Metabolic and physical changes during calcium paradox induced in the rat heart

Early changes in metabolic and physical properties were determined in rat hearts during calcium paradox. Calcium paradox was induced under constant perfusion pressure (60 mmHg) or constant coronary flow rate (9.8 ml/min). Within 30 s after calcium repletion, in either case, NADH increased, despite a decrease in ATP and increases in ADP and AMP. Surface spectrophotometry showed a deoxygenation of the myoglobin, thereby indicating myocardial oxygen depletion. These changes were predominant under conditions of constant pressure perfusion. In association with a rapid development of contracture, there were also a reduction in coronary flow (18%) in constant pressure perfusion, and an increase in perfusion pressure (208%) under constant flow perfusion. Thus, tissue deoxygenation has to be given due attention in the early development of calcium paradox, particularly in case of a constant pressure perfusion. Under constant flow perfusion, the physical stress due to high pressure perfusion against contracture may play an important role in the development of calcium paradox. This may be the first reported evidence for tissue anoxia in calcium paradox.     

Metabolic and physical changes during calcium paradox induced in the rat heart.

Early changes in metabolic and physical properties were determined in rat hearts during calcium paradox. Calcium paradox was induced under constant perfusion pressure (60 mmHg) or constant coronary flow rate (9.8 ml/min). Within 30 s after calcium repletion, in either case, NADH increased, despite a decrease in ATP and increases in ADP and AMP. Surface spectrophotometry showed a deoxygenation of the myoglobin, thereby indicating myocardial oxygen depletion. These changes were predominant under conditions of constant pressure perfusion. In association with a rapid development of contracture, there were also a reduction in coronary flow (18%) in constant pressure perfusion, and an increase in perfusion pressure (208%) under constant flow perfusion. Thus, tissue deoxygenation has to be given due attention in the early development of calcium paradox, particularly in case of a constant pressure perfusion. Under constant flow perfusion, the physical stress due to high pressure perfusion against contracture may play an important role in the development of calcium paradox. This may be the first reported evidence for tissue anoxia in calcium paradox.     

Drug-induced myocardial infarction secondary to coronary artery spasm in teenagers and young adults

There is no published registry for drug-induced acute myocardial infarction (AMI) with subsequent patent coronary angiogram in teenagers. To highlight the mechanism and impact of drug-induced MI with patent coronary arteries among teenagers who have relatively few coronary risk factors in comparison with older patients, we conducted a review of the literature. In this review most of the pertinent published (English and non-English) articles through the Medline, Scopus, Cochrane Database of Systematic Reviews and EBSCO Host research databases from 1970 to 2005 have been revised. Teenagers and young adults with AMI and subsequent patent coronary angiogram were included. In those cases drug-induced coronary spasm was highlighted. Among 220 articles (>12000 cases) related with AMI with normal coronary angiogram, 50 articles (approximately 100 cases) reported the role of drug in AMI secondary to coronary artery spasm (CAS). There is no well-conducted trial for AMI secondary to CAS in young adults but only a series of case reports and the diagnosis in most of cases was based on the clinical and laboratory findings without provocation. CAS was associated with 12 illicit substances in teenagers (i.e, cocaine, marijuana, alcohol, butane and amphetamine). Smoking is not only the initiative but also might harbor other illicit substances that increase the risk for CAS. Cocaine-associated AMI is the most frequent in various research papers. CAS was reported with 19 types of medications (i.e, over-the-counter, chemotherapy, antimigraine and antibiotics) without strong relation to age. Despite drug-induced AMI being not a common event, attention to smoking and drugs in teenagers and young adults will have major therapeutic and prognostic implications.     

Cocaine-induced coronary-artery vasoconstriction

Intranasal cocaine is used frequently as a local anesthetic during many rhinolaryngologic procedures. Although its "recreational" use in high doses has been associated with chest pain and myocardial infarction, this association has not been established when cocaine is used in low doses as a topical anesthetic, and its effect on the coronary vasculature of humans is unknown. We studied the effects of intranasal cocaine (10 percent cocaine hydrochloride; 2 mg per kilogram of body weight) on the blood flow in and dimensions of the coronary arteries and on myocardial oxygen demand in 45 patients (34 men and 11 women, 36 to 67 years of age) who were undergoing cardiac catheterization for the evaluation of chest pain. Heart rate, arterial pressure, blood flow in the coronary sinus (measured by thermodilution), and the dimensions of the epicardial left coronary artery (measured by quantitative arteriography) were measured before and 15 minutes after the intranasal administration of saline (in 16 patients) or cocaine (in 29). No variables changed after the administration of saline. After cocaine was administered, the heart rate and arterial pressure rose, the coronary-sinus blood flow fell (from a mean [+/- SD] of 149 +/- 59 ml per minute to 124 +/- 53 ml per minute), and the diameter of the left coronary artery decreased by 8 to 12 percent (P less than 0.01 for all comparisons). No patient had chest pain or electrocardiographic evidence of myocardial ischemia after the administration of cocaine. Subsequently, the administration of the alpha-adrenergic blocking agent phentolamine caused all these values to return to base-line levels. There was no difference in response between the patients found to have disease of the left coronary artery (n = 28) and those without such disease (n = 17). We conclude that the intranasal administration of cocaine near the dose used for topical anesthesia causes vasoconstriction of the coronary arteries, with a decrease in the coronary blood flow, despite an increase in myocardial oxygen demand, and that these effects are mediated by alpha-adrenergic stimulation. It is reasonable to assume that these effects would be more pronounced at the much higher doses associated with the recreational use of cocaine.     

Cocaine and the heart

There is increasing evidence that cocaine can have serious adverse effects on the heart. Angina, myocardial infarction, coronary artery spasm, arrhythmia, and sudden death have been reported in association with its use. There have been only two reports of actual myocardial pathology. In an attempt to clarify the pathophysiology of cocaine-associated cardiotoxicity and to search for pathologic changes that might be useful forensically, we reviewed random microscopic sections of hearts from 30 cases of cocaine-associated death seen by the San Francisco Medical Examiner. The age of the patients at death ranged from 25 to 74 years (mean 33.9 years). Pathologic findings included the presence of mild atherosclerotic coronary artery disease without evidence of thrombosis in three cases, associated with mild interstitial fibrosis in one case as well as mild focal myocardial fibrosis without coronary disease in four other cases. The most notable abnormality was the presence of myocardial contraction bands in 28 (93 per cent) cases. In comparison to 20 control cases of death secondary to sedative-hypnotic overdose, the hearts from the cases of cocaine-associated contained significantly more myocardial contraction bands (P less than .001; two-sided). The diffuseness of the contraction bands correlated directly with the level of cocaine found in the urine and blood at autopsy during routine screening. The presence and number of contraction bands in these cases was independent of other drugs found in the urine and blood, the number of sections of myocardium examined, and a history of attempted resuscitation. Contraction bands may act to supply the anatomic substrate for the arrhythmias associated with cocaine use. They may also provide a morphologic marker that can be sought in suspected cases of lethal cocaine overdose. Their presence may also suggest a cause of death in cases of sudden and unexpected death in which autopsy reveals no other pathology, and a drug screen is positive for cocaine.     

Invasive examination of cardiovascular disease

Invasive cardiovascular examination by coronary angioscopy and by using a Doppler guide wire, a pressure guide wire and intravascular ultrasound has extensively developed. A Doppler guide wire is used for measurement of flow velocity and evaluation of coronary blood flow. Previous studies demonstrated by assessing maximum coronary vasodilatory capacity that endothelium-dependent or independent vasodilation was impaired in hypertension and hypercholesterolemia or in syndrome X. Elevation of coronary vascular resistance during coronary microvascular spasm has been verified by using a Doppler wire. A pressure guide wire provides coronary transstenotic pressure and is available in calculating myocardial fractional flow reserve(FFRmyo). FFRmyo is an important parameter to assess the coronary functional stenosis that is culprit for myocardial ischemia. It is calculated from the ratio of the mean transstenotic pressure to the mean pressure proximal to the stenosis during maximum coronary hyperemia. The value of FFRmyo considered as necessary for coronary intervention is below 0.75. Intravascular ultrasound(IVUS) is applied as both a diagnostic tool and for intervention purpose. It enabled tissue characterization of the vascular wall as well as measurements of vascular diameter, vascular lumen area and plaque area. It also aided in optimal devise selection, decision of interventional endpoint and assessment of restenosis. IVUS promoted deployment of high-pressure stents to obtain a large post-procedural lumen area as well as abolition of anticoagulation in case of optimal stent deployment. Coronary angioscopy has been developed to investigate the pathogenesis of acute coronary syndrome, where disrupted yellow plaque and overlying thrombus play important roles. Angioscopy has also evidenced regression of intimal hyperplasia after coronary stenting.     

Effects of myocardial contraction on coronary blood flow: An integrated model

The effects of myocardial contraction on the coronary flow are studied by means of an integrated structural model of left ventricular (LV) mechanics, coronary flow, and fluid and mass transport. This model relates global LV performance, and in particular coronary flow dynamics, to myocardial composition and structure and contractile sarcomere activity. Extravascular pressure is identified with hydrostatic tissue pressure,i. e., intramyocardial pressure (IMP), and is determined by the dynamics of myocardial contraction and fluid transport. Consistent with available experimental data, changes in myocardial function and contractile state are simulated by changing the sarcomere contractile properties or changing the LV loading conditions. The model's predictions are successfully compared with a wide range of experimental studies; all but one were performed at a constant coronary perfusion pressure and maximal vasodilation. The results indicate a domiant effect of the myocardial contractile state on coronary flow and a dissocation between coronary compression and LV cavity pressure (LVP) when the pressure is controlled by load changes. However, when active sarcomere contraction is regionally impaired by lidocaine, LVP plays an important role in the coronary flow characteristics. The model adequately predicts observations on the effect of cardiac contraction on systolic and diastolic coronary flows, as well as the role of LVP at different loading and contractile conditions. The analysis supports the hypothesis that coronary compression, as mediated through IMP, is independent of LV loading conditions and depends on myocardial contractility and coronary perfusion pressure.     

Spasm of small coronary arteries and ischemic myocardial injury induced by hypothalamic stimulation in the rat.

Electrical stimulation of the lateral hypothalamus resulted in electrocardiographic evidence of acute myocardial ischemia in 35% of normal adult rats under anesthesia. Mean arterial blood pressure was also elevated. Study of vascular corrosion casts disclosed that spasm of smaller branches of the coronary circulation, rather than the major epicardial arteries, was the main cause of the ischemic response. The histologic changes of the same experimental treatment in a separate group of animals revealed multiple focal areas of tissue damage throughout the myocardium, which were quantitatively assessed. The results may be relevant for the clinical problem of various forms of ischemic heart disease in which little evidence is found for organic (atherosclerosis) or dynamic (spasm) stenosis involving the major coronary arteries.     

Dual intoxication with diazepam and amphetamine: this drug interaction probably potentiates myocardial ischemia

Drug-induced myocardial infarction is not a common phenomenon and the underlying mechanism has been related with the coronary artery spasm in the majority of cases. It is mainly related to illicit substances such as cocaine, ecstasy, LSD and amphetamine. According to the findings in the literature, it is most likely that myocardial ischemia due to amphetamine abuse is a result of combined mechanisms which include coronary artery vasospasm, and in lesser extent thrombus formation or direct myocardial toxicity. Diazepam is also usually found as a substance of abuse. Recent findings indicate that diazepam exerts an inhibitory activity on different isoforms of the enzyme cyclic nucleotide phosphodiesterase, which can be found in the heart muscle and also show that diazepam potentate the positive inotropic effect of both noradrenaline and adrenaline, which subsequently leads to increase in myocardial contractility. We propose that dual intoxication with amphetamine and benzodiazepine potentate their effects on cardiac tissue and coronary arteries which results in larger myocardial injury.     

Pathogenesis of cocaine-induced ischemic heart disease. Autopsy findings in a 21-year-old man

A 21-year-old man with a five-year history of recreational intravenous cocaine abuse developed chest pain within one minute and cardiopulmonary arrest within one hour following an injection. He died and, on autopsy, was found to have severe coronary obstructive lesions, as a result of chronic intimal proliferation, and acute platelet thrombosis. Secondary chronic and acute myocardial ischemic lesions also were observed. Cocaine-induced coronary artery spasm may have occurred and produced focal endothelial injury and platelet aggregation; this pathogenetic mechanism may have accounted for both the chronic and the acute coronary obstructive lesions. In addition, lymphocytic myocarditis was present and may have been related to the long-term cocaine abuse.     

Stress and disease: The missing link. A vasospastic theory I. Acute myocardial infarction — A potentially reversible event?

A review of the evidence in acute myocardial infarction indicates that it might well be initiated by coronary artery spasm, and that coronary thrombosis, although important in tipping the balance between severe damage and death of heart muscle, may merely be secondary to the spasm-induced reduction in coronary blood flow.     

Adrenoreceptor blockade in angiotensin-induced hypertension: effect on rat coronary arteries and myocardium

Adrenoreceptor blockade has been used to separate the actions of elevated blood pressure, angiotensin II, and catecholamines on the coronary vasculature and myocardium of rats. Twenty-two male Wistar-Kyoto rats received phentolamine (an alpha-receptor blocker, 10 mg/kg body weight) and/or propranolol (a beta-receptor blocker, 1 mg/kg body weight) followed by an infusion for 2 hours of angiotensin amide (1.7 micrograms/min/kg) or saline. Sections of left ventricle were examined by light and electron microscopy. Blood pressure was elevated only in animals receiving angiotensin II with or without propranolol. Epicardial arteries were devoid of lesions in all animals. Small intramural arteries and arterioles in the hypertensive animals exhibited vasoconstriction, endothelial cell vacuolization with bleb formation, and medial smooth muscle cell fragmentation and necrosis. Foci of irreversible ischemic or anoxic myocardial injury consisting of contraction zones and bands and translocated mitochondria with granular matrix densities were seen in angiotensin-infused animals. Similar but less severe myocardial changes were found in the animals pretreated with propranolol. Vascular lesions were also seen in animals receiving phentolamine, propranolol, and angiotensin II; but myocardial alterations consisted solely of areas with contraction zones. Vascular but not myocardial lesions were observed in animals that received angiotensin II and phentolamine. It is concluded that angiotensin II can produce vascular injury in the absence of elevated systemic blood pressure or catecholamine effects. In contrast, irreversible myocardial injury seems to depend upon the increased pressure and/or coronary artery vasoconstriction associated with angiotensin administration.     

Impact of myocardial infarct proteins and oscillating pressure on the differentiation of mesenchymal stem cells: effect of acute myocardial infarction on stem cell differentiation

Stem cell transplantation in acute myocardial infarction (AMI) has emerged as a promising therapeutic option. We evaluated the impact of AMI on mesenchymal stem cell (MSC) differentiation into cardiomyocyte lineage. Cord blood-derived human MSCs were exposed to in vitro conditions simulating in vivo environments of the beating heart with acute ischemia, as follows: (a) myocardial proteins or serum obtained from sham-operated rats, and (b) myocardial proteins or serum from AMI rats, with or without application of oscillating pressure. Expression of cardiac-specific markers on MSCs was greatly induced by the infarcted myocardial proteins, compared with the normal proteins. It was also induced by application of oscillating pressure to MSCs. Treatment of MSCs with infarcted myocardial proteins and oscillating pressure greatly augmented expression of cardiac-specific genes. Such expression was blocked by inhibitor of transforming growth factor beta(1) (TGF-beta(1)) or bone morphogenetic protein-2 (BMP-2). In vitro cellular and electrophysiologic experiments showed that these differentiated MSCs expressing cardiomyocyte-specific markers were able to make a coupling with cardiomyocytes but not to selfbeat. The pathophysiologic significance of in vitro results was confirmed using the rat AMI model. The protein amount of TGF-beta(1) and BMP-2 in myocardium of AMI was significantly higher than that in normal myocardium. When MSCs were transplanted to the heart and analyzed 8 weeks later, they expressed cardiomyocyte-specific markers, leading to improved cardiac function. These in vitro and in vivo results suggest that infarct-related biological and physical factors in AMI induce commitment of MSCs to cardiomyocyte-like cells through TGF-beta/BMP-2 pathways.     

Evaluation of the porcine ameroid constrictor model of myocardial ischemia for therapeutic angiogenesis studies.

The porcine ameroid model of chronic myocardial ischemia has been widely used for the evaluation of coronary collateralization development. The impact of target vessel occlusion on the presence of myocardial ischemia, and the relationship between morphological, functional, and hemodynamic measurements in the context of therapeutic angiogenesis studies, however, has not been studied thus far. The authors therefore performed a systematic analysis of 94 animals undergoing ameroid constrictor placement around the left circumflex coronary artery (LCX) and, furthermore, a comprehensive evaluation including echocardiography and coronary angiography 26 +/- 1 (mean +/- SEM) days after ameroid placement. Complete LCX occlusion was observed in 34/94 animals (36%) and identified those with myocardial ischemia of the lateral wall, both at rest and under pharmacological stress. By applying a set of angiographic criteria (TIMI or= 1), another 27/94 animals with myocardial ischemia under conditions of pharmacological stress conditions could be identified. Interestingly, echocardiographic parameters of regional and global myocardial function were not correlated with myocardial blood flow or the degree of ischemia. There was no relationship between the extent of coronary collateralization, as assessed by angiography, echocardiographic parameters, or myocardial blood flow. The authors therefore conclude that complete occlusion of the ameroid instrumented coronary artery is not a prerequisite for successfully establishing the pathophysiology of myocardial ischemia. Defined angiographic criteria are important in identifying ischemic animals, thus reducing total animal numbers. Angiographic assessment of the degree of coronary collateralization, however, is not associated with myocardial blood flow or function and should not be used as a primary outcome measure of therapeutic angiogenesis studies in this model.     

Myocardial substrate utilization in perfused hearts isolated from adrenalectomizedcats.

Isolated hearts form chronically adrenalectomized cats were perfused with Krebs-Henseleit buffer plus either glucose (10mM) or palmitate (0.4 mM) under various conditions of constant pressure and constant flow. Glucose uptake in adrenalectomizedhearts was not diminished from control values under conditions of constant pressure, constant flow, anoxia, or insulin stimulation. Palmatic acid uptake and oxygen consumption were significantly reduced (P less than 0.02) in adrenalectomized hearts. This diminished fatty acid utilization was also reflected in a significantly lower CO'2 production and incorporation of the palmitate into myocardial triglycerides. The decreased fatty acid uptake by adrenalectomized cat hearts may represent aserious defect in myocardial metabolism since lipids are the major energy substrate forthe heart. Whether the defect occurs in fatty acid transport or activation cannot beelucidated by this study. However, it is unlikely that this defect has a major contributory effect on the dysfunction of adrenalectomized hearts since the myocardium iscabable of using other energy substrates readily.     

Effect of hyperosmotic mannitol on myocardial oxygen consumption.

Hyperosmotic mannitol produces salutary hemodynamic and histologic effects during experimental myocardial ischemia. However, the administration of hyperosmotic mannitol is associated with a positive inotropic influence. Positive inotropic interventions, which increase myocardial oxygen consumption (MVO2), also tend to increase the extent of ischemic myocardial injury. Thus, the purpose of this study was to determine the effect of mannitol on MVO2. Anesthetized dogs on right-heart bypass under conditions of controlled hemodynamics were studied. Both coronary arteries were perfused; mannitol was infused via the coronary perfusion cannulas to produce a 35 mosmol increase in osmolality. Heart rate was maintained constant. Cardiac output was held constant or deliberately increased so that left ventricular end-diastolic pressure and tension-time index, two other hemodynamic correlates of MVO2, remained constant or increased. MVO2 significantly decreased under conditions of decreased myocardial perfusion (P less than 0.025). This was in spite of a significant increase (P less than 0.001) in the peak rate of rise of left ventricular pressure (LV dP/dt), a hemodynamic correlate of MVO2. Thus, hyperosmotic mannitol under conditions of reduced coronary perfusion increases myocardial efficiency.     

Coronardurchblutung bei Erhöhung des arteriellen Kohlensäuredrucks

Summary In 9 dogs the heart rate was kept constant by electrical stimulation of the right auricle after elimination of the sinus node. Hypercapnia was induced by increasing inspiratory carbonic acid concentration at constant oxygen concentration. The mean arterial carbonic acid partial pressure increased from 40.5 to 70.5 mm Hg. The mean pH decreased from 7.30–7.14. Under these conditions the coronary flow did not change. Systolic and diastolic aortic pressure, left ventricular pressure, and the maximal rate of pressure rise in the left ventricle remained unchanged. Alterations of coronary blood flow caused by increased carbonic acid concentrations as described by other authors can be explained by a change of hemodynamic conditions.

     

Reduction of infarct size estimated enzymatically in patients with acute myocardial infarction after treatment with recombinant tissue type plasminogen activator or after spontaneous coronary recanalisation: A randomised,placebo controlled study

In a double-blind trial, 56 patients with suspected myocardial infarction (AMI) of a duration of less than 5 h were randomised to either 100 mg recombinant human tissue type plasminogen activator (rt PA) treatment or placebo intravenously over 3 h. We studied the possible influence of endogenous coronary recanalisation on the extent of myocardial damage in relation to the estimate of myocardial salvage by early treatment of AMI patients with rt PA. We used a computerised serum CK MB time activity curve method for estimation of reperfusion and infarct size. Patients with a first AMI had a significantly higher reperfusion rate than patients with a previous AMI (p=0.01). In the placebo group, the median enzymatic estimated infarct size was significantly lower in the patients with spontaneous reperfusion compared to patients with no endogenous reperfusion (p < 0.05). The median infarct size was significantly lower (33%) in patients treated with rt PA than in patients without spontaneous reperfusion (p < 0.05).We conclude that rt PA is efficient in inducing coronary reperfusion in the majority of patients with a first AMI. Our results confirm that intravenously, administered rt PA treatment can reduce the infarct size in patients with AMI. Our study extends previous observations by indicating that the extent of myocardial salvage induced by such treatment has been underestimated in the past, where patients with spontaneous coronary reperfusion have been included in the reference group.     

Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy

The morbidity and mortality associated with cocaine abuse has markedly increased in recent years. Although several articles indicate a possible connection of cocaine with coronary spasm and acute myocardial infarction, this study in seven patients with a history of cocaine abuse, who underwent endomyocardial biopsy, suggests that cocaine may cause direct toxicity to the myocardium. Myocardial specimens from five of seven patients showed multifocal myocyte necrosis, of which two specimens revealed focal myocarditis, while three specimens had changes consistent with dilated cardiomyopathy. Ultrastructurally, extensive loss of myofibrils and sarcoplasmic vacuolization were observed. It is postulated that the pathogenesis of acute cocaine-induced toxicity is direct destruction of myofibrils resulting in myocyte necrosis and that these changes may or may not be associated with interstitial inflammatory cell infiltrates. Long-term abuse of cocaine may lead to interstitial fibrosis and eventually congestive heart failure.     

Inflammation in variant angina: Is there any evidence?

Variant angina, defined as spontaneous angina pectoris associated with transient ST-segment elevation, has proved to be caused usually by episodic coronary spasm since Prinzmetal and his associates described a form of angina quite different from classic Heberden angina pectoris in 1959. Currently, coronary artery spasm is defined as reversible coronary stenosis, which limits coronary blood flow under resting conditions, and it plays an important role in ischemic heart disease, particularly in variant angina. Data available in respect of coronary vasospasm showed that it is closely related to atherosclerotic coronary artery disease, since intravascular ultrasound studies reveal atherosclerotic plaques in almost any spastic segment. Risk factors for coronary artery disease and coronary vasospasm, however, differ profoundly. Cigarette smoking is the only established risk factor. Although several candidates and predisposing factors, such as serotonin, histamine, thromboxane, and endothelin, have been described, the mediators and the pathogenesis of the disease remain unknown. There are abundant studies that inflammation plays an important role in the initiation, development as well as evolution of atherosclerosis, suggesting that atherosclerosis is an inflammation disease. The evidence regarding the role of inflammatory pathways in different clinical entities of coronary artery disease has significantly been accumulated. And also, primary studies have showed that inflammation may be a contributor for variant angina or vasospastic coronary disease is at least partially driven by inflammation. Although much more research is obviously needed, primary evidence provide us with some direction for that research.