Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic left ventricular cardiomyopathy is an increasingly recognized cause of recurrent myocarditis, a mimicker of acute coronary syndrome, and an important cause of malignant ventricular arrythmias and heart failure. Desmoplakin is a protein that is critical to maintaining the structural integrity of the myocardium. Disruption of desmoplakin leads to fibrofatty infiltration of the myocardium which leads to congestive heart failure, cardiac arrhythmias, and sudden cardiac death. However, desmoplakin cardiomyopathy is often misdiagnosed, resulting in significant morbidity and mortality. We report 2 contrasting cases illustrating the natural history-hot and cold phases-of arrhythmogenic left ventricular cardiomyopathy. Case Series: The first case demonstrates a common phenotypic presentation of desmoplakin cardiomyopathy manifested as recurrent myocarditis and myocardial injury representing the hot phase. The second case is an undulating course of chronic systolic heart failure and ventricular arrhythmias representing the cold phase. Conclusion: Arrhythmogenic cardiomyopathy manifests as a spectrum of disease processes that involve the right, left, or both ventricles. Mutations in the desmoplakin gene are often associated with a left dominant ventricular cardiomyopathy. Diagnosis remains difficult as the condition has no signature clinical presentation, and imaging findings are variable.

Exercise-induced pulmonary artery hypertension in a patient with compensated cardiac disease: hemodynamic and functional response to sildenafil therapy.

We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization-combined with the use of a symptom-limited, bedside bicycle ergometer-revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class.

Variations in institutional staffing and clinical practice are predictive of center-specific 1-year survival post-transplant.

BACKGROUND: The accuracy of various risk models to predict early post-transplant mortality is limited by the type, quality, and era of the data collected. Most models incorporate a large number of recipient-derived and donor-derived variables; however, other factors related to specific institutional practices likely influence early mortality. The goal of this study was to determine if the addition of institutional practice variables would improve the predictive accuracy of a recipient/donor risk model in a modern cohort of heart transplant recipients. METHODS: Between 1999 and 2007, 3,591 primary heart transplants were performed at the 26 institutions participating in the Cardiac Transplant Research Database. Multivariable regression analysis in the hazard domain was used to identify recipient, donor, and institutional practice variables that were predictive of 1-year mortality. The derived model was used to predict institutional outcomes and compare them with observed outcomes first without and then with the inclusion of the institutional practice variables. RESULTS: Eleven individual plus 2 interaction recipient variables and 2 individual plus 2 interaction donor variables were predictive of increased mortality. The addition of institutional practice variables to the model identified 4 variables associated with decreased mortality: greater number of transplant cardiologists, a thoracic surgery fellowship, a surgery or cardiology attending taking donor call, and routine surveillance for antibody-mediated rejection. By using a p-value > 0.10 as a robust measure of similarity, the addition of institutional practice variables increased the number of institutions with similar predicted vs. observed mortality from 18 of 26 institutions (69%) to 26 of 26 (100%), demonstrating improved predictive accuracy of the model. CONCLUSIONS: Multiple recipient and donor variables influence early survival but do not fully explain the difference in predicted and observed outcomes at the institutional level. Variations in staffing and clinical practice contribute to risk, and the addition of these variables to our risk model improved predictive accuracy.

Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure.

BACKGROUND: Insulin resistance is present in the setting of congestive heart failure. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties. METHODS AND RESULTS: We investigated the safety and efficacy of a 5-week infusion of GLP-1 (2.5 pmol/kg/min) added to standard therapy in 12 patients with New York Heart Association class III/IV heart failure and compared the results with those of 9 patients with heart failure on standard therapy alone. Echocardiograms, maximum myocardial ventilation oxygen consumption (VO2 max), 6-minute walk test, and Minnesota Living with Heart Failure quality of life score (MNQOL) were assessed. Baseline demographics, background therapy, and the degree of left ventricular dysfunction were similar between groups. GLP-1 significantly improved left ventricular ejection fraction (21 +/- 3% to 27 +/- 3% P < .01), VO2 max (10.8 +/- .9 ml/O2/min/kg to 13.9 +/- .6 ml/O2/min/kg; P < .001), 6-minute walk distance (232 +/- 15 m to 286 +/- 12 m; P < .001) and MNQOL score (64 +/- 4 to 44 +/- 5; P < .01). Benefits were seen in both diabetic and non-diabetic patients. There were no significant changes in any of the parameters in the control patients on standard therapy. GLP-1 was well tolerated with minimal episodes of hypoglycemia and gastrointestinal side effects. CONCLUSION: Chronic infusion of GLP-1 significantly improves left ventricular function, functional status, and quality of life in patients with severe heart failure.

The effects of combined versus selective adrenergic blockade on left ventricular and systemic hemodynamics, myocardial substrate preference, and regional perfusion in conscious dogs with dilated cardiomyopathy.

OBJECTIVES: Given that adverse effects of chronic sympathetic activation are mediated by all three adrenergic receptor subtypes (beta1, beta2, alpha1), we examined the effects of standard doses of carvedilol and metoprolol succinate (metoprolol controlled release/extended release [CR/XL]) on hemodynamics, myocardial metabolism, and regional organ perfusion. BACKGROUND: Both beta1 selective and combined adrenergic blockade reduce morbidity and mortality in heart failure. Whether there are advantages of one class over the other remains controversial, even in the wake of the Carvedilol Or Metoprolol European Trial (COMET). Similarly, the mechanistic basis for the relative differences is incompletely understood. METHODS: Thirty-three conscious, chronically instrumented dogs with pacing-induced (240 min(-1) for 4 weeks) dilated cardiomyopathy (DCM) were randomized to carvedilol (25 mg twice daily, Coreg, Glaxo Smith Kline, Research Triangle, North Carolina) or metoprolol succinate (100 mg qd, Toprol XL, Astra Zeneca, Wilmington, Delaware). Left ventricular and systemic hemodynamics, myocardial substrate uptake, and norepinephrine spillover were measured before and after three days of treatment. Regional (renal, hepatic, skeletal muscle) blood flows were measured using neutron-activated microspheres. RESULTS: Both agents had comparable heart rate effects. However, carvedilol-treated dogs showed significantly greater increases in stroke volume and cardiac output and decreases in left ventricular end-diastolic pressure and systemic vascular resistance. Carvedilol increased renal, hepatic, and skeletal muscle blood flow. Carvedilol increased myocardial glucose uptake and suppressed norepinephrine and glucagon. Carvedilol antagonized the response to exogenous norepinephrine to a greater extent than metoprolol CR/XL. CONCLUSIONS: At doses inducing comparable heart rate reductions, short-term treatment with carvedilol had superior hemodynamic and metabolic effects compared with metoprolol CR/XL. These data suggest important advantages of blocking all three adrenergic receptor subtypes in DCM.

Chronic exposure to cocaine binging predisposes to an accelerated course of dilated cardiomyopathy in conscious dogs following rapid ventricular pacing.

Despite extensive study, the extent to which cocaine use predisposes to cardiac injury remains unknown. We hypothesized that chronic cocaine binging would increase susceptibility to a subsequent cardiac insult, even in the absence of demonstrable effects on baseline hemodynamics. We studied progression of dilated cardiomyopathy (DCM) induced by rapid ventricular pacing (240 beats per minute) in five conscious, chronically instrumented dogs, after exposure to repetitive cocaine binging (COC) in the form of four consecutive 1 mg/kg i.v. boluses daily for 8 days, to simulate human cocaine abuse. We compared the results with nine control dogs (CON) undergoing the exact pacing protocol, without prior cocaine exposure. Baseline hemodynamics were not significantly altered by chronic cocaine exposure. Following 2 weeks of pacing, COC dogs exhibited accelerated progression to DCM, depressed plasma nitric oxide levels (CON, 17 +/- 2 microM; COC, 10 +/- 2 microM, p < 0.05), and a significantly greater increase in plasma epinephrine (CON, 33 +/- 6 pg/ml; COC, 104 +/- 24 pg/ml). After only 2 weeks of pacing, COC dogs demonstrated progressive DCM of a magnitude comparable with end-stage pacing-induced DCM. Chronic cocaine binging increases susceptibility to a subsequent myocardial insult and accelerates progression of DCM in conscious dogs following rapid pacing. These data suggest that although chronic cocaine use alone may not affect myocardial function, it predisposes to greater susceptibility to a superimposed insult.

Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.

We have shown previously that the glucagon-like peptide-1 (GLP-1)-(7-36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after acute myocardial infarction. However, GLP-1-(7-36) is rapidly degraded in the plasma to GLP-1-(9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7-36) (1.5 pmol.kg(-1).min(-1)) to GLP-1-(9-36) (1.5 pmol.kg(-1).min(-1)) in 28 conscious, chronically instrumented dogs with pacing-induced DCM by measuring LV function and transmyocardial substrate uptake under basal and insulin-stimulated conditions using hyperinsulinemic-euglycemic clamps. As a result, dogs with DCM demonstrated myocardial insulin resistance under basal and insulin-stimulated conditions. Both GLP-1-(7-36) and GLP-1-(9-36) significantly reduced (P < 0.01) LV end-diastolic pressure [GLP-1-(7-36), 28 +/- 1 to 15 +/- 2 mmHg; GLP-1-(9-36), 29 +/- 2 to 16 +/- 1 mmHg] and significantly increased (P < 0.01) the first derivative of LV pressure [GLP-1-(7-36), 1,315 +/- 81 to 2,195 +/- 102 mmHg/s; GLP-1-(9-36), 1,336 +/- 77 to 2,208 +/- 68 mmHg] and cardiac output [GLP-1-(7-36), 1.5 +/- 0.1 to 1.9 +/- 0.1 l/min; GLP-1-(9-36), 2.0 +/- 0.1 to 2.4 +/- 0.05 l/min], whereas an equivolume infusion of saline had no effect. Both peptides increased myocardial glucose uptake but without a significant increase in plasma insulin. During the GLP-1-(9-36) infusion, negligible active (NH2-terminal) peptide was measured in the plasma. In conclusion, in DCM, GLP-1-(9-36) mimics the effects of GLP-1-(7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics through insulinomimetic as opposed to insulinotropic effects. These data suggest that GLP-1-(9-36) amide is an active peptide.

Coronary blood flow responses are impaired independent of NO and endothelial function in conscious dogs with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by nitric oxide (NO) deficiency and endothelial dysfunction. Whether endothelium-independent vasodilation is preserved, particularly in the coronary circulation, remains controversial. METHODS AND RESULTS: We studied systemic and coronary flow responses to the endothelium-dependent agonist, acetylcholine, the cGMP-dependent NO-donor, nitroglycerin, the predominantly endothelium-independent agonist, adenosine, the beta-adrenergic cAMP-dependent agonist, isoproterenol, and the calcium channel antagonist, nicardipine, in conscious dogs with pacing-induced DCM. Systemic blood flow response was impaired to acetylcholine but preserved to other vasodilators in DCM. In contrast, coronary blood flow response was significantly ( P < .05) depressed to all agonists. (Peak coronary blood flow response, control versus DCM: acetylcholine: 221 +/- 14% versus 156 +/- 11%; nitroglycerin: 220 +/- 17% versus 138 +/- 9%; adenosine: 635 +/- 65% versus 376 +/- 56%; nicardipine: 338 +/- 59% versus 115 +/- 23%; isoproterenol: 219 +/- 18% versus 86 +/- 20%). The attenuation was independent of systemic hemodynamic differences. CONCLUSION: In contrast to systemic responses, coronary blood flow responses in DCM are impaired dependent or independent of NO or second messenger mechanisms, implying either distal signaling defects or structural abnormalities in the coronary vasculature.

Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines.

We have recently demonstrated the benefits of glucagon-like peptide-1 (GLP-1) in enhancing regional and global myocardial function after reperfusion in the clinical setting of acute myocardial infarction. We hypothesized that GLP-1 facilitates recovery from myocardial stunning after an ischemic event. To investigate this, we administered GLP-1 (1.5 pmol/kg/min) to six dogs undergoing 10-min occlusion of the left circumflex coronary artery, followed by 24-h reperfusion. We compared the responses of coronary blood flow and regional thickening of the posterior wall with a group of eight vehicle-treated dogs undergoing the same occlusion-reperfusion protocol. Although recovery of coronary blood flow was identical, regional wall motion recovery occurred significantly ((*)p < 0.05) earlier (92 +/- 4 versus 57 +/- 5%(*) at 15 min) and was complete in the GLP-1-treated dogs, whereas residual contractile dysfunction persisted in the control group (99 +/- 4 versus 78 +/- 3%(*) at 24 h). This phenomenon was independent of changes in systemic hemodynamics or global systolic function. However, isovolumic left ventricular relaxation improved significantly in GLP-1-treated dogs. GLP-1 caused an insulinotropic effect, but no hypoglycemia. We conclude that GLP-1 enhances recovery from ischemic myocardial stunning after successful reperfusion.

Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy.

BACKGROUND: The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. METHODS AND RESULTS: Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol x kg(-1) x min(-1)). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group. CONCLUSIONS: rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.

Hepatitis C virus-associated pericardial effusion and tamponade in a liver transplant recipient.

A liver transplant recipient with hepatitis C presented with unexplained dyspnea, fatigue and edema. Diagnostic evaluation revealed a pericardial effusion with echocardiographic features of tamponade. The patient underwent therapeutic pericardial drainage, resulting in symptomatic relief. The pericardial fluid tested positive for hepatitis C virus (viral quantitation of 200,000 copies/mL, genotype 1b) and negative for other plausible etiologies. Pericardial biopsy revealed normal tissue. This is the fifth case of hepatitis C virus-associated pericardial disease worldwide and the first case in North America. It is the first in a liver transplant recipient. In contrast to previous reports, this patient demonstrated tamponade in the absence of cryoglobulinemia or systemic extrahepatic manifestations of hepatitis C.

Catecholamines restore myocardial contractility in dilated cardiomyopathy at the expense of increased coronary blood flow and myocardial oxygen consumption (MvO2 cost of catecholamines in heart failure).

To investigate the metabolic cost of catecholamine use in heart failure, we administered intravenous dobutamine or norepinephrine to dogs with moderate and severe LV dysfunction until LV contractile function was restored to normal levels. Both drugs were associated with significant increases in myocardial O(2) consumption, increased coronary blood flow requirements and decreased myocardial mechanical efficiency. These mechanisms may contribute to the deleterious effects of catecholamines in heart failure.

Peroxisome proliferator activator receptors (PPAR), insulin resistance, and cardiomyopathy: friends or foes for the diabetic patient with heart failure?

Diabetes is a risk factor for coronary atherosclerosis, myocardial infarction, and ischemic cardiomyopathy. Insulin resistance is associated with left ventricular (LV) hypertrophy and hypertensive cardiomyopathy. Even in the absence of coronary artery disease or hypertension, "diabetic cardiomyopathy" can develop because of myocardial autonomic dysfunction or impaired coronary flow reserve. The relationship between insulin resistance and cardiomyopathy is bidirectional. Systemic and myocardial glucose uptake is compromised in heart failure independent of etiology. These abnormalities are associated with cellular deficits of insulin signaling. Insulin resistance in heart failure can be detrimental, because transcriptional shifts in metabolic gene expression favor glucose over fat as a substrate for high-energy phosphate production. Although preexisting diabetes accelerates this process of "metabolic death," insulin resistance can also develop secondary to cardiomyopathy-associated overabundance of neurohormones and cytokines. Insulin resistance and fatty acid excess are potential therapeutic targets in heart failure, striving for efficient myocardial substrate utilization. Peroxisome proliferator activator receptor gamma (PPARgamma) agonists are antidiabetic agents with antilipemic and insulin-sensitizing activity. Experimental studies suggest salutary effects in limiting infarct size, attenuating myocardial reperfusion injury, inhibiting hypertrophic signaling and vascular antiinflammatory actions through cytokine inhibition. However, clinical applicability in diabetic patients experiencing heart failure has been hampered because of increased edema and even fewer reports of exacerbation associated with these compounds. Evidence to date argues for peripheral mechanisms of edema unrelated to central hemodynamics. Nevertheless, they are currently contraindicated in New York Heart Association (NYHA) III-IV patients, particularly in combination with insulin. Investigations are underway to decipher mechanisms, risks, and benefits of PPARgamma agonists, as well as the role of the structurally related PPARalpha receptor on cardiovascular metabolism and function.

Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.

BACKGROUND: Glucose-insulin-potassium infusions are beneficial in uncomplicated patients with acute myocardial infarction (AMI) but are of unproven efficacy in AMI with left ventricular (LV) dysfunction because of volume requirements associated with glucose infusion. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties that stimulate glucose uptake without the requirements for concomitant glucose infusion. METHODS AND RESULTS: We investigated the safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF) <40% after successful primary angioplasty compared with 11 control patients. Echocardiograms were obtained after reperfusion and after the completion of the GLP-1 infusion. Baseline demographics and background therapy were similar, and both groups had severe LV dysfunction at baseline (LVEF=29+/-2%). GLP-1 significantly improved LVEF (from 29+/-2% to 39+/-2%, P<0.01), global wall motion score indexes (1.94+/-0.11-->1.63+/-0.09, P<0.01), and regional wall motion score indexes (2.53+/-0.08-->2.02+/-0.11, P<0.01) compared with control subjects. The benefits of GLP-1 were independent of AMI location or history of diabetes. GLP-1 was well tolerated, with only transient gastrointestinal effects. CONCLUSIONS: When added to standard therapy, GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty.

The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy.

BACKGROUND: The failing heart demonstrates a preference for glucose as its metabolic substrate. Advanced, severe DCM is characterized by depletion of adenosine triphosphate (ATP) stores, which may be a consequence of impaired insulin mediated glucose uptake and oxidation at a time when the myocardium prefers glucose as its substrate. We examined the time course and magnitude of myocardial insulin resistance during the evolution of dilated cardiomyopathy. METHODS AND RESULTS: Thirty-four conscious, chronically instrumented dogs were studied at four stages during the evolution of dilated cardiomyopathy (DCM) induced by rapid RV pacing [control, early, late and advanced severe]. Transmyocardial glucose, lactate, and non-esterified fatty acid (NEFA) concentrations were measured in the fasting state. The cellular insulin signaling cascade and ATP levels were measured on myocardial samples. NEFA and insulin concentrations increased early and progressively in DCM in association with increased norepinephrine concentrations and progressive hemodynamic impairment. In advanced DCM but not earlier stages, myocardial ATP levels were decreased by 34%. There was decreased myocardial glucose uptake evident under both basal (-29 +/- 5%) and insulin stimulated (-32 +/- 4%) conditions in advanced, severe DCM, associated with a 31% reduction in GLUT-4 translocation. Importantly, there were no alterations in proximal steps in insulin signaling, but significant reductions in serine (Ser473) phosphorylation of Akt-1. CONCLUSIONS: Advanced, severe DCM is associated with the development of myocardial insulin resistance. There is impaired myocardial glucose uptake and altered myocardial insulin signaling, involving decreased Ser 473 phosphorylation of Akt-1. Myocardial insulin resistance in advanced, severe DCM was also associated with reduced myocardial ATP levels.

Angiotensin-converting enzyme inhibitors improve coronary flow reserve in dilated cardiomyopathy by a bradykinin-mediated, nitric oxide-dependent mechanism.

BACKGROUND: ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT1 antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM). METHODS AND RESULTS: Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91+/-0.11; enalaprilat, 1.02+/-0.07 mL/min per g; P<0.05) and during atrial pacing (baseline, 0.82+/-0.11; enalaprilat, 0.98+/-0.07; P<0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89+/-0.11; enalaprilat CFR, 2.74+/-0.33; P<0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-L-arginine. The effects were recapitulated by the bradykinin(2) receptor agonist cereport but not by the AT1 antagonist losartan. CONCLUSIONS: The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT1 receptor antagonists.

Allergic angina and allergic myocardial infarction: a new twist on an old syndrome.

A series of eight patients admitted to a single-centre coronary care unit over a two-year period is described. All of the patients presented with an acute coronary syndrome within less than 48 h from the onset of an allergic reaction (six patients), or during an acute asthmatic paroxysm (two patients). None of the patients had any history of cardiac diseases, yet two had risk factors and two were former smokers. Four patients developed subendocardial myocardial infarction, three developed transmural myocardial infarction and one had unstable angina with no elevation in cardiac enzyme levels. Coronary angiograms were performed in seven of the eight patients; hemodynamically significant stenosis (greater than 70%) of one or more coronary arteries was detected in all patients. All seven patients underwent successful revascularization and recovered without complications. The present observational report hypothesizes that atopic people expressing an amplified mast cell degranulation may be more vulnerable to plaque rupture.

Catecholamine stimulation is associated with impaired myocardial O(2) utilization in heart failure.

OBJECTIVES: To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM). METHODS: We studied 19 conscious, instrumented dogs with pacing-induced DCM. We evaluated systemic, coronary hemodynamics and M(v)O(2) in response to norepinephrine (NOR, 0.05-0.4 microg/kg per min), dobutamine (DOB, 1-10 microg/kg per min), phenylephrine (PHE, 1-5 microg/kg per min) and isoproterenol (ISO, 0.05-0.4 microg/kg per min) alone or in the presence of metoprolol (ISO+MET). Experiments were conducted in control state and in advanced DCM, 4-5 weeks after the initiation of pacing. RESULTS: Contractile responses (LV dP/dt) to catecholamines were desensitized and accompanied by a parallel decrease in heart rate-adjusted myocardial O(2) consumption (M(v)O(2/beat)), when alpha(PHE) or beta(1) (DOB) or both alpha/beta(1) (NOR) AR were stimulated in DCM. This was due to impaired transmyocardial (Ao-Cs) O(2) extraction rather than limitations in CBF responses. There was an associated shift in myocardial metabolism, evidenced by an increased preference for glycolytic substrates (Respiratory Quotient) following administration of any of these three adrenergic agonists in DCM. Combined beta(1)/beta(2) stimulation with ISO or beta(2)-AR stimulation (ISO+MET) in DCM resulted in greater M(v)O(2/beat), [(Ao-Cs) O(2)] extraction, and decreases in myocardial RQ consistent with a shift toward oxidation of FFA. CONCLUSIONS: The impairment in contractile responses to dobutamine and norepinephrine in DCM is associated with impaired myocardial O(2) extraction, and a shift toward a preference for glycolysis. A different myocardial metabolic pattern suggestive of increased oxidation of FFA with increased myocardial O(2) extraction was observed in the presence of combined beta(1)/beta(2) stimulation with isoproterenol or beta(2) stimulation (ISO+MET). These data suggest that beta(2)-AR stimulation in DCM shifts substrate preference toward FFA oxidation associated with greater M(v)O(2) requirements. These findings identify a putative metabolic effect of beta(2) -AR in DCM that may be deleterious.