B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

Splenic Marginal Zone B Lymphocytes Regulate Cardiac Remodeling After Acute Myocardial Infarction in Mice

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

Myocardial infarction is a major cause of death and disability worldwide. Coronary atherosclerosis is a chronic disease with stable and unstable periods. During unstable periods with activated inflammation in the vascular wall, patients may develop a myocardial infarction. Myocardial infarction may be a minor event in a lifelong chronic disease, it may even go undetected, but it may also be a major catastrophic event leading to sudden death or severe hemodynamic deterioration. A myocardial infarction may be the first manifestation of coronary artery disease, or it may occur, repeatedly, in patients with established disease. Information on myocardial infarction attack rates can provide useful data regarding the burden of coronary artery disease within and across populations, especially if standardized data are collected in a manner that demonstrates the distinction between incident and recurrent events. From the epidemiological point of view, the incidence of myocardial infarction in a population can be used as a proxy for the prevalence of coronary artery disease in that population. Furthermore, the term myocardial infarction has major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world, and it is an outcome measure in clinical trials and observational studies. With these perspectives, myocardial infarction may be defined from a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics. In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction. In studies of disease prevalence, the World Health Organization (WHO) defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a …

Cessation of coronary blood flow, due to stenosis or acute blockage, produces prolonged ischemia that results in myocardial infarction (MI) and impaired cardiac function and blood pumping activity of heart. Increasing coronary blood flow to the ischemic area and/or reducing myocardial work are predicted to mitigate the damage typically associated with an acute MI injury. Recent studies from our group have demonstrated that pharmacological enhancement of endothelial KCa2.3 and KCa3.1 channels by the activator SKA‐31 improves agonist‐evoked vasodilation in small resistance arteries from multiple vascular beds and species. The goal of our present study is to investigate the potential cardio‐protective effects of SKA‐31 administration in male mice (12–15 weeks of age, C57B1/6 strain) following an acute myocardial infarct (MI) induced by permanent surgical ligation of the left‐anterior descending (LAD) coronary artery. Within 48 h post‐surgery, MI and sham surgery mice were treated orally with either vehicle or 10 mg/kg of SKA‐31 for 6–7 weeks. Myocardial damage in MI mice was confirmed by histological staining. Echocardiographic assessment of cardiac structure and function 2 weeks post‐surgery revealed that left ventricular (LV) wall thickness during systole and diastole was similar in sham animals treated with either vehicle or SKA‐31. In contrast, LV wall thickness during systole and diastole was ~30% greater in MI surgery mice receiving SKA‐31 treatment. At 4 weeks post‐surgery, sham animals exhibited LV wall thickness values during systole (1.00 mm ± 0.03, n=3) and diastole (0.82 mm ± 0.10, n=3) that were similar to those observed at 2 weeks, indicating that SKA‐31 treatment did not adversely affect these parameters. In MI surgery animals receiving SKA‐31 administration for 4 weeks, LV wall thickness during systole (0.97 mm ± 0.10, n=5) and diastole (0.80 mm ± 0.08, n =5) decreased to the values observed in sham surgery mice. At the end of the SKA‐31 treatment period, cardiac output (CO) and LV ejection fraction (EF) measured by pressure‐volume loop analysis were both higher in sham mice (CO = 6.49 mL/min, EF = 50.9%) compared with MI surgery animals (CO = 5.83 mL/min, EF = 40.7%). Following completion of ongoing measurements and analyses, we will present additional data describing changes in cardiac function in MI surgery mice treated with drug vehicle, and histological assessment of myocardial integrity in sham and MI surgery mice. Our preliminary findings thus far suggest that enhancement of endothelial KCa channel activity by SKA‐31 administration improves recovery of cardiac function following ischemic damage associated with blockade of the LAD coronary artery.Support or Funding InformationThis work was supported by research funding to APB from the Canadian Institutes of Health Research (MOP 142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116).

Management of Acute Coronary Syndromes

Experimental myocardial infarction (MI) in mice is an important disease model, in part due to the ability to study genetic manipulations. MRI has been used to assess cardiac structural and functional changes after MI in mice, but changes in myocardial perfusion after acute MI have not previously been examined. Arterial spin labeling noninvasively measures perfusion but is sensitive to respiratory motion and heart rate variability and is difficult to apply after acute MI in mice. To account for these factors, a cardiorespiratory-gated arterial spin labeling sequence using a fuzzy C-means algorithm to retrospectively reconstruct images was developed. Using this method, myocardial perfusion was measured in remote and infarcted regions at 1, 7, 14, and 28 days post-MI. Baseline perfusion was 4.9 +/- 0.5 mL/g min and 1 day post-MI decreased to 0.9 +/- 0.8 mL/g min in infarcted myocardium (P < 0.05 versus baseline) while remaining at 5.2 +/- 0.8 mL/g min in remote myocardium. During the subsequent 28 days, perfusion in the remote zone remained unchanged, while a partial recovery of perfusion in the infarct zone was seen. This technique, when applied to genetically engineered mice, will allow for the investigation of the roles of specific genes in myocardial perfusion during infarct healing.

Recent advances in the management of unstable angina and non-Q-wave myocardial infarction

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

Background and Objectives：Myocardial infarction (MI) elicits nerve sprouting. However, the time course and spatial distribution of this nerve sprouting and its relationship to the expression of neurotrophic factors is unclear. The aim of this study was to identify the association of nerve sprouting with the expression of neurotrophic factors. Materials and Methods：We induced MI in FVB mice by ligating the left coronary artery. The hearts were removed at 3 hours to 13 months after MI for growth associated protein 43 (GAP-43) immunostaining. The nerve density (μm 2 /mm 2 ) was determined by ImagePro software. In another group of mice, their myocardial tissues were processed and analyzed with using an Affymetrix RG U74V2 array. Results：The density of the nerve fibers that were immunopositive for GAP-43 was the highest 3 hours after MI in both the peri-infarct areas and the remote areas. The outer loop of the ventricle had a higher nerve density than that in the inner loop of the ventricle. The differences were at a peak 3 hours after MI, but they persisted for 2 months afterwards. The expressions of nerve growth factor, insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-β3 and interleukin-1α were increased for up to 2 months after MI as compared to the normal control. qRT PCR analyses showed increased mRNA for tyrosine hydroxylase, synaptophysin, nerve growth factor and leukemia inhibiting factor in the peri-infarct areas for up to 2 months after MI, but this occurred only for roughly 3 days after MI in the remote areas. Conclusion：We conclude that MI resulted in immediate upregulation of nerve growth factor, insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-β3 and interleukin-1α in the peri-infarct areas and this all occurred to a lesser extent in the remote areas. These changes persisted for at least 2 months, and they were associated with increased nerve sprouting activity, which was most active in the outer loop of the heart. (Korean Circulation J 2007;37:399-407)

Endothelial dysfunction (ED) is a common underlying feature of several premorbid conditions (e.g. obesity, Type 2 Diabetes (T2D), atherosclerosis, hypertension) associated with the development of myocardial infarction (MI). The ability of an artery to dilate properly and oppose plaque formation within the vascular wall is compromised by ED, which ultimately leads to reduced blood flow. In the coronary circulation, ED can decrease blood supply to the working myocardium and the resulting prolonged ischemia can promote MI. Recent studies from our group have demonstrated that a small molecule activator of endothelial KCa2.3 and KCa3.1 channel activity (i.e. SKA‐31) improves agonist‐evoked vasodilation in resistance arteries from multiple vascular beds and species, and this effect remains robust in arteries from T2D tissues. We have further observed that prolonged administration of SKA‐31 to aged rats improves both their cardiac and vascular functions. Thus, the goal of this project is to investigate the potential cardio‐protective effects of SKA‐31 in male mice (12‐15 weeks of age, C57B1/6 strain) following an acute MI induced by permanent surgical ligation of the left‐anterior descending coronary artery. Within 48 h post‐surgery, MI and sham surgery mice were treated orally with either vehicle or 10 mg/kg of SKA‐31 daily for 6 weeks. Myocardial damage in MI mice was confirmed by histological staining. Echocardiographic assessment of cardiac function 4 weeks post‐surgery revealed that Ejection Fraction (EF) and Fractional Shortening (FS) were similar in sham animals treated with either vehicle or SKA‐31 (Table 1). Similar results were observed for measurements of end systolic volume (ESV) and end diastolic volume (EDV). In contrast, the MI animals treated with vehicle displayed ~50% decreases in EF and FS, and significantly larger values for ESV and EDV. These functional and structural parameters thus confirm the presence of sustained cardiac dysfunction in the MI mice. Treatment of MI mice with SKA‐31 did not lead to improvements in EF, FS, ESV or EDV compared with vehicle treated animals. Our preliminary findings indicate that SKA‐31 treatment did not affect the healthy cohort, but also did not improve gross cardiac function in the MI group. Recent data indicate that an acute MI is typically followed by a robust inflammatory response within the injured myocardium that peaks 3 days post‐MI and declines to baseline by 7‐9 days. We speculate that this local immune response is exacerbated by SKA‐31 administration within 48 h post‐injury, thereby negating any potential benefit of SKA‐31 at the level of the vasculature. Delaying SKA‐31 administration to coincide with the full decline of the local immune response may prove more effective in restoring cardiac function.

Fibrosis, which occurs in various heart diseases like acute myocardial ischemia and pressure overload, is triggered by the differentiation of fibroblasts into myofibroblasts. Dysregulation of this reparative mechanism results in excessive collagen accumulation leading to cardiac stiffness and impaired heart function. The aim of this study was to determine whether the rhubarb anthraquinone Rhein, a drug already used as treatment for chondroarthritis, prevents the transdifferentiation of cardiac fibroblasts. We observed that Rhein pre-treatment ameliorates the cardiac function and reduces adverse remodeling after acute myocardial infarction in mice, in vivo . In primary human cardiac fibroblasts, Rhein incubation dose-dependently inhibited the TGF-β-mediated upregulation of α-SMA, the master marker for myofibrolasts, and prevented the contraction of fibroblast-populated collagen gel lattices upon TGF-β stimulation. Further, Rhein reduced TGFβ-R1 expression in primary human cardiac fibroblast, resulting in decreased SMAD2 phosphorylation and blunting of the fibrogenic response. Furthermore, Rhein stabilized protein levels of SMAD7, a key inhibitor of TGF-β signaling. Collectively, these data show for the first time that Rhein administration prevents cardiac fibrosis in vivo and in vitro by blunting the TGF-β signaling pathway, and identify Rhein as potential therapeutic treatment to prevent excessive fibrosis and adverse remodeling in cardiac pathologies.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

Cardiomyocyte loss via apoptosis plays a crucial role in ventricular remodeling following myocardial infarction (MI). Cell-based therapy approaches using bone marrow derived c-kit+ pluripotent cells may attenuate apoptosis following ischemic injury. We therefore thought to examine the early course of apoptosis following myocardial infarction - in-vivo - and non-invasively determine the effect of c-kit+ bone marrow cells on post-MI remodeling. We studied apoptosis in wild-type Kit+/+, c-kit mutant KitW/KitW-v and KitW/KitW-v mice after cell therapy with bone-marrow derived c-kit+ cells after ischemia-reperfusion injury. Mice were followed by hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) at 6h, 24h and 7 days after ischemia-reperfusion injury using an Annexin V-based fluorescent nanosensor targeting phosphatidylserine. KitW/KitW-v mice showed increased and prolonged apoptosis compared to control Kit+/+ mice while c-kit cell therapy was able to attenuate the altered apoptosis rates. Increased apoptosis was accompanied by severe decline in heart function, determined by cardiac Magnetic Resonance Imaging, and cell therapy was able to rescue the animals from deleterious heart failure. Post-mortem cryoslicing and immunohistochemistry localized the fluorescence signal of the Annexin V sensor within the infarcted myocardium. Flow cytometry of digested infarct specimens identified apoptotic cardiomyocytes as the major source for the in-vivo Annexin V signal.In-vivo molecular imaging using hybrid FMT-XCT reveals increased cardiomyocyte apoptosis in KitW/KitW-v mice and shows that c-kit+ cardioprotective cells are able to attenuate post-MI apoptosis and rescue mice from progressive heart failure.

BackgroundA prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice.Methods and ResultsONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group.ConclusionsSustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.

Aim. To identify regional specifics of changes in mortality rates from acute types of coronary artery disease (CAD) in 82 Russian regions for the period from 2015 to 2019.Material and methods. The study used data from the Federal State Statistics Service of Russia on mortality from acute CAD types in 82 Russian regions. Standardized death rates (SDRs) for 2015 and 2019 were estimated based on the European standard. We analyzed the SDRs of the population from acute (primary) and recurrent myocardial infarction (MI), other acute CAD types (I21-I22, I24.8 in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10)).Results. Over the period from 2015 to 2019, mortality from all acute CAD types decreased by 21%, from acute MI — by 9%, from recurrent MI — by 22%, from any MI (acute/recurrent) recurrent — by 14%, and from other CAD types — by 21%. A decrease in mortality from all acute CAD types was recorded in 69 regions, from acute MI — in 58 regions, and recurrent MI — in 62 regions. However, a simultaneous decrease in SDRs from each of the acute CAD types (acute MI, recurrent MI and other acute CAD types) for the period 2015-2019 occurred only in 29 Russian regions. An increase in mortality from all acute CAD types was noted in 14 regions and from any MI — in 21 regions. The coefficient of variation (Cv) for recurrent MI and other acute CAD types of 69% and 103%, respectively, in 2015 and its growth (up to 75% and 134%, respectively) by 2019 indicate growing problems with the coding of death causes.Conclusion. In 2019, compared to 2015, a decrease in mortality from acute CAD types was recorded in most Russian regions. The identified regional specifics require clarification of approaches to death cause coding and the introduction of additions to mortality reduction programs, taking into account the specifics of each Russian region.