Reduction In Coronary Flow Research Articles

Coronary Microvascular Dysfunction Is Associated With Augmented Lysosomal Signaling in Hypercholesterolemic Mice.

Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease. However, the molecular pathways associated with compromised coronary microvascular function before the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms. Mice were fed a hypercholesterolemic Paigen's diet for 8 weeks. Echocardiography data showed that Paigen's diet caused CMD, characterized by significant reductions in coronary blood flow and coronary flow reserve, but did not affect cardiac remodeling or dysfunction. Immunofluorescence studies revealed that Paigen's diet-induced CMD was associated with activation of coronary arterioles inflammation and increased myocardial inflammatory cell infiltration. These pathological changes occurred in parallel with the upregulation of lysosomal signaling pathways in endothelial cells (ECs). Treating hypercholesterolemic mice with the cholesterol-lowering drug ezetimibe significantly ameliorated Paigen's diet-induced adverse effects, including hypercholesterolemia, steatohepatitis, reduced coronary flow reserve, coronary endothelial cell inflammation, and myocardial inflammatory cell infiltration. In cultured mouse cardiac ECs, 7-ketocholesterol increased mitochondrial reactive oxygen species and inflammatory responses. Meanwhile, 7-ketocholesterol induced the activation of transcriptional factor EB and lysosomal signaling in mouse cardiac ECs, whereas the lysosome inhibitor bafilomycin A1 blocked 7-ketocholesterol-induced transcriptional factor EB activation and exacerbated 7-ketocholesterol-induced inflammation and cell death. Interestingly, ezetimibe synergistically enhanced 7-ketocholesterol-induced transcriptional factor EB activation and attenuated 7-ketocholesterol-induced mitochondrial reactive oxygen species and inflammatory responses in mouse cardiac ECs. These results suggest that CMD can develop and precede detectable cardiac functional or structural changes in the setting of hypercholesterolemia and that upregulation of transcriptional factor EB-mediated lysosomal signaling in endothelial cells plays a protective role against CMD.

Ischemic Heart Disease; An Overview of Atypical Presentation & Misdiagnosis

Cardiovascular disease is considered to be one of the main causes of death worldwide. The most common cardiovascular disease is ischemic heart disease (IHD). The cause of IHD is coronary blood flow reduction therefore also known as “coronary heart disease”. Incidence of IHD has been increase worldwide. IHD symptoms and sign range from typical classic chest pain to atypical e.g., epigastric discomfort and seizure. Patients present with atypical picture been misdiagnosed, this lead in delay of providing the appropriate care and treatment which will lead to worse outcomes and even death. In this review we are aiming to study the different clinical pictures of IHD mainly atypical presentation so patient can be treated earlier. Also, we are studying risk factors associated with IHD so can be managed as long as possible.

Unveiling the role of long non-coding RNA MALAT1: a comprehensive review on myocardial infarction.

Myocardial infarction (MI) stands at top global causes of death in developed countries, owing mostly to atherosclerotic plaque growth and endothelial injury-induced reduction in coronary blood flow. While early reperfusion techniques have improved outcomes, long-term treatment continues to be difficult. The function of lncRNAs extends to regulating gene expression in various conditions, both physiological and pathological, such as cardiovascular diseases. The objective of this research is to extensively evaluate the significance of the lncRNA called Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in the development and management of MI. According to research, MALAT1 is implicated in processes such as autophagy, apoptosis, cell proliferation, and inflammation in the cardiovascular system. This investigation examines recent research examining the effects of MALAT1 on heart function and its potential as a mean of diagnosis and treatment for post- MI complications and ischemic reperfusion injury.

Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice.

Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease (CAD). However, the molecular pathways associated with compromised coronary microvascular function prior to the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms. Mice were fed with a hypercholesterolemic Paigen's diet (PD) for 8 weeks. Echocardiography data showed that PD caused CMD, characterized by significant reductions in coronary blood flow and coronary flow reserve (CFR), but did not affect cardiac remodeling or dysfunction. Immunofluorescence studies revealed that PD-induced CMD was associated with activation of coronary arterioles inflammation and increased myocardial inflammatory cell infiltration. These pathological changes occurred in parallel with the upregulation of lysosomal signaling pathways in endothelial cells (ECs). Treating hypercholesterolemic mice with the cholesterol-lowering drug ezetimibe significantly ameliorated PD-induced adverse effects, including hypercholesterolemia, steatohepatitis, reduced CFR, coronary EC inflammation, and myocardial inflammatory cell infiltration. In cultured mouse cardiac endothelial cells (MCECs), 7-ketocholesterol (7K) increased mitochondrial reactive oxygen species (ROS) and inflammatory responses. Meanwhile, 7K induced the activation of TFEB and lysosomal signaling in MCECs, whereas the lysosome inhibitor bafilomycin A1 blocked 7K-induced TFEB activation and exacerbated 7K-induced inflammation and cell death. Interestingly, ezetimibe synergistically enhanced 7K-induced TFEB activation and attenuated 7K-induced mitochondrial ROS and inflammatory responses in MCECs. These results suggest that CMD can develop and precede detectable cardiac functional or structural changes in the setting of hypercholesterolemia, and that upregulation of TFEB-mediated lysosomal signaling in ECs plays a protective role against CMD.

O Valor Preditivo do Índice Prognóstico Inflamatório para Detecção de No-Reflow em Pacientes com Infarto do Miocárdio com Supradesnivelamento do Segmento ST

Abstract Background: No-reflow (NR) is characterized by an acute reduction in coronary flow that is not accompanied by coronary spasm, thrombosis, or dissection. Inflammatory prognostic index (IPI) is a novel marker that was reported to have a prognostic role in cancer patients and is calculated by neutrophil/lymphocyte ratio (NLR) multiplied by C-reactive protein/albumin ratio. Objective: We aimed to investigate the relationship between IPI and NR in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). Methods: A total of 1541 patients were enrolled in this study (178 with NR and 1363 with reflow). Lasso panelized shrinkage was used for variable selection. A nomogram was created based on IPI for detecting the risk of NR development. Internal validation with Bootstrap resampling was used for model reproducibility. A two-sided p-value <0.05 was accepted as a significance level for statistical analyses. Results: IPI was higher in patients with NR than in patients with reflow. IPI was non-linearly associated with NR. IPI had a higher discriminative ability than the systemic immune-inflammation index, NLR, and CRP/albumin ratio. Adding IPI to the baseline multivariable logistic regression model improved the discrimination and net-clinical benefit effect of the model for detecting NR patients, and IPI was the most prominent variable in the full model. A nomogram was created based on IPI to predict the risk of NR. Bootstrap internal validation of nomogram showed a good calibration and discrimination ability. Conclusion: This is the first study that shows the association of IPI with NR in STEMI patients who undergo pPCI.

The Predictive Value of the Inflammatory Prognostic Index for Detecting No-Reflow in ST-Elevation Myocardial Infarction Patients.

No-reflow (NR) is characterized by an acute reduction in coronary flow that is not accompanied by coronary spasm, thrombosis, or dissection. Inflammatory prognostic index (IPI) is a novel marker that was reported to have a prognostic role in cancer patients and is calculated by neutrophil/lymphocyte ratio (NLR) multiplied by C-reactive protein/albumin ratio. We aimed to investigate the relationship between IPI and NR in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). A total of 1541 patients were enrolled in this study (178 with NR and 1363 with reflow). Lasso panelized shrinkage was used for variable selection. A nomogram was created based on IPI for detecting the risk of NR development. Internal validation with Bootstrap resampling was used for model reproducibility. A two-sided p-value <0.05 was accepted as a significance level for statistical analyses. IPI was higher in patients with NR than in patients with reflow. IPI was non-linearly associated with NR. IPI had a higher discriminative ability than the systemic immune-inflammation index, NLR, and CRP/albumin ratio. Adding IPI to the baseline multivariable logistic regression model improved the discrimination and net-clinical benefit effect of the model for detecting NR patients, and IPI was the most prominent variable in the full model. A nomogram was created based on IPI to predict the risk of NR. Bootstrap internal validation of nomogram showed a good calibration and discrimination ability. This is the first study that shows the association of IPI with NR in STEMI patients who undergo pPCI.

A Case Report of Kounis Syndrome Developing Anaphylaxis Secondary to Vitamin B and C Infusion

Kounis syndrome is a condition characterized by temporary coronary spasm, reduction in coronary blood flow and myocardial ischemia by activated mast cells as a result of an abnormal immune reaction to a drug or molecule. It is also called allergic angina and allergic myocardial infarction. It was first described by Kounis and Zarvas in 1991. (1) Kounis syndrome can be observed in all age groups regardless of the history of coronary artery disease. Kounis syndrome may occur due to environmental factors such as drugs, intracoronary stent implantation, foods, insect bites, bee stings, pollen, latex exposure etc. In our case report, acute coronary syndrome occurring during anaphylaxis secondary to vitamin B and C infusion, which is frequently used in clinical practice, will be explained.

Multiaxial pressure-strain analysis of regional myocardial work in the setting of graded coronary stenoses and dobutamine stress.

We present a detailed analysis of regional myocardial blood flow and work to better understand the effects of coronary stenoses and low-dose dobutamine stress. Our analysis is based on a unique open-chest model in anesthetized canines that features invasive hemodynamic monitoring, microsphere-based blood flow analysis, and an extensive three-dimensional (3-D) sonomicrometer array that provides multiaxial deformational assessments in the ischemic, border, and remote vascular territories. We use this model to construct regional pressure-strain loops for each territory and quantify the loop subcomponent areas that reflect myocardial work contributing to the ejection of blood and wasted work that does not. We demonstrate that reductions in coronary blood flow markedly alter the shapes and temporal relationships of pressure-strain loops, as well as the magnitudes of their total and subcomponent areas. Specifically, we show that moderate stenoses in the mid-left anterior descending coronary artery decrease regional midventricle myocardial work indices and substantially increase indices of wasted work. In the midventricle, these effects are most pronounced along the radial and longitudinal axes, with more modest effects along the circumferential axis. We further demonstrate that low-dose dobutamine can help to restore or even improve function, but often at the cost of increased wasted work. This detailed, multiaxial analysis provides unique insight into the physiology and mechanics of the heart in the presence of ischemia and low-dose dobutamine, with potential implications in many areas, including the detection and characterization of ischemic heart disease and the use of inotropic support for low cardiac output.NEW & NOTEWORTHY Our unique experimental model assesses cardiac pressure-strain relationships along multiple axes in multiple regions. We demonstrate that moderate coronary stenoses decrease regional myocardial work and increase wasted work and that low-dose dobutamine can help to restore myocardial function, but often with further increases in wasted work. Our findings highlight the significant directional variation of cardiac mechanics and demonstrate potential advantages of pressure-strain analyses over traditional, purely deformational measures, especially in characterizing physiological changes related to dobutamine.

Ultra-High-Resolution Electrocardiography Enables Earlier Detection of Transmural and Subendocardial Myocardial Ischemia Compared to Conventional Electrocardiography.

The sensitivity of exercise ECG is marginally sufficient for the detection of mild reduction of coronary blood flow in patients with early coronary atherosclerosis. Here, we describe the application of a new technique of ECG registration/analysis-ultra-high-resolution ECG (UHR ECG)-for early detection of myocardial ischemia (MIS). The utility of UHR ECG vs. conventional ECG (C ECG) was tested in anesthetized rats and pigs. Transmural MIS was induced in rats by the ligation of the left coronary artery (CA). In pigs, subendocardial ischemia of a variable extent was produced by stepwise inflation of a balloon within the right CA, causing a 25-100% reduction of its lumen. In rats, a reduction in power spectral density (PSD) in the high-frequency (HF) channel of UHR ECG was registered at 60 s after ischemia (power 0.81 ± 0.14 vs. 1.25 ± 0.12 mW at baseline, p < 0.01). This was not accompanied by any ST segment elevation on C ECG. In pigs, PSD in the HF channel of UHR ECG was significantly decreased at a 25% reduction of CA lumen, while the ST segment on C ECG remained unchanged. In conclusion, UHR ECG enabled earlier detection of transmural MIS compared to C ECG. PSD in the HF channel of UHR ECG demonstrated greater sensitivity in the settings of subendocardial ischemia.

INOCA/ANOCA: Mechanisms and novel treatments

Angina or ischemia with no obstructive coronary disease (ANOCA/INOCA) is a common but under-treated condition due to poorly understood pathophysiologic mechanisms, limited diagnostic tools, and lack of proven targeted therapy. Coronary microvascular dysfunction (CMD) occurs when the microvasculature inadequately perfuses the myocardium under stress, or at rest in the case of microvascular spasm resulting in ANOCA/INOCA. Coronary functional angiography (CFA) measures endothelial independent microvascular dysfunction (coronary flow reduction <2.5) in response to adenosine and endothelial dependent microvascular dysfunction (lack of dilation and/or constriction) to acetylcholine testing as well as epicardial and microvascular spasm. Current treatment for coronary microvascular dysfunction is limited to renin-angiotensin system (RAS) inhibitors and statins as well as antianginal medications. Novel therapies targeting the underlying pathology are under development and include the coronary sinus reducer, CD34+ stem cell therapy, and novel pharmacologic agents such as sGC stimulators or endothelin-receptor blockers. We review the current understanding of pathophysiology, diagnostic tools, and novel therapies for coronary microvascular dysfunction in ANOCA/INOCA.

Effect of Beta Blockers on the Hemodynamics and Thrombotic Risk of Coronary Artery Aneurysms in Kawasaki Disease.

This study aims to simulate beta blockers' (BB) effects on coronary artery aneurysms' (CAA) hemodynamics and thrombotic risk in Kawasaki disease (KD). BB are recommended in cases of large aneurysms due to their anti-ischemic effect. Coronary blood flow (CBF) was simulated in KD patient-specific CAA models using computational fluid dynamics. Hemodynamic indices that correlate with thrombotic risk were calculated following two possible responses to BB: (1) preserved coronary flow (third BB generation) and (2) reduction in coronary flow (first and second BBgenerations) at reduced heart rate. Following CBF reduction scenario, mean TAWSS and HOLMES significantly decreased compared to normal conditions, leading to a potential increase in thrombotic risk. Preserved CBF at lower heart rates, mimicking the response to vasodilating BBs, does not significantly affect local CAA hemodynamicscompared with baseline, while achieving the desired anti-ischemic effects. Different BB generations lead to different hemodynamic responses in CAA.

Absent Right Coronary Artery in an Active Young Female

Absent Right Coronary Artery in an Active Young Female

The Effects of Different Doses of Sildenafil on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts.

The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of oxidative stress, including nitrite outflow, and superoxide anion production in coronary effluent, were determined for isolated rat hearts. The experiments were performed during control conditions and in the presence of sildenafil (10, 20, 50, 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). Sildenafil was shown to result in a significant increase in coronary flow at lower coronary perfusion pressure (CPP) values at all administered doses, whereas, with an increase in CPP, a reduction in coronary flow was observed. An increase in nitric oxide (NO) was most pronounced in the group treated with the lowest dose of sildenafil at the highest CPP value. After the inhibition of the NO-cyclic guanosine monophosphate (cGMP) signaling (NOS) system by L-NAME, only a dose of 200 nM sildenafil was high enough to overcome the inhibition and to boost release of O2-. That effect was CPP-dependent, with statistical significance reached at 80, 100 and 120 mmHg. Our findings indicate that sildenafil causes changes in heart vasculature in a dose-dependent manner, with a shift from a vasodilatation effect to vasoconstriction with a pressure increase. The highest dose administered is capable of producing superoxide anion radicals in terms of NOS system inhibition.

Acute coronary syndrome and associated factors among patients visiting Dessie comprehensive specialized hospital emergency department, Dessie, Ethiopia, cross-sectional study, 2020

BackgroundAcute coronary syndrome is a constellation of signs and symptoms caused by an abrupt reduction in coronary blood flow. It imposes a high burden to developing countries due to an increased prevalence of non-communicable diseases. This study assessed the magnitude and factors associated with acute coronary syndrome in patients who visited the emergency department at Dessie Comprehensive Specialized Hospital, Ethiopia. MethodsA facility-based cross-sectional study is conducted in Dessie Comprehensive Specialized Hospital from May 1-June 30, 2020. Epi-data and SPSS statistical software are used for data entry and analysis, respectively. Descriptive statistics are summarized using means, medians, and frequencies and presented in texts, tables, and graphs. A bivariable and multivariable logistic regression analyses are conducted, and a P-value < 0.05 and odds ratio are used to show the significant relationship between dependent and independent variables. ResultsThe magnitude of acute coronary syndrome was 7.93% (95% CI: 5.4%–11.3%), and of these, 60% were STEMI, 20% were NSTEMI, and 20% were unstable angina. The presence of syncope (AOR 95% CI = 1.56(1.29–4.81), use of aspirin two weeks before admission (AOR 95% CI = 3.92(3.5–4.41), electrocardiographic change (AOR 95% CI = 4.79(2.593–8.43), elevated cardiac-biomarker (AOR 95% CI = 2.28(1.68–2.95) and elevated serum cholesterol (AOR 95% CI = 3.09(2.50–3.85) are significantly associated with the development of acute coronary syndrome. ConclusionsThe magnitude of acute coronary syndrome is high in Dessie Comprehensive Specialized Hospital. IncreasedBody-Mass-Index, syncope, elevated blood cholesterol, elevated cardiac-biomarkers, electrocardiographic changes, and aspirin use are all linked to the development of acute coronary syndrome.

Enhanced Peripheral Chemoreflex Drive Is Associated with Cardiorespiratory Disorders in Mice with Coronary Heart Disease.

Coronary heart disease (CHD) is a prevalent cardiovascular disease characterized by coronary artery blood flow reductions caused by lipid deposition and oxidation within the coronary arteries. Dyslipidemia is associated with local tissue damage by oxidative stress/inflammation and carotid bodies (CB) peripheral chemoreceptors are heavily modulated by both reactive oxygen species and pro-inflammatory molecules (i.e., cytokines). Despitethis,it is not know whether CB-mediated chemoreflex drive may be affected in CHD. In the present study, we evaluated peripheral CB-mediated chemoreflex drive, cardiac autonomic function, and the incidence of breathing disorders in a murine model of CHD. Compared to age-matched control mice, CHD mice showed enhanced CB-chemoreflex drive (twofold increase in the hypoxic ventilatory response), cardiac sympathoexcitation, and irregular breathing disorders. Remarkably, all these were closely linked to the enhanced CB-mediated chemoreflex drive. Our results showed that mice with CHD displayed an enhanced CB chemoreflex, sympathoexcitation, and disordered breathing and suggest that CBs may be involved in chronic cardiorespiratory alterations in the setting of CHD.

High-Intensity Focused Ultrasound in Interventricular Septal Myocardial Ablation.

High-intensity focused ultrasound (HIFU) can cause necrotic damage in deep tissues through thermal ablation and cavitation, without significant damage to the surrounding tissues. High blood perfusion of heart affects the energy deposition. This study aimed to evaluate the effect of cooling of coronary blood flow for HIFU ablation.Continuous and pulsed HIFU (2000 J) at duty cycles of 100% and 25% were examined for their capacity to ablate the perfused porcine heart tissue in vitro. After ablation, grayscale changes and pathological features were observed or measured, and the area and volume of tissue necrosis were calculated.The cardiomyocytes in the lesions underwent necrosis with a clear boundary. The endocardial surface was intact without necrosis. The three-dimensional morphology of the lesions appeared approximately as ellipsoids. With the increase in perfusion speed, the necrotic volume in the target area was gradually reduced.HIFU has the potential to become a new minimally invasive surgery for ventricular septal myocardial ablation. Reduction of coronary blood flow can improve the ablation effect.

The diastolic blood pressure U-curve

Abstract Introduction It is known that low diastolic blood pressure (DBP) at admission is associated with short-term cardiovascular events after acute coronary syndrome (ACS). However, there is a lack of further investigation into the nonlinear relationship between admission diastolic blood pressure (DBP) and adverse outcomes of ACS patients. Objective To investigate the relationship between admission diastolic blood pressure and subsequent cardiovascular mortality in patients with acute coronary syndrome. Methods Retrospective study of patients with ACS periodically included in our center registry between October/2012 and September/2018. Patients with class killip 4 at admission or that needed ionotropic support during hospitalization were excluded. The association between admission DBP and cardiovascular mortality during the follow-up period among this population was analyzed using multivariate COX regression model. Results were presented according to DBP quartiles: Q1, less than 70 mm Hg; Q2, from 71 to 80 mm Hg; Q3, from 81 to 90 mm Hg; Q4, above 90 mmHg. Results A total of 548 patients were included in this cohort study. Mean patient age was 65.9±13.1 years and 75.2% were men. A nonlinear relation was observed between DBP at admission and cardiovascular mortality over the follow-up. During a median follow-up of 42 months (IQR: 27–59), 47 patients (8.6%) died from cardiovascular causes. After adjusting for potential confounders (age and diabetes mellitus), patients in Q3 had the lowest risk for cardiovascular death by Cox proportional hazard model (HR 0.44; 95% CI: 0.16–1.00). Meanwhile, compared with Q1, Q3 patients had significantly lower risk for cardiovascular death (HR 0.35, 95% CI: 0.13–0.92). Conclusion Among patients admitted for ACS, there is a U curve relationship between admission DBP and risk for cardiovascular death. These results could be explained by a reduction in diastolic coronary blood flow which influences myocardial oxygen supply relative to the necessary demand in an ACS. Funding Acknowledgement Type of funding sources: None.

Montelukast and Acute Coronary Syndrome: The Endowed Drug.

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS.

Chronic High‐Rate Pacing Induces Heart Failure with Preserved Ejection Fraction‐Like Phenotype in Obese Ossabaw Swine

The lack of pre‐clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. This study tested the hypothesis that chronic, high‐rate pacing induces a HFpEF‐like phenotype in obese Ossabaw swine. Swine were fed standard chow or an excess calorie, high‐fat, high‐fructose diet for ~18 weeks. Obese swine were implanted with a pacemaker to increase heart rate to 180 beats/min for 4 weeks (obese HF). Compared to lean swine, chronic pacing did not affect baseline (un‐paced) blood pressure or heart rate, but increased heart weight (P= 0.03), fibrosis (P&lt; 0.001), and tended to reduce capillary density (P= 0.06). Cardiac output was increased in obese HF (P= 0.02) and associated with ~45% increase in ventricular stroke volume (P= 0.01), elevated end‐diastolic pressure (25 ± 2 mmHg; P&lt; 0.001), and a normal ejection fraction of 56 ± 7% (P= 0.57). Baseline coronary blood flow was increased in obese HF (P= 0.03); however, MVO2 (P= 0.48) and coronary venous PO2 (P= 0.14) remained unchanged. Hemorrhage studies revealed impairment of the chronotropic response (59 ± 10 to 158 ± 19 bpm in lean control vs. 70 ± 5 vs. 84 ± 5 bpm in obese HF; P&lt; 0.001) and augmented reductions in coronary blood flow (0.39 ± 0.03 to 0.19 ± 0.04 ml/min/g in lean control vs. 0.60 ± 0.05 to 0.21 ± 0.04 ml/min/g in obese HF) as blood pressure decreased from 109 ± 3 to 42 ± 1 mmHg in lean control vs. 102 ± 4 to 42 ± 1 mmHg in obese HF swine. These findings support that chronic high‐rate pacing of obese Ossabaw swine induces key phenotypic features of the human HFpEF condition and provides a distinct preclinical tool for future mechanistic and therapeutic study.

Teriflunomide treatment exacerbates cardiac ischemia reperfusion injury in isolated rat hearts.

PurposePrevious work suggests that Dihydroorotate dehydrogenase (DHODH) inhibition via teriflunomide (TERI) may provide protection in multiple disease models. To date, little is known about the effect of TERI on the heart. This study was performed to assess the potential effects of TERI on cardiac ischemia reperfusion injury.MethodsMale and female rat hearts were subjected to global ischemia (25 min) and reperfusion (120 min) on a Langendorff apparatus. Hearts were given either DMSO (VEH) or teriflunomide (TERI) for 5 min prior to induction of ischemia and during the reperfusion period. Left ventricular pressure, ECG, coronary flow, and infarct size were determined using established methods. Mitochondrial respiration was assessed via respirometry.ResultsPerfusion of hearts with TERI led to no acute effects in any values measured across 500 pM–50 nM doses. However, following ischemia–reperfusion injury, we found that 50 nM TERI-treated hearts had an increase in myocardial infarction (p < 0.001). In 50 nM TERI-treated hearts, we also observed a marked increase in the severity of contracture (p < 0.001) at an earlier time-point (p = 0.004), as well as reductions in coronary flow (p = 0.037), left ventricular pressure development (p = 0.025), and the rate-pressure product (p = 0.008). No differences in mitochondrial respiration were observed with 50 nM TERI treatment (p = 0.24–0.87).ConclusionThis study suggests that treatment with TERI leads to more negative outcomes following cardiac ischemia reperfusion, and administration of TERI to at-risk populations should receive special considerations.