Myocardial Infarct Expansion Research Articles

0191 : The increase in myocardial infarct size induced by intermittent hypoxia and HIF-1 activation, is attenuated by endoplasmic reticulum stress inhibition

Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by repetitive upper airway collapse during sleep leading to chronic intermittent hypoxia (IH). It has been shown in patients that OSA contributes to myocardial infarct expansion. The lack of knowledge about the mechanisms involved in OSA-associated cardiovascular complications had limited the development of specific treatment whereas the gold standard treatment is little tolerated. In the context of cardiomyocytes death or life, this study purposes to investigate the role of endoplasmic reticulum (ER) stress and hypoxia inducible factor-1 (HIF-1) in myocardial susceptibility to ischemia-reperfusion (I/R) induced by chronic IH. C57Bl6J, HIF-1α +/– and their control mice were exposed to 14 days of IH (21–5% FiO2, 60s cycle, 8h/day). Then, mice were submitted to an in vivo ischemia-reperfusion to assess infarct size (IS, in % relative to area at risk) or hearts were removed to assess ER stress markers and HIF-1 activity using Western-blot and ELISA. In additional groups, TUDCA (an ER stress inhibitor, 75mg. kg-1) was administered daily during N or IH exposition to assess the role of ER stress in IH-susceptibility to I/R. Whereas chronic IH induced an increase in infarct size (33.7±9.4 vs 61.0±5.6% in N and IH groups, respectively, p<0.05), IH failed to increase infarct size in HIF1α +/- mice (42.4±2.7 vs 24.7±3.4% in HIF1α +/- -N and HIF1α +/- -IH, respectively). An increase in HIF-1 activity and ER stress markers was also observed in IH-mice. By the way, TUDCA totally abolished the IH-increased in infarct size (49.9±3.0 vs 61.0±5.6% in IH-TUDCA, respectively) as well as the IH-increased in HIF-1 activity (1.3±0.04 vs 0.14±0.02 fold increase in IH and IH/TUDCA, p<0.0001 vs non treated mice). These results suggest that the “ER stress-HIF-1“axe should be considered in apneic patients as a potential therapeutic target to limit myocardial ischemic damages.

Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate-capped Nanosilver.

Silver nanoparticles (AgNP) have garnered much interest due to their antimicrobial properties, becoming one of the most utilized nano-scale materials. However, any potential evocable cardiovascular injury associated with exposure has not been reported to date. We have previously demonstrated expansion of myocardial infarction after intratracheal (IT) instillation of carbon-based nanomaterials. We hypothesized pulmonary exposure to Ag core AgNP induces a measureable increase in circulating cytokines, expansion of cardiac ischemia-reperfusion (I/R) injury and is associated with depressed coronary constrictor and relaxation responses. Secondarily, we addressed the potential contribution of silver ion release on AgNP toxicity. Male Sprague-Dawley rats were exposed to 200 μl of 1 mg/ml of 20 nm citrate-capped Ag core AgNP, 0.01, 0.1, 1 mg/ml Silver Acetate (AgAc), or a citrate vehicle by intratracheal (IT) instillation. One and 7 days following IT instillation the lungs were evaluated for inflammation and the presence of silver; serum was analyzed for concentrations of selected cytokines; cardiac I/R injury and coronary artery reactivity were assessed. AgNP instillation resulted in modest pulmonary inflammation with detection of silver in lung tissue and alveolar macrophages, elevation of serum cytokines: G-CSF, MIP-1α, IL-1β, IL-2, IL-6, IL-13, IL-10, IL-18, IL-17α, TNFα, and RANTES, expansion of I/R injury and depression of the coronary vessel reactivity at 1 day post IT compared to vehicle treated rats. Silver within lung tissue was persistent at 7 days post IT instillation and was associated with an elevation in cytokines: IL-2, IL-13, and TNFα and expansion of I/R injury. AgAc resulted in a concentration dependent infarct expansion and depressed vascular reactivity without marked pulmonary inflammation or serum cytokine response. Based on these data, IT instillation of AgNP increases circulating levels of several key cytokines, which may contribute to persistent expansion of I/R injury possibly through an impaired vascular responsiveness.

C60 Exposure Augments Cardiac Ischemia/Reperfusion Injury and Coronary Artery Contraction in Sprague Dawley Rats

The potential uses of engineered C₆₀ fullerene (C₆₀) have expanded in recent decades to include industrial and biomedical applications. Based on clinical findings associated with particulate matter exposure and our data with multi-walled carbon nanotubes, we hypothesized that ischemia/reperfusion (I/R) injury and pharmacological responses in isolated coronary arteries would depend upon the route of exposure and gender in rats instilled with C₆₀. Male and female Sprague Dawley rats were used to test this hypothesis by surgical induction of cardiac I/R injury in situ 24 h after intratracheal (IT) or intravenous (IV) instillation of 28 μg of C₆₀ formulated in polyvinylpyrrolidone (PVP) or PVP vehicle. Serum was collected for quantification of various cytokines. Coronary artery segments were isolated for assessment of vasoactive pharmacology via wire myography. Both IV and IT exposure to C₆₀ resulted in expansion of myocardial infarction in male and female rats following I/R injury. Serum-collected post-I/R showed elevated concentrations of interleukin-6 and monocyte chemotactic protein-1 in male rats exposed to IV C₆₀. Coronary arteries isolated from male rats exposed to IT C₆₀ demonstrated augmented vasocontraction in response to endothelin-1 that was attenuated with Indomethacin. IV C₆₀ exposure resulted in impaired acetylcholine relaxation in male rats and IT C₆₀ exposure resulted in depressed vasorelaxation in response to sodium nitroprusside in female rats. Based on these data, we conclude that IT and IV exposure to C₆₀ results in unique cardiovascular consequences that may favor heightened coronary resistance and myocardial susceptibility to I/R injury.

Staged Hybrid Treatment for Contained Rupture of a Large Right Coronary Artery Aneurysm

We describe a staged approach to the management of a rare acute condition--contained rupture of a large right coronary artery aneurysm. A covered stent was deployed percutaneously to isolate the aneurysm at presentation followed by planned coronary bypass grafting. Treatment interval was complicated by new-onset pulmonary tuberculosis and subacute thrombosis of the covered stent leading to nonfatal inferior myocardial infarction. Coronary surgery was performed after complete antitubercular treatment and resolution of the acute pericarditis/thrombosis as a consequence of the contained rupture. The advantages of this staged approach included the following: (a) The covered stent prevented both acute myocardial infarction and progressive pseudoaneurysm expansion in the acute phase. (b) Deferred surgery was rendered technically less hazardous while avoiding the undesirable option of having to exclude an extremely calcified dominant right coronary artery. The patient made an excellent postoperative recovery with complete resolution of her symptoms at 6 weeks' follow-up.

Chronic Administration of Small Nonerythropoietic Peptide Sequence of Erythropoietin Effectively Ameliorates the Progression of Postmyocardial Infarction–Dilated Cardiomyopathy

The cardioprotective properties of erythropoietin (EPO) in preclinical studies are well documented, but erythropoietic and prothrombotic properties of EPO preclude its use in chronic heart failure (CHF). We tested the effect of long-term treatment with a small peptide sequence within the EPO molecule, helix B surface peptide (HBSP), that possesses tissue-protective, but not erythropoietic properties of EPO, on mortality and cardiac remodeling in postmyocardial infarction-dilated cardiomyopathy in rats. Starting 2 weeks after permanent left coronary artery ligation, rats received i.p. injections of HBSP (60 µg/kg) or saline two times per week for 10 months. Treatment did not elicit an immune response, and did not affect the hematocrit. Compared with untreated rats, HBSP treatment reduced mortality by 50% (P < 0.05). Repeated echocardiography demonstrated remarkable attenuation of left ventricular dilatation (end-diastolic volume: 41 versus 86%; end-systolic volume: 44 versus 135%; P < 0.05), left ventricle functional deterioration (ejection fraction: -4 versus -63%; P < 0.05), and myocardial infarction (MI) expansion (3 versus 38%; P < 0.05). A hemodynamic assessment at study termination demonstrated normal preload independent stroke work (63 ± 5 versus 40 ± 4; P < 0.05) and arterioventricular coupling (1.2 ± 0.2 versus 2.7 ± 0.7; P < 0.05). Histologic analysis revealed reduced apoptosis (P < 0.05) and fibrosis (P < 0.05), increased cardiomyocyte density (P < 0.05), and increased number of cardiomyocytes in myocardium among HBSP-treated rats. The results indicate that HBSP effectively reduces mortality, ameliorates the MI expansion and CHF progression, and preserves systolic reserve in the rat post-MI model. There is also a possibility that HBSP promoted the increase of the myocytes number in the myocardial wall remote from the infarct. Thus, HBSP peptide merits consideration for clinical testing.

Abstract 9927: Helix B Surface Peptide, a Small Non-erythropoietic Molecule Based on the Erythropoietin Structure, Effectively Ameliorates the Progression of Chronic Heart Failure in the Rat Post Myocardial Infarction Model

The cardioprotective properties of Erythropoietin (EPO) are well documented in pre-clinical studies. However, due to its erythropoietic and prothrombotic properties, the EPO treatment cannot be used in chronic heart failure (CHF), unless indicated by accompanied anemia. Helix B surface peptide (HBSP), a small peptide synthetized on the basis of EPO molecule (ARA290, Araim Pharmaceutical), does not stimulate erythropoiesis. We have reported similarly strong cardioprotective effects of HBSP and EPO in the rat model of myocardial infarction (MI). In this study, we tested the effect of long-term treatment with HBSP on mortality and cardiac remodeling in post-MI CHF in rats. For the 10 months, starting two weeks after left coronary artery ligation, rats received the i.p. injections of HBSP (60µg/kg; n=33) or saline (n=33) 2 times per week. Compared to saline-treated rats, HBSP treatment significantly reduced mortality (35% vs. 65%; p&lt;0.05). Repeated Echocardiography demonstrated remarkable attenuation of left ventricular (LV) chamber dilatation (EDV: 41% vs. 86%; ESV: 44% vs. 135%; p&lt;0.05), LV functional deterioration (EF: -4% vs. -63%; p&lt;0.05) and MI expansion (3% vs. 38%; p&lt;0.05) in HPSP-treated rats compared to saline-treated rats. Blood hematocrit level measured monthly was not affected by HBSP treatment. An invasive hemodynamic assessment at the end of 10-mo treatment showed better LV systolic function (PRSW: 63±5 vs. 40±4; p&lt;0.05) and Arterio-ventricular coupling (Ea/Ees: 1.2±0.2 vs. 2.7±0.7; p&lt;0.05) in HBSP-treated rats compared to saline-treated rats. Histological analysis revealed less apoptosis (0.6±0.1% vs. 0.9±0.1%; p&lt;0.05), myocardial fibrosis (2.6±0.2% vs. 4.1±0.5%; p&lt;0.05), and myocyte hypertrophy (cell diameter: 31±1µm vs. 37±1µm; p&lt;0.05) in non-infarcted myocardium among HBSP-treated rats compared to saline-treated rats. Results suggest that HBSP could be considered as a safe alternative to EPO for a further clinical testing in the patients with chronic heart failure.

Activated protein C improves left ventricular remodelling after ischemia–reperfusion injury in rats

Myocardial infarction (MI) and its associated complications are one of the largest contributors to mortality and morbidity. Paradoxically, coronary reperfusion can cause further myocardial damage through processes such as generation of reactive oxygen species, accumulation of intracellular calcium, and abrupt pH change [ [1] Yellon D.M. Hausenloy D.J. Myocardial reperfusion injury. N Engl J Med. 2007; 357: 1121-1135 Crossref PubMed Scopus (2784) Google Scholar ]. Within the infarcted region contractile muscle is progressively replaced with fibrotic tissue leading to structural remodelling to compensate for altered hemodynamic load. The infarcted left ventricular (LV) wall undergoes thinning and expansion, leading to eventual heart failure [ [2] Hochman J.S. Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation. 1987; 75: 299-306 Crossref PubMed Scopus (406) Google Scholar ]. Activated protein C (APC) is an endogenous anticoagulant with powerful cytoprotective properties that make it an attractive therapeutic for treatment of IR injury. While short term benefit in rat myocardial IR injury has been shown with recombinant human APC (rhAPC) [ [3] Wang J. Yang L. Rezaie A.R. Li J. Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling. J Thromb Haemost. 2011; 9: 1308-1317 Crossref PubMed Scopus (71) Google Scholar ], the translation of this action to long term remodelling remains to be demonstrated.

Activated Protein C Reduces Myocardial Infarct Size and Infarct Expansion in Rats

Activated Protein C Reduces Myocardial Infarct Size and Infarct Expansion in Rats

Survival and Cardioprotective Benefits of Long-Term Blueberry Enriched Diet in Dilated Cardiomyopathy Following Myocardial Infarction in Rats

BackgroundDespite remarkable progress in treatment of chronic heart failure (CHF) over the last two decades, mortality, personal suffering and cost remain staggering, and effective interventions are still a challenge. Previously we reported that a blueberry-enriched diet (BD) attenuated necroapoptosis and inflammation in periinfarct area in a rat model of myocardial infarction (MI).ObjectivesTo test the hypothesis that BD will attenuate the course of CHF, including mortality and cardiac remodeling during the first year after induction of MI in rats.Method and ResultsTwo weeks after coronary artery ligation, rats were divided into two groups of similar average MI size, measured by echocardiography, and then12-mo dietary regimens were initiated as follows: ad libitum regular diet (control, CD, n = 27) and isocaloric food with 2% blueberry supplement (BD, n = 27) also available ad libitum. These dietary groups were compared to each other and to sham group (SH). Mortality over the 12 mo was reduced by 22% in BD compared with CD (p<0.01). In the course of developing CHF, BD had no effect on the body weight, heart rate or blood pressure. Bi-monthly Echo revealed significant attenuation of the LV chamber remodeling, LV posterior wall thinning, and MI expansion in BD compared with CD. In fact, BD arrested the MI expansion.ConclusionThis is the first experimental evidence that a blueberry-enriched diet has positive effects on the course of CHF and thus warrants consideration for clinical evaluation.

Blueberry-Enriched Diet Protects Rat Heart from Ischemic Damage

Objectivesto assess the cardioprotective properties of a blueberry enriched diet (BD).BackgroundReactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. The attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in natural products. Blueberries are readily available product with the highest antioxidant capacity among fruits and vegetables.Methods and ResultsFollowing 3-mo of BD or a regular control diet (CD), the threshold for mitochondrial permeability transition (tMPT) was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001) of ROS indexed tMPT. The remaining animals were subjected to a permanent ligation of the left descending coronary artery. 24 hrs later resulting myocardial infarction (MI) in rats on BD was 22% less than in CD rats (p<0.01). Significantly less TUNEL(+) cardiomyocytes (2% vs 9%) and 40% less inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.01). In the subgroup of rats, after coronary ligation the original diet was either continued or switched to the opposite one, and cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Measurements suggested that continuation of BD or its withdrawal after MI attenuated or accelerated rates of post MI cardiac remodeling and MI expansion.ConclusionA blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.

Cardioprotective and Survival Benefits of Long-Term Combined Therapy with β2 Adrenoreceptor (AR) Agonist and β1 AR Blocker in Dilated Cardiomyopathy Postmyocardial Infarction

We have reported therapeutic effectiveness of pharmacological stimulation of beta2 adrenoreceptors (ARs) to attenuate the cardiac remodeling and myocardial infarction (MI) expansion in a rat model of dilated cardiomyopathy (DCM) post-MI. Furthermore, the combination of beta2 AR stimulation with beta1 AR blockade exceeded the therapeutic effectiveness of beta1 AR blockade. However, these studies were relatively short (6 weeks). In this study, in the same experimental model, we compared different effects, including survival benefit, of combined therapy with the beta1 AR blocker, metoprolol, plus the beta2 AR agonist, fenoterol (beta1-beta2+), and either therapy alone (beta1- or beta2+) during the 1-year study. Therapy was started 2 weeks after permanent ligation of the left coronary artery. Cardiac remodeling, MI expansion, and left ventricular function were assessed by serial echocardiography and compared with untreated animals (nT). Sixty-seven percent mortality in nT was reduced to 33% in the beta1-beta2+ (p < 0.01). Progressive cardiac remodeling observed in nT and beta1- was significantly attenuated in beta1-beta2+ during the first 6 months of treatment. In beta1-beta2+, MI expansion was completely prevented, and functional decline was significantly attenuated during the entire year. Myocardial apoptosis was significantly reduced in both beta1-beta2+ and beta1-. A reduction of cardiac beta1 AR density and decreases in chronotropic and contractile responses to beta2 AR-specific stimulation in the absence of a reduction of beta2 AR density in nT were precluded in rats receiving combined therapy. The results demonstrate the cardioprotective and survival benefit of long-term combination therapy of beta2 AR agonists and beta1 AR blockers in a model of DCM.

ANGIOTENSIN II AND MYOCARDIAL INFARCTION

The role of angiotensin II in pathogenesis of cardiovascular diseases is discussed. Angiotensin II participates in development of acute myocardial infarction (MI) in patients with atherosclerosis. It contributes to inflammation of vessel intimae, oxidative stress, cells apoptosis, matrix remodeling, has pro-thrombosis action, promotes MI expansion and post-MI remodeling. Angiotensin converting enzyme (ACE) inhibitors reduce mortality and improve prognosis of patients with acute MI. In patients with ischemic heart disease including patients after MI ACE inhibitors reduce mortality, risk of repeated MI as well as improve quality of life.

Intracardiac lipid accumulation, lipoatrophy of muscle cells and expansion of myocardial infarction in type 2 diabetic patients

The overall mortality of diabetic patients after myocardial infarction is 3–4 times higher than non-diabetics. The cellular mechanisms underlying such a poor clinical prognosis remain incompletely understood. Recent reports suggest that lipotoxicity associated with impaired liporegulation is among the leading factors in the pathogenesis of type 2 diabetes. The goal of this study was to investigate whether excess lipid accumulation specifically in heart muscle cells contributes to the expansion of myocardial infarction in type 2 diabetic patients. Comparative structural analysis of cardiac tissue was performed on autopsy samples from the infracted hearts of diabetic and non-diabetic individuals with special reference to the expansion of the infarction, degenerative changes, lipoatrophy, cell death, and replacement fibrosis. We found that progressive accumulation of lipids in cardiac myocytes was accompanied by considerable loss of myofibrils and was frequently observed in the heart tissue of type 2 diabetic patients. This indicates that disassembly of the contractile apparatus in the cells infiltrated with lipids weakens their capability for functional activity. Analysis of degenerative changes in the diabetic tissue has shown that lipid-laden cardiac myocytes were more susceptible to necrotic and apoptotic cells death leading to expansion of the infarction and the development of progressive focal replacement fibrosis both in the perinecrotic zone and in the areas located far from the site of injury. Our data show that lipoatrophy and loss of muscle cells during the post-infarction period aggravate the functional impairment in the diabetic heart and limits its adaptive capacity for compensatory remodeling. This suggests that lipotoxic myocardial injury associated with defects of lipid metabolism in type 2 diabetes predisposes its evolution toward congestive heart failure and is an important factor contributing to a high mortality following infarction.

The Transforming Growth Factor-β/Smad3 Pathway

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …

Effects of SM-20550 Against Myocardial Infarction-induced Arrhythmias, Late Infarct Expansion, and Left Ventricular Dysfunction

The aim of the study was to evaluate the cardioprotective and antiarrhythmic effects of intravenous Na+/H+ blockers (cariporide and SM-20550) in a rat model of ischemia and a long period reperfusion (14 days). This model allowed study of the role of Na+/H+ exchanger against late myocardial infarct expansion and left ventricular dysfunction. Each compound was administered 5 min before ischemia. Cariporide (from 0.16 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly and dose-dependently reduced the number of ventricular premature beats during ischemia. The duration of ventricular tachycardia was importantly shortened in the presence of cariporide (0.63 mg/kg) and SM-20550 (0.16 mg/kg). Furthermore, cariporide (0.63 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly reduced the infarct expansion: 43 +/- 2% in the cariporide group and 42 +/- 2% at 0.16 mg/kg SM-20550 versus 48 +/- 1% in the vehicle group. Cariporide and SM-20550 significantly prevented the left ventricular free wall thinning associated with the thickness ratio, suggesting a significant reduction of the ventricular dilation. Cariporide and SM-20550 significantly improved the negative dP/dtmax, suggesting a partial restoration of the cardiac relaxation. Collectively, Na+/H+ blockers administered before ischemia reduced arrhythmias and also prevented the remodeling process of the heart during postinfarction.

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

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 …

Serial Multimodality Assessment of Myocardial Infarction in Mice Using Magnetic Resonance Imaging and Micro–Positron Emission Tomography Provides Complementary Information on the Progression of Scar Formation

Recent technological advances have made imaging the mouse heart possible using both 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI),1–4 thus facilitating the investigation of mechanisms underlying the progression toward heart failure after myocardial infarction (MI). These imaging modalities provide complementary information regarding cellular metabolism and infarct location, respectively. To demonstrate this, we used FDG PET and MRI in a serial study of male C57Bl/6 mice that were subjected to a 1-hour coronary occlusion and then 30 days of reperfusion. Imaging was performed 1, 7, and 28 days after coronary occlusion. Gd-enhanced ECG-gated cardiac MRI was performed using a 4.7-T MRI scanner (Varian, Inc, …

Cardioprotection by Intermittent Fasting in Rats

Intermittent fasting (IF), a dietary regimen in which food is available only every other day, increases the life span and reduces the incidence of age-associated diseases in rodents. We have reported neuroprotective effects of IF against ischemic injury of the brain. In this study, we examined the effects of IF on ischemic injury of the heart in rats. After 3 months of IF or regular every-day feeding (control) diets started in 2-month-old rats, myocardial infarction (MI) was induced by coronary artery ligation. Twenty-four hours after MI, its size in the IF group was 2-fold smaller, the number of apoptotic myocytes in the area at risk was 4-fold less, and the inflammatory response was significantly reduced compared with the control diet group. Serial echocardiography revealed that during 10 weeks after MI (with continuation of the IF regimen), the left ventricular (LV) remodeling and MI expansion that were observed in the control diet group were absent in the IF group. In a subgroup of animals with similar MI size at 1 week after MI, further observation revealed less remodeling, better LV function, and no MI expansion in the IF group compared with the control group. IF protects the heart from ischemic injury and attenuates post-MI cardiac remodeling, likely via antiapoptotic and antiinflammatory mechanisms.

Wound model of myocardial infarction

ischemic heart disease is the major etiology for heart failure today ([3][1]). The initial event is frequently a large or recurrent myocardial infarction. Acute myocardial infarction starts with thrombotic occlusion of a coronary artery, develops during several hours, and terminates when necrosis

Cardioprotective potential of intermittent fasting in rats

Background: Intermittent Food Deprivation (IF), i.e., the feeding regimen when ad lib food is available only every other day, increases the life span and reduces the incidence of age-associated diseases including cancer, diabetes and kidney disease. We have reported the neuroprotective effects of IF against ischemic injury of the brain (Yu and Mattson, J. Neurosci. Res. 57:830–9; 1999). The mechanisms of neuroprotection of IF is not clear, but diminishing free-radical production, a mild cellular stress response, and attenuated inflammatory response are implicated. Here we investigated the cardioprotective effect of IF in rats. Method: After three months of IF or regular, daily, feeding ad libitum (AF), 5-mo old rats were subjected to coronary ligation or sham operation. A subset of rats was sacrificed 24 hours later to measure the size of myocardial infarction (MI) and the extent of apoptosis. The remaining animals were continued for 10 weeks on the same food regimen, during which time the progression of left ventricular (LV) remodeling was assessed by serial echocardiography. After ten weeks LV function was measured by pressure-volume loops analyses, and hearts were evaluated histologically. Results: 24 hrs following coronary ligation the ischemic area of myocardium, i.e., the area at risk (AAR), was similar in both groups, but in IF rats MI size, expressed as a percent of AAR, was more than 2-fold smaller, apoptosis in the AAR was reduced by more than 4-fold (Fig.1), and the inflammatory response was significantly reduced. At 10-wks late LV remodeling and MI expansion occurred in AF rats but did not occur in IF rats, and LV pump function and arterio-ventricular coupling were superior in IF vs AF rats. The myocyte hypertrophy in areas remote from the MI was also absent in IF rats. Conclusion: Intermittent Food Deprivation protects the heart from ischemic injury in part, at least, via an anti-apoptotic mechanism.