Left Ventricular Pressure Research Articles

Cardiac resynchronization therapy using endocardial versus trans-coronary sinus, epicardial left ventricular pacing: the Epi-Endo study

Abstract Aims Some studies have suggested that cardiac resynchronization therapy (CRT) using endocardial left ventricular (LV) pacing (Endo-CRT) is superior to a conventional transvenous, epicardial CRT (Epi-CRT). To determine whether, in CRT recipients, endocardial LV pacing is haemodynamically superior to trans-coronary vein (trans-CV) LV epicardial pacing. Methods and results At implantation patients (n=16; aged 68.9±8.32 years; 13 male) underwent Epi-CRT and Endo-CRT in basal, mid and apical myocardial segments, delivered using the trans-CS lead and an intra-cavitary, roving EP catheter to achieve juxtapositions of the epicardial and endocardial side of the LV free wall respectively. Myocardial scar was quantified using cardiovascular magnetic resonance. An acute haemodynamic response (AHR) was defined as a ≥10% increase in the maximal rate of rise of LV pressure (%LV dP/dtmax) in relation to RV pacing (DOO). When the 84 paired segments were taken together, the %ΔLV dP/dtmax was higher with Endo-CRT than with Epi-CRT (9.9±8,6% vs 7.9±8.3% respectively, p<0.002; 52.3% vs 28.6% responders [p<0.045). However, Endo-CRT was not always superior to epi-CRT in individual patients. For example, in basal segments, only 5/10 (50%) patients were converted from non-responders with epi-CRT to responders with endo-CRT whereas 1/4 (25%) epi-CRT responder was converted to a non-responder with endo-CRT (Figure). There was no difference in ΔLV dP/dtmax between Epi-CRT and endo-CRT in segments with myocardial scar. Conclusions On average, endo-CRT provides a better AHR than epi-CRT. Within patients, however, endo-CRT is not always better.Epicardial versus Endocardial CRT

Right ventricular pacing-evoked left ventricular dysfunction is exaggerated by sustained left ventricular pressure overload in a rat model

Abstract Introduction A growing body of evidence suggests that in the presence of left bundle branch block-induced electromechanical dyssynchrony, the function of the left ventricle (LV) becomes extremely sensitive to arterial afterload. However, data is scarce whether right ventricular pacing (RVP) also sensitizes the LV to alterations in afterload. Purpose Hence, in the present translational study we aimed to characterize the acute effect of RVP on LV hemodynamics under standard laboratory conditions using a rat model of chronic LV pressure overload (PO). Methods Transverse aortic constriction (TAC group) was carried out in male Wistar rats to evoke sustained LV PO for six weeks. Age- and sex-matched sham-operated animals served as controls (Sham group). LV hemodynamics was assessed in anesthetized rats by pressure-volume analysis using a pressure-conductance micro-catheter (SPR-838) introduced to the LV via the right carotid artery. To evoke RVP, the right jugular vein was cannulated and an ultra-miniature octopolar electrophysiology catheter (EPR-800) was placed into the right ventricle. Pressure-volume loops were registered in the TAC and the Sham groups during intrinsic narrow QRS rhythm (termed as TAC-Vsense and Sham-Vsense) as well as during RVP (termed as TAC-Vpace and Sham-Vpace). Results RVP was associated with impaired diastolic function (active relaxation time constant [τ]: 8.6±0.3 vs. 9.6±0.3ms, Sham-Vsense vs. Sham-Vpace and 8.0±0.3 vs. 9.6±0.4ms, TAC-Vsense vs. TAC-Vpace; P<0.001 for both comparisons) and decreased LV contractility (preload recruitable stroke work [PRSW]: 139±9 vs. 114±9mmHg, Sham-Vsense vs. Sham-Vpace and 255±23 vs. 169±17mmHg, TAC-Vsense vs. TAC-Vpace; P<0.001 for both comparisons) in both the TAC and the Sham groups. Nevertheless, the extent of RVP-evoked active relaxation prolongation (Δτ: 12±2 vs. 20±2%, Sham vs. TAC, P=0.005) and LV contractility reduction (ΔPRSW: -18±4 vs. -34±3%, Sham vs. TAC, P=0.007) was found to be more robust in rats with sustained LV PO compared to controls. Conclusion Our experimental results indicate that RVP-induced LV dysfunction is exaggerated in case of sustained LV PO.

Enhancing Heart Transplantation: Utilizing Gas-Loaded Nanocarriers to Mitigate Cold/Hypoxia Stress.

Gas-loaded nanocarriers (G-LN) show promise in improving heart transplantation (HTx) outcomes. Given their success in reducing cell death during normothermic hypoxia/reoxygenation (H/R) in vitro, we tested their integration into cardioplegic solutions and static cold storage (SCS) during simulated HTx. Wistar rat hearts underwent four hours of SCS with four G-LN variants: O2- or N2-cyclic-nigerosyl-nigerose-nanomonomers (CNN), and O2- or N2-cyclic-nigerosyl-nigerose-nanosponges (CNN-NS). We monitored physiological-hemodynamic parameters and molecular markers during reperfusion to assess cell damage/protection. Hearts treated with nanomonomers (N2-CNN or O2-CNN) showed improvements in left ventricular developed pressure (LVDP) and a trend towards faster recovery of the rate pressure product (RPP) compared to controls. However, nanosponges (N2-CNN-NS or O2-CNN-NS) did not show similar improvements. None of the groups exhibited an increase in diastolic left ventricular pressure (contracture index) during reperfusion. Redox markers and apoptosis/autophagy pathways indicated an increase in Beclin 1 for O2-CNN and in p22phox for N2-CNN, suggesting alterations in autophagy and the redox environment during late reperfusion, which might explain the gradual decline in heart performance. The study highlights the potential of nanomonomers to improve early cardiac performance and mitigate cold/H/R-induced stunning in HTx. These early improvements suggest a promising avenue for increasing HTx success. Nevertheless, further research and optimization are needed before clinical application.

The hybrid (physical-computational) cardiovascular simulator to study valvular diseases

To better understand the impact of valvular heart disease (VHD) on the hemodynamics of the circulatory system, investigations can be carried out using a model of the cardiovascular system. In this study, a previously developed hybrid (hydro-numerical) simulator of the cardiovascular system (HCS) was adapted and used. In our HCS Björk-Shiley mechanical heart valves were used, playing the role of mitral and aortic ones. In order to simulate aortic stenosis (AS) and mitral regurgitation (MR), special mechanical devices have been developed and integrated with the HCS. The simulation results proved that the system works correctly. Namely, in the case of AS − the mean pulmonary arterial pressure was increased due to increased preload of the left ventricle and the decrease in right ventricular preload was caused by a decrease in systemic arterial pressure. The severity of AS was performed based on the transaortic pressure gradient as well as using the Gorlin and Aaslid equations. In the case of severe AS, when the mean gradient was above 40 mmHg, the aortic valve orifice area was 0.5 cm2, which is in line with ACC/AHA guidelines. For the case of MR − with increasing severity of MR, there was a decrease in the left ventricular pressure and an increase in left atrial pressure. Using mechanical heart valves to simulate VHD by the HCS can be a valuable tool for biomedical research, providing a safe and controlled environment to study and understand the pathophysiology of VHD.

Twenty-four-hour Normothermic Ex Vivo Heart Perfusion With Low Flow Functional Assessment in an Adult Porcine Model.

Cold static storage and normothermic ex vivo heart perfusion are routinely limited to 6 h. This report describes intermittent left atrial (LA) perfusion that allows cardiac functional assessment in a working heart mode. Using our adult porcine model, general anesthesia was induced and a complete cardiectomy was performed following cardioplegic arrest. Back-table instrumentation was completed and normothermic ex vivo heart perfusion (NEHP) was initiated in a nonworking heart mode (Langendorff). After 1 h of resuscitation and recovery, LA perfusion was initiated and the heart was transitioned to a coronary flow-only working heart mode for 30 min. Baseline working heart parameters were documented and the heart was returned to nonworking mode. Working heart assessments were performed for 30 min every 6 h for 24 h. Twenty-four-hour NEHP on 9 consecutive hearts (280 ± 42.1 g) was successful and no significant differences were found between working heart parameters at baseline and after 24 h of perfusion. There was no difference between initial and final measurements of LA mean pressures (5.0 ± 3.1 versus 9.0 ± 6.5 mm Hg, P = 0.22), left ventricular systolic pressures (44.3 ± 7.2 versus 39.1 ± 9.0 mm Hg, P = 0.13), mean aortic pressures (30.9 ± 5.8 versus 28.1 ± 8.1 mm Hg, P = 0.37), and coronary resistance (0.174 ± 0.046 versus 0.173 ± 0.066 mL/min/g, P = 0.90). There were also no significant differences between lactate (2.4 ± 0.5 versus 2.6 ± 0.4 mmol/L, P = 0.17) and glucose (173 ± 75 versus 156 ± 70 mg/dL, P = 0.37). A novel model using intermittent LA perfusion to create a coronary flow-only working heart mode for assessment of ex vivo cardiac function has been successfully developed.

Left Atrial Mechanics Following Preeclamptic Pregnancy.

Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension, cardiac dysfunction or both. In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) IN A PATIENT WITH RECENT TAVI AND NUMEROUS CORONARY FISTULAS OF THE LEFT CORONARY ARTERY DRAINING INTO THE VENTRICULAR CAVITY

Abstract Coronary fistula is a rare form of congenital heart disease and is defined as an abnormal connection between a coronary branch and a cardiac chamber or a large intrathoracic vessel without the interposition of the capillary circulation. The right coronary artery is the most common site of origin for coronary fistula. Other sites include the left anterior descending artery and left circumflex artery. The clinical presentation and the natural history can be extremely variable depending on the patient‘s age, fistula size, and anatomy. Small to medium–sized coronary fistulas may be asymptomatic. Large fistulas can manifest with angina pectoris due to myocardial ischemia secondary to the coronary steal phenomenon. Shunting through large fistulas can have hemodynamic consequences secondary to volume overload in the pulmonary or systemic circulation, leading to symptoms and signs of heart failure. We describe the case of an 83–year–old woman recently undergoing TAVI and suffering from primary myelofibrosis requiring periodic transfusions. Pre–TAVI coronary angiography showed coronary vessels free from significant hemodynamic lesions and multiple coronary–ventricular fistulas draining into the left ventricle. Total body aortic CT angiography did not reveal other abnormal vascular connections. One month after the aortic valve correction procedure, the patient presented with heart failure (HfpEF). At a recent follow–up visit, diuretic therapy was discontinued due to the successful correction of aortic valve disease and normal ejection fraction. Due to further anemization from the underlying hematologic condition, the patient underwent blood transfusion with worsening of dyspnea despite correction of hemoglobin levels. Discontinuation of diuretic therapy and transfusion of red blood cell units resulted in volume overload with worsening clinical condition. The presence of multiple coronary fistulas precluded an interventional approach, but therapeutic optimization and reintroduction of diuretic therapy restored the patient‘s hemodynamic compensation. Usually fistulas drain into the low–pressure venous circulation like right ventricle and right atrium. This case represents a rare instance of multiple left coronary fistulas draining into the left ventricle (only 3% of cases). Aortic valve correction may have further reduced left ventricular telediastolic pressures, worsening the shunt of coronary fistulas resulting in heart failure due to volume overload.

Interval training suppresses nod-like receptor protein 3 inflammasome activation to improve cardiac function in myocardial infarction rats by hindering the activation of the transforming growth factor-β1 pathway

ObjectiveMyocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI.MethodsRats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-β1 (TGF-β1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-β1 and receptor was detected.ResultsMI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening (LVFS), left ventricular systolic pressure (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-β1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-β1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats.ConclusionIT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-β1 pathway, thus improving the cardiac function of MI rats.

Association between Aquaporin 7 Expression and Myocardial Protection with Nicorandil or Del Nido Cardioplegia: An Experimental Study

Background: Aquaporin 7 (AQP7), a member the aquaglyceroporin subgroup of the AQP family, is a water channel that controls transport of glycerol and water in heart tissues. It facilitates the uptake of glycerol, a substrate for cardiac energy production, in cardiomyocytes. St. Thomas' Hospital cardioplegic solution No. 2 has cardio-protective effect even in AQP7-deficient hearts. Here, we aimed to determine whether nicorandil or del Nido cardioplegia (DNC) solution can protect AQP7-deficient hearts. Methods: The hearts of male AQP7 knockout (KO) and wild-type (WT) C57/B6N mice (age &gt;15 weeks) were aerobically perfused using the Langendorff technique, and cardiac function was measured as left ventricular diastolic pressure (LVDP) throughout the study. Troponin T was measured as an indicator of myocardial damage after reperfusion for 60 min. We compared WT and KO controls subjected to 25 min of global ischemia as well as WT and KO groups infused with nicorandil (100 µM) for 10 min followed by 25 min of global ischemia. We also compared WT-DNC and KO-DNC hearts administered with DNC for 2 min followed by 23 min of global ischemia (Study 2). Results: The final recovery rates of LVDP were 20.8 ± 7.0%, 28.1 ± 7.6%, 40.0 ± 8.4%, and 38.7 ± 4.7% in the WT control, KO control, WT nicorandil, and KO nicorandil groups, respectively. The LVDP recovered faster in the hearts treated with DNC and reached a significantly higher plateau in the KO than in the WT hearts. Troponin T values were 2144 ± 493 and 1313 ± 717 in the WT and KO groups, respectively (p = 0.041). Conclusion: The Langendorff perfusion model revealed similar myocardial protective effects of nicorandil in AQP7-deficient mice as in WT mice. AQP7 deficiency did not impair the cardioprotective effects of DNC solution.

Left ventricular unloading during venoarterial extracorporeal membrane oxygenation implantation: benefits or complications?

Abstract Funding Acknowledgements None. Introduction Peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) is a therapeutic option for refractory cardiogenic shock (CS). However, the retrograde flow increases afterload, leading to pulmonary edema, blood stasis in the left ventricle (LV) and formation of thrombi. Several strategies try to reduce LV pressure, including the percutaneous transvalvular microaxial pump (p-MCS) and intra-aortic balloon pump (IABP). However, these interventions are associated to complications, such as limb ischemia, embolism, bleeding and hemolysis. Purpose This study aims to investigate whether simultaneous LV unloading at ECMO implant yields clinical benefits or complications compared to ECMO implantat alone. Methods Consecutive patients (pts) with CS requiring peripheral VA ECMO from January 2020 to August 2023 were prospectively included, comparing the group that received LV unloading through IABP or p-MCS to the group that received ECMO only. Standard statistical methods were used. Results A total of 38 pts required VA ECMO. 18 of them received LV unloading since cannulation (8 with IABP and 10 with p-MCS). In the group without initial LV-unloading (20), 3 pts required IABP and 1 p-MCS during support and 1 was changed to VAV ECMO. Change to axillar configuration was perfomed in 1 pts in the unloaded group and in 2 in the only-ECMO group. A higher prevalence of SCAI E (72.2%) was observed in the unloaded-ECMO, compared to the only-ECMO, where SCAI D was more prevalent (60%) (p=0.024). In the LV unloaded group, acute myocardial infarction (AMI) was the leading cause of CS, while myocarditis was the predominant one in the other group (p=0.01). The simultaneous support had a higher rate of intubation (94.4% vs 50% p=0.004) and more acute pulmonary edema (44.4% vs 10% p=0.027). In the ECMO-only 2 pts required intubation during support and LV stasis was observed in 1, whereas no cases were reported in the LV-unloaded group (p=0.036). The mean PaO2/FiO2 during support were higher in the not unloaded group (284.54 vs 200.50 mmHg p=0.036), necessitating lower FiO2 levels (40.89 vs 61.47% p=0.003). In terms of complications, we included the 4 patients from the ECMO-only group who eventually required LV unloading in the unloaded-ECMO. There were no significant differences in the duration of support, in-hospital mortality, stroke, embolism, systemic and local bleeding, or hemolysis. Conclusions Pts with ECMO and LV unloading since cannulation debuted with more severe CS, more AMI as the underlying cause, higher rates of acute pulmonary edema, and intubation. Despite these challenges, they did not experience worse outcomes in terms of in-hospital mortality or ischemic and hemorrhagic events. Notably, 4 patients initially managed with ECMO eventually required subsequent LV unloading. Consequently, the simultaneous implantation of ECMO and a LV unloading device appears to be a reasonable alternative for select patients with a higher risk profile.

Echocardiography to predict left ventricular filling pressure for long-term paediatric heart transplant patients.

Left ventricular diastolic dysfunction is a recognised sequela following transplantation in paediatric heart transplant patients. Traditional echocardiographic indices do not correlate well with left ventricular filling pressure immediately after transplantation. This study aimed to assess whether these indices have any long-term correlation after transplantation in paediatric patients. A retrospective chart review of 41 patients who had a heart transplant before the age of 24 years was performed. The median time since the transplantation was 11 years. Data obtained from surveillance cardiac catheterisation and echocardiographic examination were reviewed. Traditional echocardiographic indices of diastolic function were compared with the pulmonary capillary wedge pressure and left ventricular end-diastolic pressure obtained from cardiac catheterisation. The median age at transplant was 12.1 years, and the median time since transplant was 11 years. Eighteen patients (43%) had a history of at least one rejection episode and 12 patients (29%) had a history of cardiac allograft vasculopathy. There was no correlation between mitral inflow E velocity, mitral E/A ratio, tissue Doppler velocities, mitral E/e' (mitral inflow E velocity to mitral annular velocity), and elevated pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure. There was no correlation between mitral valve deceleration time or isovolumetric relaxation time with elevated pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure. Our findings suggest that traditional echocardiographic indices of diastolic function do not correlate well with elevated invasive pulmonary capillary wedge pressure or elevated left ventricular end-diastolic pressure in paediatric heart transplant patients' long-term post-transplantation.

Ethanol-induced lung and cardiac right ventricular inflammation and remodeling underlie progression to pulmonary arterial hypertension.

Current research on ethanol-induced cardiovascular anomalies has focused on left ventricular (LV) function and blood pressure. To extend this area of research, we sought to determine whether ethanol-induced alterations in the structure and function of the right cardiac ventricle (RV) and pulmonary artery (PA) lead to pulmonary arterial hypertension (PAH). Two groups of male Sprague-Dawley rats received a balanced liquid diet containing 5% ethanol (w/v) or a pair-fed isocaloric liquid diet for 8 weeks. Weekly echocardiography was conducted to evaluate cardiopulmonary function, and lung and RV tissues were collected for exvivo histological and molecular studies. The ethanol-treated rats exhibited: (1) Elevated mean pulmonary arterial pressure and decreased pulmonary artery acceleration time/ejection time; (2) Pulmonary vascular remodeling comprising intrapulmonary artery medial layer thickening; and (3) RV hypertrophy along with increased RV/LV + septum, RV diameter, RV cardiomyocyte cross-sectional area, and LV mass/body weight ratio. These responses were associated with increased lung and RV pro-inflammatory markers, endothelin-1 (ET-1), TNF-α, and IL-6 levels and higher ET-1,ET-1 type A/B receptor ratio, and downregulation of the cytoprotective protein, bone morphogenetic protein receptor 2 (BMPR2), in the lungs. These findings show that moderate ethanol-induced cardiopulmonary changes underlie progression to PAH via an upregulated proinflammatory ET1-TNFα-IL6 pathway and suppression of the anti-inflammatory BMPR2.

PM2.5 toxicity in blood impairs cardiac redox balance and promotes mitochondrial dysfunction in rat heart that further aggravates ischemia reperfusion injury by modulating PI3K/AKT/mTOR/NF-kB signaling axis.

According to the pathophysiological mechanisms linking particulate matter (PM2.5) exposure and cardiovascular diseases, PM2.5 may directly translocate into the blood stream and remote target organs and thereby induce cardiovascular effects. The toxicity of PM2.5 is known to induce oxidative stress in pulmonary tissue, but its impact on the redox state in heart (distant organ) is unknown and how it modulates the cardiac response to ischemia reperfusion (IR) remains unclear. In the present study, we evaluated the toxic effect of PM2.5 on cardiac physiology in the presence and absence of IR after introducing PM2.5 into the blood. Female Wistar rats were injected with diesel particulate matter (DPM) via i.p & i.v routes at a concentration of 10 µg/ml. The toxic impact of PM2.5 not only adversely affects the cardiac ultra-structure (leading to nuclear infiltration, edema, irregularities in heart muscle and nuclear infiltration), but also altered the cellular redox balance, elevated inflammation and promoted the upregulation of proapoptotic mediator genes at the basal level of myocardium. The results showed alterations in cardiac ultrastructure, elevated oxidative stress and significant redox imbalance, increased inflammation and proapoptotic mediators at the basal level of myocardium. Moreover, the cardioprotective pro survival signaling axis was declined along with an increased NF-kB activation at the basal level. IR inflicted further injury with deterioration of cardiac hemodynamic indices (Heart rate [HR], Left ventricular developed pressure [LVDP], Left ventricular end-diastolic pressure [LVEDP] and rate pressure product [RPP]) along with prominent inactivation of signaling pathways. Furthermore, the levels of GSH/GSSG, NADH/NAD, NADPH/NADP were significantly low along with increased lipid peroxidation in mitochondria of PM2.5 treated IR rat hearts. This observation was supported by downregulation of glutaredoxin and peroxiredoxin genes in the myocardium. Similarly the presence of oxidative stress inducing metals was found at a higher concentration in cardiac mitochondria. Thus, the toxic impact of PM2.5 in heart augment the IR associated pathological changes by altering the physiological response, initiating cellular metabolic alterations in mitochondria and modifying the signaling molecules.

MORIN, A BIOFLAVONOID, ATTENUATES MYOCARDIAL ISCHEMIA-REPERFUSION INJURY BY ATTENUATING RISK/SAPK PATHWAY

Objective: It is important to address the impact of rising incidence of mortality and morbidity associated with myocardial infarction (MI). There is need to explore new safer and efficacious drugs with novel mechanisms to manage MI. Morin, (2-(2,4-Dihydroxyphenyl)-3, is a bioflavanoid which is found in Maclura cochinchinensis, Maclura tinctoria, Maclura pomifera and leaves of Psidium guajava. It possesses good anti-apoptotic, anti-inflammatory, and antioxidant activity. Hence, we have evaluated the cardio-protective effect of Morin in Myocardial Ischemia-Reperfusion (IR) injury model of rat. Design and method: Male albino Wistar rats were pre-treated with Morin (40 and 80 mg/kg; p.o.) for 28 days and on the 29th day, the chest cavity was opened and myocardial ishemia was induced for 45 minutes by ligatiing the LAD coronary artery. Thereafter, reperfusion was carried out for 60 minutes. The hemodynamic parameters as well as left ventricular pressures (±LV dp/dt and LVEDP) were recorded throughout the ischemia and reperfusion. At the end of the procedure, the blood and heart were collected for evaluation of cardiac-injury markers, antioxidant-oxidant parameters, inflammatory markets, histopathological evaluation and molecular signalling pathway protein expressions. Results: Morin pretreatment for 28 days at 40 mg/kg and 80 mg/kg doses significantly controlled hemodynamic parameters, reduced cardiac injury markers, inflammation and apoptosis and reduced oxidative stress and mitigated histological changes following IR injury in rat heart. Morin also downregulated expression of pro-inflammatory and pro-apoptotic SAPK pathway proteins (p38 and JNK), and upregulated the survival kinase protein expression i.e. RISK pathway (ERK, eNOS). Conclusions: Morin reduced myocardial oxidative stress, inflammation and apoptosis in ischemia-reperfusion induced cardiac injury through upregulation of RISK and downregulation of SAPK pathways proteins.

Macrophage to Myofibroblast Transition Promotes Hypertension-Induced Cardiac Diastolic Dysfunction

Cardiac diastolic dysfunction is a pathological continuum of hypertension eventually leading to heart failure—which is responsible for ~13% of all deaths in the United States. A hallmark of this disease is cardiac fibrotic remodeling, in which excessive extracellular matrix components are deposited into the myocardium. Recent studies have shown the novel ability of macrophages to differentiate into a fibrotic myofibroblast-like phenotype—termed macrophage to myofibroblast transition (MMT). This phenomenon has been implicated in renal fibrosis but, has not been investigated in the heart during hypertension or diastolic dysfunction. Therefore, we hypothesize that MMT plays a causal role in cardiac fibrotic remodeling in hypertension, promoting diastolic dysfunction. As such, we seek to investigate the prevalence of myofibroblast-transitioned macrophages in the heart, as well as determine the gravity of MMT-mediated fibrotic cardiac remodeling. To understand the pathological progression of hypertension to diastolic dysfunction, we utilized the classic DOCA + NaCl model of hypertension in C57BL/6 mice. This investigation is multi-pronged, in that, we seek to gauge diastolic function in vivo, as well as investigate the microenvironment of the heart in primary in vitro experiments. To achieve this, we employ echocardiography and direct left ventricular pressure and volume measurements to determine the progression of hypertension to diastolic dysfunction in the adult mouse heart. For primary in vitro analyses, mouse hearts were isolated and digested, and leukocytes were isolated by Percoll gradient. Cells were stained with α-SMA (myofibroblast) and CD68 (monocyte/macrophage). Finally, the deposition of fibrotic collagen was assessed by both Masson’s trichrome and picrosirius red tissue stains. Mice were subjected to DOCA + salt to induce hypertension. Ten days after this treatment, the left ventricular pressure change as a function of time was measured in the left ventricle. This analysis revealed degraded heart function, realized by a significant decrease in -dp/dt as soon as ten days following the onset of hypertension. Following, another cohort of hypertensive WT mouse hearts was isolated for staining. The results of these assays revealed increased cardiac fibrosis in the hearts of hypertensive mice—likely contributing to the deficit in cardiac function. Finally, in addition to this, flow cytometric analyses of isolated cardiac leukocytes revealed that hypertensive mice had a significant increase in the α-SMA+/CD68+ population of cells in the hypertensive mouse heart, implicating MMT in the rapid pathological progression of hypertension to diastolic dysfunction. These results characterize the presence of MMT cells in the hypertensive mouse heart. Furthermore, the increase of myofibroblast transition is accompanied by decreased cardiac diastolic function and enhanced fibrotic remodeling in the heart—alluding to the role of MMT in the pathological progression of hypertension to diastolic dysfunction. Future efforts into this phenomenon involve the real-time progression of hypertension to diastolic dysfunction via echocardiography, as well as a final, definitive measurement of diastolic function by PV loop. Finally, we will employ an angiotensin II model of hypertension to ensure that this phenomenon is encapsulated in other forms of hypertension, rather than just the DOCA + Salt model. We thank our sources of funding:NIG R01-HL146713, AHA 23TPA1076467. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physiopathological Mechanisms of Type 1 Cardiorenal Syndrome Induced by Acute Myocardial Infarction

Objectives: Cardiovascular diseases are the leading global cause of mortality. Approximately 20 to 31% of acute myocardial infarction (AMI) cases progress to renal dysfunction, indicating concurrent cardiac and renal alterations, characterizing Cardiorenal Syndrome Type 1 (CS1). Therefore, this study evaluates the CS1 onset and progression three days after AMI by examining renal and cardiac function and their inflammatory responses. The study hypothesizes that inflammatory mediators are a key component contributing significantly to the onset and progression of CS1 pathophysiology. Methods: Male Sprague-Dawley rats (250-300g) were divided into AMI-SHAM (undergoing sham surgery for AMI) and AMI (left coronary artery ligation) groups. Samples were collected three days post-AMI from blood, urine, heart, and renal tissues. Assessments included osmolality (plasma and urine), creatinine (plasma and urine), glomerular filtration rate (GFR), and tissue cytokine levels. Left ventricular end-diastolic pressure (LVEDP) represented cardiac function. Results are presented as mean ± standard error. Results: LVEDP measurements (mmHg) demonstrated similar results from SHAM (5.89 ± 0.61, n=14) and AMI groups (6.38 ± 0.43, n=6). Tumor Necrosis Factor-Alpha (TNF-α) levels (pg/mg of tissue) from the heart [SHAM (2.74 ± 0.50, n=10) vs AMI (5.05 ± 0.83, n=8)] and renal tissue [SHAM (2.37 ± 0.69, n=7) vs AMI (5.53 ± 0.41, n=5)] were significantly different (p&lt;0.05) concerning their respective groups. Of note, molecular biochemical analyses revealed similar results. Plasma Osmolality (kgH2O): SHAM (310.8 ± 5, n=13) vs AMI (310.4 ± 2.57, n=10); Urinary Osmolality: SHAM (1653 ± 140, n=14) vs AMI (2054 ± 166.9, n=9); Plasma Creatinine (mg/dL): SHAM (0.35 ± 0.21, n=14) vs AMI (0.39 ± 0.25, n=10); Urinary Creatinine: SHAM (118.9 ± 12.35, n=14) vs AMI (126.5 ± 18.90, n=10). GFR (mL/min/100g) was also similar: SHAM (1.22 ± 0.18, n=14) vs AMI (1.22 ± 0.12, n=9). Conclusions: The study shows that the increase of TNF-α is contributing to the onset and progression of the pathophysiology of CS1, in line with the original hypothesis. On the other hand, because the three-day post-surgery timeframe addressed the primary mechanisms triggering the CS1, it seems that the functional impairment of the heart and kidneys was not manifest yet. Support or Funding Information: FAPESP Process 2020/06043-7. CNPq Processes 306994/21-6 and 423999/21-4; FAEPA; CAPES/PROEX. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Simultaneous alcohol septal ablation and intravascular imaging-guided percutaneous transluminal coronary angioplasty – An effective approach in patients with hypertrophic obstructive cardiomyopathy and critical coronary artery disease

Abstract We report a case of symptomatic hypertrophic obstructive cardiomyopathy refractory to medical management with a left ventricular outflow tract pressure gradient (LVOTPG) of 160 mmHg associated with a significant calcific coronary artery disease treated using simultaneous percutaneous transluminal septal myocardial ablation (PTSMA) and an intravascular imaging-guided percutaneous transluminal coronary angioplasty. The left anterior descending artery stenosis distal to the third septal perforator was stented using a drug-eluting stent under optical coherence tomography guidance. Subsequently, the LVOTPG was addressed using PTMSA. Following the procedure, the patient had an uncomplicated recovery. A follow-up echo revealed an LVOTPG of 15 mmHg 4 weeks later.

Sex Dependent Exacerbation of Salt Sensitive Hypertension and Cardiac Dysfunction Is Associated With Upregulation of miRNA Targeting ADAM17 and ACE2 in the Brain

Background: The DOCA-salt model has been widely used to study salt-sensitive hypertension and we previously reported that it is associated with ADAM17-mediated ACE2 shedding in the central nervous system. However, previously reported data are mainly from male mice, and it is unclear whether female mice exhibit the same phenotypes. Objective: We aimed to compare sex specific development of salt sensitive hypertension and cardiac dysfunction and investigate miRNA regulation associated with these changes. Methods: C57 mice (male and females, n = 8 -15) underwent uninephrectomy and telemetry implantation (DSI Inc.) for blood pressure (BP) conscious recording. After baseline recording, a DOCA pellet (50 mg, 21 days, Innovative Research of America) was implanted subcutaneously and drinking water was replaced by 1% NaCl solution to induce salt sensitive hypertension. Cerebral Spinal fluid (CSF) was collected at baseline and after 3 weeks of DOCA-salt treatment for exosome miRNA sequencing (Creative Biolab). In another set of mice, cardiac function was assessed by echocardiography (Visualsonics Vevo F2) and invasive left ventricular hemodynamics (Transonic). Mortality from each group was analyzed as well. Results: Baseline BP was not different between male and female mice. Following DOCA-salt treatment for 3 weeks, BP was increased in both sexes, with higher systolic BP observed in males compared to females (active phase: 173.0 ± 19.6 vs. 154.2 ± 19.1 mmHg, p&lt;0.05). Although ejection fraction was not changed in either male or female mice, mitral peak early diastolic filling velocity and tissue doppler showed that E/E’ was increased in both sexes compared to baselines (Male: 33.4 ± 4 vs. 26.6 ± 1.9; Female: 30.3 ± 5.0 vs. 26.4 ± 4), with a greater increase in males (25.3% vs. 14.4%). In addition, hemodynamics revealed increased left ventricular end-diastolic pressure (11.1 ± 1.9 vs. 4.5 ± 0.5 mmHg, p&lt;0.01) and relaxation time constant Tau (6.7 ± 1.0 vs. 4.9 ± 0.5 msec, p&lt;0.01) in DOCA-salt treated males compared to non-treated controls, with no changes shown in female mice. These data suggest worsened cardiac diastolic function in males compared to females following DOCA-salt treatment. Moreover, a 20% mortality was observed in males while no death occured in females, confirming a more severe phenotype in males. Furthermore, miRNAseq analysis of CSF exosomes showed several upregulated miRNA in males but not in females following DOCA-salt treatment. Notably, miR206 associated with increased ADAM17 activity was increased by 8-fold in males but only 3-fold n females. Conclusion: DOCA-salt treatment promotes exacerbated hypertension, impaired cardiac function and mortality in a sex dependent manner, associated with upregulation of key miRNA targeting the brain renin-angiotensin system. The changes of ADAM17 and ACE2 targeted exosome miRNAs in the central nervous system might contribute to the sex difference in the cardiovascular dysfunction phenotypes in this model. This work was supported in part by a research grant from the National Institutes of Health (HL163588). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Naltrindole attenuates irreversible Hypercontracture during Myocardial Ischemia by a Novel Mechanism and elicits robust cardioprotective effects in Myocardial Ischemia/Reperfusion Injury

Introduction: Previous studies have shown that naltrindole (NTI) produced robust cardioprotective effects (e.g.~80% reduction of infarct size) in both ex-vivo (2.5-5μM) and in-vivo (3.75-7.5 mg/kg) rat myocardial ischemia-reperfusion (MIR) injury models. We recently showed that NTI 100-200μM attenuated phorbol 12-myristate 13-acetate (PMA) induced polymorphonuclear leukocytes (PMNs) superoxide (SO) release by a novel mechanism of action (MOA) devoid of opioid receptors. We hypothesize NTI’s novel MOA is a reduction of intracellular calcium (Ca2+). To test this hypothesis, we conducted PMN SO release and isolated perfused MIR assays using KB-R7943(KB). KB is known to reduce intracellular Ca2+ via inhibition of reverse mode Na+/Ca2+ exchanger and therefore should attenuate PMN SO release, myocardial ischemic hypercontracture, infarct size, and left ventricular end diastolic pressure (LVEDP). Methods: PMNs and hearts isolated from anesthetized male Sprague Dawley (SD) rats (~400g SO release assay, ~300g for perfused hearts). PMN SO release was stimulated using PMA (100nM) ± NTI 10-200 μM, KB 5-20 μM, or vehicle (0.5% DMSO; controls) and measured spectrophotometrically as a change in absorbance @ 550nm over 390 secs and cell viability was determined using 0.2% Trypan blue exclusion. We then infused NTI 1.25-5μM, KB 10-20μM, or naloxone (NX; negative control) 10μM for 5 min into perfused hearts, just prior to global I (30min)/R(45min). Cardiac LV function was measured via a pressure transducer and infarct size using 1% triphenyltetrazolium chloride staining in MIR assay. Data were analyzed using ANOVA and Fischers post-hoc analysis, with p&lt;0.05 considered statistically significant. Results: PMN SO release assay: KB 10 μM, KB 20 μM, NTI 100 μM (~3.75 mg/kg), and NTI 200 μM(~7.5 mg/kg) significantly attenuated PMA induced PMN SO release by ~40% (KB 10μM, n=7, p&lt;0.05), ~50% ((KB 20μM, n=7, p&lt;0.05), ~30% (NTI 100 μM, n=7, p&lt;0.05), 75% (NTI 200μM, n=7, p&lt;0.05) respectively when compared to untreated control (n=10). MIR assay: NTI 5μM, 2.5μM, 1.25μM and KB 20 μM reduced infarct size (4.8±3%, n=5, p&lt;0.05), (6.8±0.8%, n=6, p&lt;0.05), (12.2±3%, n=5), and (2.9±2%, n=5, p&lt;0.05) respectively compared to vehicle (14.1±2%, n=9) and NX 10μM controls (18±3%, n=3). NTI 5 μM and KB 20 μM had significantly improved LVEDP to (32.4±11%, n=5, p&lt;0.05) and (22.8±4%, n=5, p&lt;0.05) respectively compared to vehicle control (72.4±6%, n=9) and NX 10μM controls(54.2±8%, n=3) Conclusion: NTI and KB showed concentration-dependent effects on reducing PMN SO release. Both NTI (2.5μM, 5μM) and KB (20μM) reduced infarct size and improved LVEDP. The novel MOA of NTI is most likely mediated via a reduction in intracellular Ca2+ and subsequent hypercontracture during myocardial ischemia. The infarct reducing effect of NTI can benefit patients who will undergo elective PCI, CABG, and transplants. Funding: This study was funded by the Philadelphia College of Osteopathic Medicine, Department of Biomedical Sciences, Division of Research, and the Center for Chronic Diseases of Aging and Young Therapeutics, LLC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

An Innovative Apical-4-Chamber-long-axis Imaging Approach Precisely Tracks Progressive Deterioration of Mouse Ventricles, Atria, and Atrioventricular Valves

Transthoracic echocardiography stands as the primary non-invasive method for cardiac function evaluation in clinical settings. It’s widely used to assess chamber sizes, heart wall integrity, as well as the hemodynamic performance of the left ventricle (LV), right ventricle (RV), atria, and valves. However, applying comprehensive echocardiography assessments to mice has been challenging, primarily due to diffculties in obtaining on-axis apical 4-chamber views; most mouse studies have thus been restricted to evaluating the LV using short-axis M-mode assays. To overcome this limitation, we’ve recently developed a novel methodology to consistently obtain high-quality apical 4-chamber-long-axis (A4CLAX) view images of mouse heart. This advancement permits a range of clinically relevant functional assessments, including Long Axis Biplane (LAX-BP) assay, which has been shown to surpasses M-mode in estimating LV function. In this study, we delve into the breadth of comprehensive echocardiography assessments made possible for mice through the A4CLAX imaging approach. We performed a severe transverse aortic constriction (TAC) surgery on mice and monitored the pathological development in their hearts post-surgery. Alongside the expected hypertrophy, the LAX-BP assay revealed LV volumetric dilation as early as 1-week after TAC surgery Indicative of decompensated heart failure; however, m-mode was not able to pick up on this early dilation due to its lack of longitudinal assessment and inconsistent measurements of EDV and ESV. The apical 4 chamber view significantly improved the consistency and reliability of trans mitral and pulmonary vein doppler recordings and enabled us to reliably estimate the pressure relationships of the LV and Left Atrial (LA) pressure, which is consistent with the LAX-BP detected LV decompensation. Additionally, the high clarity of the 4 chamber images achieved improved visualization of both mitral and tricuspid valve leaflets. This allowed more precise characterization of valvular issues, including mitral regurgitation caused by LV dilatation, as well as identification of less common pathological occurrences like desynchronization of the tricuspid and mitral valve opening. A speckle tracking assay of the Right ventricle (RV) showed that a delayed contraction of the lateral apical RV wall caused the tricuspid valve to not open during the early filling phase, but rather at the atrial kick, leading to this valve desynchrony. This delayed contraction indicates a possible elevation of pulmonary pressure, as evidenced by pulmonary vein doppler indices and the analysis of pulmonary congestion. In conclusion, the innovative A4CLAX imaging technique revolutionizes murine heart analysis, bringing it in line with clinical echocardiography standards allowing for a whole heart analysis approach. It sensitively identifies subtle anomalies, providing a precise characterization of cardiac remodeling and disease progression in mouse hearts. This study has been supported by grants NIH-R01HL139006 and R21OD031965. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.