .36) or heart failure (0.17 ± 0.35 vs 0.14 ± 0.31 admissions/patient-year, P = .36) readmissions for females vs males. There was no significant difference in the percentage of patients who achieved optimal filling pressures after speed optimization. In the subgroup with post-ramp optimal filling pressures, no significant difference was seen for rates of total (2.08 ± 1.65 vs 1.69 ± 2.22 admissions/ patient-year, P = .24) or heart failure (0.17 ± 0.33 vs 0.07 ± 0.24 admissions/patientyear, P = .51) readmissions for females vs males. Conclusion: Female patients implanted with LVAD have similar unloading characteristics as males. Female gender is not associated with a difference in readmission rate after ramp testing as compared to men, even among those with optimal filling pressures.
100 Impact of Heart Failure Etiology on Ventricular Unloading in Patients Supported with Left Ventricular Assist Devices (LVADs) David M. Tehrani, Daniel Rodgers, Sirtaz Adatya, Nitasha Sarswat, Gene H. Kim, Jayant Raikhelkar, Takeyoshi Ota, Takeyoshi Ota, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel; University of Chicago, Chicago, Illinois Purpose: LVADs are a mainstay of therapy for advanced heart failure for both those with non-ischemic and ischemic cardiomyopathy (CM). However, the hemodynamic and echocardiographic response to LVADs based on CM etiology is unknown. We aim to compare the hemodynamic/echocardiographic affects of LVADs in those with nonischemic vs ischemic CM. Methods: In this prospective study, patients undergoing hemodynamic/echocardiographic ramp testing were enrolled. Data was collected at baseline and incremental speed changes during ramp testing. Demographics, as well as hemodynamic/echocardiographic characteristics were compared between patients with ischemic and non-ischemic etiologies. Chi square analysis was used for categorical values and Wilcoxon rank sum test was used for continuous variables. Linear regression analysis was used to evaluate unloading slopes across LVAD ramp speed changes. Results: Among 65 included patients, 28 patients (43.1%) had an ischemic cardiomyopathy. Those with ischemic CM were older than those with non-ischemic CM (65.0 ± 7.3 vs 55.9 ± 12.0 years, P < .01). All other demographics including gender, device type, and history of arrhythmias were not significantly different between groups. CVP was found to be significantly higher in those with non-ischemic vs ischemic CM at baseline speed (10.3 ± 5.7 vs 7.7 ± 4.2 mmHg, P = .04) and set-speed (10.2 ± 5.8 vs 7.0 ± 4.2 mmHg, P = .02). No additional differences in hemodynamic or echocardiographic parameters were found at baseline or set-speed speed were found based on CM etiology. During the ramp study, there was no significant difference in hemodynamic or echocardiographic unloading slopes between those with ischemic vs non-ischemic cardiomyopathy (Table). However, a trend for more rapid off-loading was seen in the non-ischemic CM group for central venous pressure slope (-0.29 ± 0.24 vs -0.17 ± 0.29, P = .07) and pulmonary artery saturation slope (1.33 ± 0.77 vs 0.96 ± 0.83, P = .07) as compared to the ischemic CM group. Conclusion: As evaluated by invasive hemodynamics and echocardiography, non-ischemic CM patients had higher CVP compared to ischemic CM, however all other echocardiographic and hemodynamics characteristics were similar. No clear relationship was found between CM etiology and a patient’s response to acute speed change during hemodynamic/echocardiographic ramp testing.
•
HFSA
S39
Cardiovascular Physiology 097 Decrease Uniplex Activity Rescue Enegetics and Inhibits Apoptosis in the Falling Heart Gerardo García-Rivas1, Yuriana Oropeza-Almazan1, Héctor Chapoy-Villanueva1, Keith A. Youker2, Guillermo Torre-Amione1; 1Tecnologico de Monterrey, Monterrey, Mexico; 2 Methodist Hospital, Houston, Texas Impairment of intracellular Ca2+ homeostasis and bioenergetics are prominent features of heart failure (HF), but the underlying metabolic perturbations are poorly understood. Intramitochondrial Ca2+ is a key factor in high-energy demand conditions, since it can activate energy metabolism. Mitochondria Ca2+ transport is mediated by the Uniplex; however, insight was limited by the complete absence of this molecular understanding. This situation has changed recently, and new perspectives have been opened by the molecular identification of the Uniplex. Along this line, we evaluated the effect of silencing Uniplex with an aim to determine the role of MCU in HF progression. We evaluated the effect of lipid nanovector with siRNA-targeting Uniplex (MCU-subunit) (NV) in mice in vivo to decrease MCU expression in heart. Additionally, we measured the expression of the Uniplex in failing human left ventricular tissue (HF) obtained at the time of orthotopic heart transplantation or left ventricular assist device insertion and compared them to non-failing left ventricular wall samples obtained from explanted hearts of patients with pulmonary hypertension. In the murine model of HF, we determined ventricular function and remodeling, mitochondrial dysfunction, energetics and cell viability using flow cytometry. First, mice treated with NV demonstrated a reduction of Uniplex expression by 30%, which resulted in significant decrease in mitochondrial Ca2+ transport. NV-treated animals showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca2+ overload. Furthermore, after HF MCU silencing decreased necrosis and apoptosis levels was observed. The expression of MCU increased 3,5 times in HF compared with nonfailing left ventricular samples (P = 0,001). In addition, the mitochondrial protein MICU1 which interacts with the uniporter pore-forming subunit Uniplex increased 1,9 times (P = 0,004). The levels of both proteins showed a sustained ratio with positive correlation (r = 0,747 P = 0,003) and this could indicate the existence of a controlled coexpression mechanism during HF. Overexpression of Uniplex could facilitate mitochondrial Ca2+ overload in HF thus making the organelle more sensitive to apoptosis.
098 Mitochondrial Hyperacetylation Contributes with Ventricular Dysfunction as Consequence of SIRT3 Deficiency in Obesity and Metabolic Syndrome Jose Morales, Elena C. Castillo, Christian Silva-Platas, Guillermo Torre-Amione, Keith A. Youker, Gerardo García-Rivas; Tecnologico de Monterrey, Monterrey, Mexico Cyclophilin D (CypD) mediates mitochondrial permeability transition pore (mPTP) opening, which contributes with mitochondrial dysfunction. CypD function is regulated by its acetylation state that depends on GCN5L1 acetyltransferase and SIRT3 deacetylate activity. Since obese rats with obesity and metabolic syndrome (MS) decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular impairment and heart failure. Male rats with obesity and MS showed diastolic dysfunction and a 34% phosphocreatine reduction. Accordingly, mitochondrial from these animals was 2.5-fold prone to mPTP opening compared with controls. SIRT3 mitochondrial expression decreased 22%, concomitantly with hyperacetylated mitochondrial profile including CypD. Additionally, SIRT3 expression from human biopsies for falling hearts showed 70% decrease expression level in obese patients in comparison to non-obese patients. The hyperacetlylation profiles correlates with Body Mass Index, ventricular dysfunction and cardiac remodeling in patients with end-state of HF. Our results indicate that obesity and MS reduces SIRT3 expression and that CypD hyperacetylation increase the mPTP opening, suggesting that activation of SIRT3 might be a potential target for ventricular dysfunction and heart failure.
099 Gender’s Effect on Hemodynamic Unloading and Readmissions in Patients Supported with Left Ventricular Assist Devices (LVADs) David M. Tehrani, Nitasha Sarswat, Daniel Rodgers, Adam Vohra, Sirtaz Adatya, Gene H. Kim, Jayant Raikhelkar, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel; University of Chicago, Chicago, Illinois Purpose: LVADs are a mainstay of therapy for advanced heart failure; however, the physiologic effects of LVADs in gender is unknown. We aim to evaluate the hemodynamic/echocardiographic affects of LVADs and subsequent readmissions after ramp testing in females. Methods: In this prospective study, consecutive patients undergoing hemodynamic/echocardiographic ramp testing were enrolled. Data was collected at baseline and incremental speed changes during ramp testing. Demographics, as well as hemodynamic/echocardiographic characteristics were compared between males and females. Readmission rates were reported per patient years of follow-up and compared with the Wilcoxon Rank Sum test. Additional readmission rate stratification was done based on post-ramp optimal filling pressures (defined as CVP ≤12 and PCWP
≤18 mmHg). Results: Among 65 enrolled patients, 25 females (38.5%) were identified. No significant difference in LVAD type or baseline hemodynamic/echocardiographic characteristics were found. During ramp test, left ventricular end-diastolic diameter (LVEDD) decreased more in the female group, which persisted when limiting to those with HeartMate 2 devices only (N = 43) [LVEDD slope: -0.26 (0.14) vs -0.15 (0.08), P < .01], but significance was lost after adjusting for BSA. All other hemodynamic/ echocardiographic responses to speed change were similar. Over a mean follow-up of 353 ± 168 days, no significant difference was noted for rates of total (2.17 ± 1.82 vs 1.96 ± 2.46 admissions/patient-year, P = .36) or heart failure (0.17 ± 0.35 vs 0.14 ± 0.31 admissions/patient-year, P = .36) readmissions for females vs males. There was no significant difference in the percentage of patients who achieved optimal filling pressures after speed optimization. In the subgroup with post-ramp optimal filling pressures, no significant difference was seen for rates of total (2.08 ± 1.65 vs 1.69 ± 2.22 admissions/ patient-year, P = .24) or heart failure (0.17 ± 0.33 vs 0.07 ± 0.24 admissions/patientyear, P = .51) readmissions for females vs males. Conclusion: Female patients implanted with LVAD have similar unloading characteristics as males. Female gender is not associated with a difference in readmission rate after ramp testing as compared to men, even among those with optimal filling pressures.
100 Impact of Heart Failure Etiology on Ventricular Unloading in Patients Supported with Left Ventricular Assist Devices (LVADs) David M. Tehrani, Daniel Rodgers, Sirtaz Adatya, Nitasha Sarswat, Gene H. Kim, Jayant Raikhelkar, Takeyoshi Ota, Takeyoshi Ota, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel; University of Chicago, Chicago, Illinois Purpose: LVADs are a mainstay of therapy for advanced heart failure for both those with non-ischemic and ischemic cardiomyopathy (CM). However, the hemodynamic and echocardiographic response to LVADs based on CM etiology is unknown. We aim to compare the hemodynamic/echocardiographic affects of LVADs in those with nonischemic vs ischemic CM. Methods: In this prospective study, patients undergoing hemodynamic/echocardiographic ramp testing were enrolled. Data was collected at baseline and incremental speed changes during ramp testing. Demographics, as well as hemodynamic/echocardiographic characteristics were compared between patients with ischemic and non-ischemic etiologies. Chi square analysis was used for categorical values and Wilcoxon rank sum test was used for continuous variables. Linear regression analysis was used to evaluate unloading slopes across LVAD ramp speed changes. Results: Among 65 included patients, 28 patients (43.1%) had an ischemic cardiomyopathy. Those with ischemic CM were older than those with non-ischemic CM (65.0 ± 7.3 vs 55.9 ± 12.0 years, P < .01). All other demographics including gender, device type, and history of arrhythmias were not significantly different between groups. CVP was found to be significantly higher in those with non-ischemic vs ischemic CM at baseline speed (10.3 ± 5.7 vs 7.7 ± 4.2 mmHg, P = .04) and set-speed (10.2 ± 5.8 vs 7.0 ± 4.2 mmHg, P = .02). No additional differences in hemodynamic or echocardiographic parameters were found at baseline or set-speed speed were found based on CM etiology. During the ramp study, there was no significant difference in hemodynamic or echocardiographic unloading slopes between those with ischemic vs non-ischemic cardiomyopathy (Table). However, a trend for more rapid off-loading was seen in the non-ischemic CM group for central venous pressure slope (-0.29 ± 0.24 vs -0.17 ± 0.29, P = .07) and pulmonary artery saturation slope (1.33 ± 0.77 vs 0.96 ± 0.83, P = .07) as compared to the ischemic CM group. Conclusion: As evaluated by invasive hemodynamics and echocardiography, non-ischemic CM patients had higher CVP compared to ischemic CM, however all other echocardiographic and hemodynamics characteristics were similar. No clear relationship was found between CM etiology and a patient’s response to acute speed change during hemodynamic/echocardiographic ramp testing.