Pathophysiology Of Myocardial Ischemia Research Articles

Circadian Influences on Myocardial Ischemia-Reperfusion Injury and Heart Failure.

The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.

Noninvasive Multimodality Imaging for the Assessment of Anomalous Coronary Artery.

Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital coronary anomaly with the potential to cause myocardial ischemia and adverse cardiac events. The presence of AAOCA anatomy itself does not necessarily implicate a need for revascularization. Therefore, the purpose of this review is to assess how noninvasive comprehensive anatomic- and physiologic evaluation may guide patient management. The assessment of AAOCA includes an accurate description of the anomalous origin/vessel course including anatomical high-risk features such as a slit-like ostium, proximal narrowing, elliptic vessel shape, acute take-off angle, intramural course, and possibleconcomitant coronary atherosclerosis and hemodynamics. Various cardiac imaging modalities offer unique advantages and capabilities in visualizing these anatomical and functional aspects of AAOCA. This review explored the role of noninvasive multimodality imaging in the characterization of AAOCA by highlighting the strengths, limitations, and potential applications of the current different cardiac imaging methods, with a focus on the pathophysiology of myocardial ischemia and stress testing protocols.

Hydroxysafflor Yellow A Alleviates Acute Myocardial Ischemia/Reperfusion Injury in Mice by Inhibiting Ferroptosis via the Activation of the HIF-1α/SLC7A11/GPX4 Signaling Pathway.

Ferroptosis is closely associated with the pathophysiology of myocardial ischemia. Hydroxysafflor yellow A (HSYA), the main active ingredient in the Chinese herbal medicine safflower, exerts significant protective effects against myocardial ischemia/reperfusion injury (MI/RI). The aim of this study was to investigate the protective effects of HSYA against MI/RI and identify the putative underlying mechanisms. An in vivo model of acute MI/RI was established in C57 mice. Subsequently, the effects of HSYA on myocardial tissue injury were evaluated by histology. Lipid peroxidation and myocardial injury marker contents in myocardial tissue and serum and iron contents in myocardial tissue were determined using biochemical assays. Mitochondrial damage was assessed using transmission electron microscopy. H9C2 cardiomyocytes were induced in vitro by oxygen-glucose deprivation/reoxygenation, and ferroptosis inducer erastin was administered to detect ferroptosis-related indicators, oxidative-stress-related indicators, and expressions of ferroptosis-related proteins and HIF-1α. In MI/RI model mice, HSYA reduced myocardial histopathological damage, ameliorated mitochondrial damage in myocardial cells, and decreased total cellular iron and ferrous ion contents in myocardial tissue. HSYA increased the protein levels of SLC7A11, HIF-1α, and GPX4 and mitigated erastin- or HIF-1α siRNA-induced damage in H9C2 cells. In summary, HSYA alleviated MI/RI by activating the HIF-1α/SLC7A11/GPX4 signaling pathway, thereby inhibiting ferroptosis.

Heterogeneous and overlapping mechanisms of myocardial ischemia in patients with ischemia and non-obstructive coronary arteries. Preliminary results from the MOSAIC-COR Registry

Abstract Background Patients with ischemia and non-obstructive coronary arteries (INOCA) account for 30–70% of all patients undergoing elective coronary angiography for angina. In these group of patients various mechanisms may be responsible for myocardial ischemia, including increased microvascular resistance, epicardial spasm or microvascular spasm. There are limited data on the prevalence and coexistence of different mechanisms in patients with INOCA. Purpose The primary objective was to assess the occurrence of coronary microcirculatory disease (CMD), epicardial vasospastic angina (EVSA), microvascular vasospastic angina (MVSA) and their coexistance in patients with INOCA. The secondary objective was the analysis of subgroups' clinical characteristics. Methods This was a single-center, prospective, observational study. In the absence of significant coronary artery stenosis, a complex functional coronary assessment was performed. Values of fractional flow reserve (FFR), RFR, coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were determined. Coronary artery and microvascular vasoreactivity was tested using the provocative acetylcholine test. Results We enrolled 90 consecutive patients with INOCA. Overlapping of CMD and CMD/EVSA phenomenon was observed. Accordingly, we distinguished 6 subgroups of INOCA patients in comparison to the CorMicA trial. Mixed pathophysiology (CMD+EVSA and CMD+MVSA) was diagnosed in 33% of patients. In the CMD+EVSA subgroup, 73% of subjects were male, while in the CMD+MVSA only 7.1% were male (p=0.005). Typical cardiovascular risk factors were common in the whole INOCA group. Conclusions The INOCA population is a heterogeneous group with various pathophysiology of myocardial ischemia. Overlapping of different pathomechanisms is a frequent phenomenon, which has to be consider for treatment optimization and future research. Funding Acknowledgement Type of funding sources: None.

Cardiac CT perfusion and FFRCTA: pathophysiological features in ischemic heart disease.

Cardiac computed tomography (CCT) has rapidly evolved, becoming a powerful integrated tool for the evaluation of coronary artery disease (CAD), and being superior to other noninvasive methods due to its high accuracy and ability to simultaneously assess both lumen stenosis and atherosclerotic plaque burden. Furthermore, CCT is regarded as an effective gatekeeper for coronary angiography, and carries independent important prognostic information. In the last decade, the introduction of new functional CCT applications, namely CCT perfusion (CCTP) imaging and CT-derived fractional flow reserve (FFRCTA), has opened the door for accurate assessment of the haemodynamic significance of stenoses. These new CCT technologies, thus, share the unique advantage of assessing both myocardial ischemia and patient-specific coronary artery anatomy, providing an integrated anatomical/functional analysis. In the present review, starting from the pathophysiology of myocardial ischemia, we evaluate the existing evidence for functional CCT imaging and its value in relation to alternative, well-established, non-invasive imaging modalities and invasive indices of ischemia (currently the gold-standard). The knowledge of clinical applications, benefits, and limitations of these new CCT technologies will allow efficient and optimal use in clinical practice in the near future.

In Memoriam: Lionel H. Opie, MD (1933-2020).

In Memoriam: Lionel H. Opie, MD (1933-2020).

Diabetes Mellitus and Ischemic Heart Disease: The Role of Ion Channels.

Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients. In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IHD.

Perilipin 5 is protective in the ischemic heart

BackgroundMyocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and resultsWe generated Plin5−/− mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5−/− mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. ConclusionOur findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia.

The Uncoordinated-5 Homolog B (UNC5B) Receptor Increases Myocardial Ischemia-Reperfusion Injury

The UNC5 receptor family are chemorepulsive neuronal guidance receptors with additional functions outside the central nervous system. Previous studies have implicated that the UNC5B receptor influences the migration of leukocytes into sites of tissue inflammation. Given that this process is a critical step during the pathophysiology of myocardial ischemia followed by reperfusion (IR) we investigated the role of UNC5B during myocardial IR. In initial in-vitro experiments, the functional inhibition of UNC5B resulted in a significant reduction of chemotactic migration of neutrophils. In-vivo, using a model of acute myocardial ischemia in UNC5B+/− and wild type (WT) animals, we found a significant reduction of infarct sizes in UNC5B+/− animals. This was associated with significantly reduced levels of troponin-I and IL-6 in UNC5B+/− mice. The repression of UNC5B using siRNA and the functional inhibition of UNC5B significantly dampened the extent of myocardial IR injury. Following depletion of neutrophils, we were not able to observe any further reduction in infarct size through functional inhibition of UNC5B in WT and UNC5B+/− mice. In summary our studies demonstrate an important role for UNC5B during myocardial IR injury, and that UNC5B might be a potential therapeutic target to control reperfusion injury in the future.

Modified Technique for Coronary Artery Ligation in Mice

Myocardial infarction (MI) is one of the most important causes of mortality in humans(1-3). In order to improve morbidity and mortality in patients with MI we need better knowledge about pathophysiology of myocardial ischemia. This knowledge may be valuable to define new therapeutic targets for innovative cardiovascular therapies(4). Experimental MI model in mice is an increasingly popular small-animal model in preclinical research in which MI is induced by means of permanent or temporary ligation of left coronary artery (LCA)(5). In this video, we describe the step-by-step method of how to induce experimental MI in mice. The animal is first anesthetized with 2% isoflurane. The unconscious mouse is then intubated and connected to a ventilator for artificial ventilation. The left chest is shaved and 1.5 cm incision along mid-axillary line is made in the skin. The left pectoralis major muscle is bluntly dissociated until the ribs are exposed. The muscle layers are pulled aside and fixed with an eyelid-retractor. After these preparations, left thoracotomy is performed between the third and fourth ribs in order to visualize the anterior surface of the heart and left lung. The proximal segment of LCA artery is then ligated with a 7-0 ethilon suture which typically induces an infarct size ~40% of left ventricle. At the end, the chest is closed and the animals receive postoperative analgesia (Temgesic, 0.3 mg/50 ml, ip). The animals are kept in a warm cage until spontaneous recovery.

Myocardial Ischemia in Women: Lessons From the NHLBI WISE Study

Cardiovascular disease (CVD) remains the leading cause of death for women. For almost 3 decades, more women than men have died from CVD, with the most recent annual statistics on mortality reporting that CVD accounted for 421 918 deaths among women in the United States. Although there have been significant declines in coronary heart disease (CHD) mortality for females, these reductions lag behind those seen in men. In addition, where there has been a decrease in mortality from CHD across all age groups over time in men, in the youngest women (age <55 years) there has been a notable increase in mortality from CHD. There are differences in the prevalence, symptoms, and pathophysiology of myocardial ischemia that occurs in women compared with men. In this paper, we review the pathophysiology and mechanisms of ischemic heart disease (IHD) in women, particularly focusing on what we have learned from the WISE study. We examine the sex-specific issues related to myocardial ischemia in women in terms of prevalence and prognosis, traditional and novel risk factors, diagnostic testing, as well as therapeutic management strategies for IHD.

The heart rate story

The role of heart rate is well established in the development and pathophysiology of myocardial ischaemia. In patients with coronary artery disease, most ischaemic episodes are triggered by an increase in heart rate, which induces an imbalance between myocardial oxygen delivery and consumption. Therefore, heart rate reduction has been considered as an important therapeutic approach in preventing ischaemia by reducing myocardial oxygen consumption and improving myocardial perfusion, by prolonging the diastolic interval. In addition to the beneficial effects of heart rate reduction for the prevention of ischaemia, a lower heart rate is associated with a more favourable prognosis. Recently, prospective investigation of the prognostic role of resting heart rate in patients with coronary artery disease and left ventricular systolic dysfunction, using the placebo arm of the BEAUTIFUL study, showed that elevated heart rate was associated with an increased risk of adverse fatal and non-fatal cardiac events. Ivabradine is a new medication which lowers heart rate by selectively inhibiting the If current, without other direct cardiovascular effects. Therefore, ivabradine opens up new opportunities in the management of patients with coronary artery disease.

Selective and specific If inhibition with ivabradine: new perspectives for the treatment of cardiovascular disease

Heart rate is a major determinant of myocardial oxygen demand and supply, and increased heart rate adversely affects the pathophysiology of myocardial ischemia. High resting heart rate is a risk factor in cardiovascular disease. The development of the heart rate-lowering agent ivabradine showed that heart rate was also an important treatment target, notably in coronary artery disease and heart failure. Indeed, heart rate reduction with ivabradine, a selective and specific If inhibitor, reduces myocardial oxygen demand, increases diastolic perfusion time and improves energetics in ischemic myocardium. Ivabradine protects the myocardium during ischemia, improves left ventricular function in heart failure and reduces remodeling following myocardial infarction. It improves prognosis in patients with coronary artery disease, left ventricular dysfunction and heart rate ≥70 beats per minute, as well as in patients with heart failure and left ventricular dysfunction. Ivabradine is safe, well tolerated and can be used in combination with the main drugs for cardiovascular disease.

Effect of acute and chronic zofenopril administration on cardiac gene expression

We investigated whether acute and chronic administration of zofenopril, an angiotensin converting enzyme inhibitor, may modulate the expression of genes which are involved in the pathophysiology of myocardial ischemia and heart failure. We used an acute and a chronic model. In the former isolated rat hearts were perfused for 120 min in the presence or in the absence of 10 μM zofenoprilat, the active metabolite of zofenopril. In the chronic model one group of rats was treated with zofenopril (15.2 mg/Kg die per os) for 15 days, while control rats were treated with the same diet, except that zofenopril was omitted. Total RNA was extracted from hearts, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of α myosin heavy chain, superoxide dismutase, heat shock protein 70 (HSP70), nitric oxide synthase 2 and 3 (NOS2, NOS3), heme oxygenase 1, atrial natriuretic peptide (ANP), muscle phosphofructokinase. Acute or chronic zofenopril administration did not produce any change in hemodynamic variables. qRT-PCR experiments showed that in the acute model ANP expression was slightly although not significantly increased. In the chronic model, significant changes in gene expression were detected: in particular, HSP70 was upregulated (1.06 ± 0.38 vs. 0.72 ± 0.20 arbitrary units, P = 0.025), while NOS3 was downregulated (0.66 ± 0.06 vs. 0.83 ± 0.18 arbitrary units, P = 0.007). In the chronic model, liver samples were also assayed, but no significant change in the expression of any gene was detected. We conclude that zofenopril can produce heart-specific effects on gene expression. Persistent changes were detected with regard to specific heat shock protein and nitric oxide synthase subtypes. This action might contribute to the therapeutical response, and particularly to the increased resistance to ischemia.

EDITORIAL: Insights Into the Development and Treatment of Cardiovascular Disease: A Role for Animal Models

Approximately one-third of the total deaths worldwide per annum, amounting to 16.6 million people, is due to cardiovascular disease [1], making it the number one cause of death [2]. Cardiovascular disease also has a major impact on morbidity [1]. Thus, reducing the incidence of deaths due to vascular disease/complications and developing better treatment strategies, remains a central goal for national economies worldwide [3, 4]. Consequently, several animal models have been developed to replicate human vascular diseases, in order to study the pathophysiology of disease progression and novel therapeutic options. This issue of The Open Cardiovascular Medicine Journal discusses some of these models. In this Editorial, each review article for the Special Issue will be briefly outlined, with consideration given to a few additional models. Tsui describes genetically predisposed, chemical and physical animal models of abdominal aortic aneurysms (AAAs) [5]. This review focuses on the pathophysiological mechanisms that underlie the development and progression of AAAs and the different treatment modalities for their management. Ou et al. discusses the development of animal models of myocardial infraction, dilated cardiomyopathy, heart failure, myocarditis and cardiac hypertrophy, emphasising the usefulness of stem cell therapy [6]. Karasu describes abnormal cardiac contractility and impaired vascular reactivity in animal models of diabetes mellitus and highlights the role of antioxidant therapy in preventing or delaying diabetic cardiovascular complications [7]. Grossman explores the use of the renal hypertension-Goldblatt kidney and uraemic cardiomyopathy animal models to look at the relationship between cardiovascular disease and renal pathophysiology [8]. Ameen and Robson describe the relationship between Duchenne Muscular Dystrophy and cardiovascular disease in spontaneous and transgenic animal models, outlining new treatment options [9]. Price et al. discusses the use of magnetic resonance imaging to follow the pathophysiology of myocardial ischaemia and atherosclerosis in animal models. Attention has also been given to imaging the rodent developing heart to assess the influence of genes and congenital diseases [10]. In addition, several other models have been developed for the study of vascular disease. This Editorial briefly addresses some of them.

In the footsteps of Abraham Jacobi, an early international medical graduate: contributions of a single South African medical school to US pediatrics.

Abraham Jacobi is generally recognized as the father of pediatrics in the United States. He was born in Germany and graduated from the University of Bonn in 1851 at a time of political turmoil. He was jailed for 2 years for high treason as a result of his activities as a member of a democratic revolutionary group. He was advised to leave the country to escape additional prosecution. After a brief, unsuccessful attempt to set up a practice in England, he made his way to the United States in 1853 during a period when immigrants from Europe were being welcomed with open arms. He established a practice in the Bowery in New York City, which, at the time, housed a quarter of a million German immigrants and hundreds of thousands of others seeking opportunities in the land of the free. His practice grew by leaps and bounds, and he began translating abstracts of articles from Germany dealing with diseases of children as well as publishing in US journals. In 1859, he co-authored the textbook Midwifery and Diseases of Women and Children. His 1860 appointment as Professor in Infantile Pathology and Therapeutics at New York Medical College was one of the first, if not the first, such academic appointment in pediatrics in the United States. In recognition of his clinical skills, his dynamic bedside teaching, and his contributions to the scientific literature, he was offered and accepted a professorial appointment at Columbia in 1870. However, he had to wait 18 years before he was granted faculty voting privileges. Jacobi’s Therapeutics of Infancy and Children was first published in 1895. He remained at Columbia until his death in 1919, having served as president of both the American Pediatric Society (APS) and the American Medical Association.1–3 As the first international … Reprint requests to (G.S.G.) Emeritus Staff Office, Plummer 10, Mayo Clinic, Rochester, MN 55905. E-mail: gilchrist-gerald{at}msn.com

Myocardial and peripheral concentrations of beta-endorphin before and following myocardial ischemia and reperfusion during coronary angioplasty.

There is substantial evidence indicating that endogenous opioid peptides are involved in the pathophysiology of myocardial ischemia and reperfusion. We measured the myocardial and peripheral concentrations of beta-endorphin before and following myocardial ischemia and reperfusion during coronary angioplasty. The results indicate that in patients with coronary artery disease, there was an augmented myocardial concentration of beta-endorphin. Moreover, there was an increased peripheral concentration of beta-endorphin following myocardial ischemia and reperfusion. The data support the previous notion that endogenous opioid peptides are involved in the pathophysiology of ischemic heart disease.

Exercise-induced myocardial ischaemia in women: factors affecting prevalence.

Coronary artery disease (CAD) is a major health care challenge, and is the leading cause of death amongst women. Both the delay in the clinical manifestations of CAD and 'atypical' symptomatology in women complicates both diagnosis and treatment strategies in this population. It appears that the age-adjusted prevalence of all-cause angina (effort, unstable, etc.) appears to be greater in women than men, although stenotic lesions are demonstrated less frequently. There are a number of factors that complicates the diagnosis and identification of CAD in women, including more diffuse anginal symptoms, a lower initial detection rate of myocardial ischemia by traditional methods, lower rates of interventional procedures, and lastly, potential differences in the pathophysiology of myocardial ischemia. The lower sensitivity and specificity of many diagnostic techniques including ECG and various imaging technologies contributes significantly to these findings. The increased presence of syndrome X in post-menopausal women may reflect an increased likelihood of microcirculatory disease, where the 'gold standard' angiography fails to detect the presence of disease. Thus nonepicardial coronary stenotic disease may be largely undetected by most studies, rendering many positive ECG stress results unverifiable. The increased co-morbidity seen with CAD in women further complicates diagnosis and interventional results. Combined, these factors act to falsely lower the post-test likelihood of disease in women, adding to the existing gender bias in the diagnosis and referral rates for treatment of CAD in women. The lower precision of disease detection in women contributes to the perception that women have less exertional angina than men, despite evidence to the contrary.

The angiotensin II AT1-receptor antagonist candesartan improves functional recovery and reduces the no-reflow area in reperfused ischemic rat hearts.

It is not yet clear if cardiac angiotensin II is involved in the pathophysiology of myocardial ischemia/ reperfusion injury. The aim of this study was to investigate the effect of the angiotensin II AT1-receptor antagonist candesartan on myocardial functional recovery in isolated rat hearts subjected to ischemia and reperfusion. Three groups of hearts perfused in the Langendorff mode with Krebs-Henseleit buffer under constant pressure received either vehicle (n = 7), candesartan, 1 nM (n = 6), or 100 nM (n = 7) at the start of 30 min of global ischemia. The recovery of the double product was significantly higher in the candesartan, 100 nM, group (75+/-9.2%) than in the vehicle group (40+/-5.1%; p < 0.05). At the end of 30 min of reperfusion, left ventricular end diastolic pressure was lower in rats given candesartan, 100 nM, than in rats given vehicle (10+/-4.3 vs. 38+/-4.8 mm Hg; p < 0.05). After ischemia and reperfusion, there was a large no-reflow area in the vehicle group (28+/-3.1% of the left ventricle), which was reduced by candesartan, 100 nM (12+/-1.3%; p < 0.05). In rats given candesartan, 1 nM, there was a trend toward a higher recovery of the double product (73+/-13.4%), a lower left ventricular end-diastolic pressure (29+/-6.6 mm Hg), and a smaller no-reflow area (19+/-3.5% of the left ventricle) compared with the rats receiving vehicle. These trends did, however, not reach statistical significance. Our results demonstrate that candesartan reduces myocardial ischemia/reperfusion injury, thus indicating that endogenous cardiac angiotensin II is involved in the tissue injury after myocardial ischemia and reperfusion.

GUARD during ischemia against necrosis (GUARDIAN) trial in acute coronary syndromes

The plasma membrane sodium–hydrogen exchange system plays a major role in the pathophysiology of myocardial ischemia and reperfusion injury. The GUARD During Ischemia Against Necrosis (GUARDIAN) trial was undertaken to assess the potential clinical benefits of cariporide, a novel inhibitor of the sodium–hydrogen exchanger, in patients with acute coronary syndromes at risk of myocardial necrosis. This prospective, double-blind, randomized, multicenter trial enrolled 11,733 patients who had unstable angina/non–Q-wave myocardial infarction (MI), or who required high-risk percutaneous interventions or coronary bypass surgery. Strict entry criteria were applied to ensure the enrollment of a population at high risk of developing complications. The patients were randomized to receive intravenous cariporide 20, 80, or 120 mg every 8 hours or placebo every 8 hours. Treatment was applied for the period of risk between 48 hours and 7 days. The primary efficacy endpoint was a composite of all-cause mortality and MI at 36 days. Secondary endpoints included the occurrence of the composite endpoint at day 10, events related to left ventricular dysfunction at day 36 and 6 months, extent of infarction, and refractory ischemia at day 36. Enrollment was completed in August 1998, and the results were presented at the American College of Cardiology meeting in New Orleans, Louisiana, USA, in March 1999.