Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope.

The importance of cardiac output (CO) to blood pressure level during vasovagal syncope is unknown. We measured thermodilution CO, mean blood pressure (MBP), and leg muscle mean sympathetic nerve activity (MSNA) each minute during 60 degrees head-up tilt in 26 patients with recurrent syncope. Eight patients tolerated tilt (TT) for 45 min (mean age 60 +/- 5 yr) and 15 patients developed syncope during tilt (TS) (mean age 58 +/- 4 yr, mean tilt time 15.4 +/- 2 min). In TT patients, CO decreased during the first minute of tilt (from 3.2 +/- 0.2 to 2.5 +/- 0.3 l x min(-1) x m(-2), P = 0.001) and thereafter remained stable between 2.5 +/- 0.3 (P = 0.001) and 2.4 +/- 0.2 l x min(-1) x m(-2) (P = 0.004) at 5 and 45 min, respectively. In TS patients, CO decreased during the first minute (from 3.3 +/- 0.2 to 2.7 +/- 0.1 l x min(-1) x m(-2), P = 0.02) and was stable until 7 min before syncope, falling to 2.0 +/- 0.2 at syncope (P = 0.001). Regression slopes for CO versus time during tilt were -0.01 min(-1) in TT versus -0.1 l x min(-1) x m(-2) x min(-1) in TS (P = 0.001). However, MBP was more closely correlated to total peripheral resistance (R = 0.56, P = 0.001) and MSNA (R = 0.58, P = 0.001) than CO (R = 0.32, P = 0.001). In vasovagal reactions, a progressive decline in CO may contribute to hypotension some minutes before syncope occurs.

A comparison of post-prandial changes in flow-mediated dilatation in patients with type 2 diabetes with and without macroalbuminuria.

During the post-prandial period there is a decrease in systemic vascular resistance. This study compared meal-induced changes in flow-mediated dilatation (FMD) in patients with Type 2 diabetes with and without evidence of diabetic nephropathy as defined by the presence of macroalbuminuria. The effects on FMD of other factors such as smoking history, antihypertensive treatment and insulin use were also examined. Twelve patients with macroalbuminuria (>300 mg albumin/day) and 12 age- and sex-matched patients with normoalbuminuria (<50 mg albumin/day) participated in the study. Following a 12-hr overnight fast, forearm basal and reactive hyperaemic blood flow was assessed by venous occlusion plethysmography before and 2-hr after ingestion of a meal (2750 kJ) consisting of 56% fat, 26% carbohydrate and 16% protein. Plasma lipid and glycaemic indices were measured at the same times. The combined and grouped data was analysed using paired t tests and correlation and regression analyses. The meal resulted in significant increases in plasma glucose and triglyceride concentrations. While the meal resulted in a similar increase in basal blood flow rate in both patient groups, post-meal reactive hyperaemic flow increased significantly (p=0.04) in normoalbuminuric patients (mean individual increase: 33%) but remained unchanged in patients with macroalbuminuria (mean individual increase: 4%). The use of antihypertensive agents and insulin was also associated with an attenuated post-prandial hyperaemic response. In summary, our study demonstrated that the degree of renal impairment in patients with Type 2 diabetes may influence vasoactivity following a meal. Patients with evidence of diabetic nephropathy had a decreased post-prandial hyperaemic response, a result that indicated a reduced vasodilator reserve. The mechanism of this reduction in vasodilatation of peripheral vessels during the post-prandial period is probably multifactorial. These changes in vasoactivity have the potential to combine with other cardiovascular risk factors to enhance the development of atheroma.

Effects of omapatrilat on systemic arterial function in patients with chronic heart failure.

The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction < or = 40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 +/- 4.5 vs 2.8 +/- 5.0 mm Hg, p < 0.05) and mean arterial (13.9 +/- 3.0 vs 0.3 +/- 3.3 mm Hg, p < 0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was improved with a dose-related decrease in augmentation index (-13.8 +/- 1.7% vs +6.1 +/- 2.1%, p < 0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the high-dose groups compared with the control group (+266 +/- 43% vs - 14 +/- 92%, p < 0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 +/- 11 vs -2 +/- 7 pmol/L, p < 0.01) in high-dose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure.

The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure.

OBJECTIVES: We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure. BACKGROUND: The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented. METHODS: Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks. RESULTS: There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated. CONCLUSIONS: The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.

Brain stem stroke causing baroreflex failure and paroxysmal hypertension.

BACKGROUND: Paroxysmal neurogenic hypertension has been associated with a variety of diseases affecting the brain stem but has only rarely been reported after brain stem stroke. The mechanism is thought to involve increased sympathetic activity and baroreflex dysfunction. We undertook microneurographic recordings of muscle sympathetic nerve activity (MNSA) during beat-to-beat blood pressure (BP) monitoring to investigate this hypothesis. CASE DESCRIPTION: We investigated a 75-year-old woman who developed paroxysmal hypertension (BP 220/110 mm Hg) after a large left-sided medullary infarct. The paroxysms were triggered by changes in posture and were accompanied by tachycardia, diaphoresis, and headache. Serum catecholamines were substantially increased (norepinephrine level, 23.9 nmol/L 9 days after stroke; normal level, <3.8 nmol/L), and heart rate variability, measured by spectral analysis, was decreased in both low- and high-frequency domains (0.04 and 0.06 ms(2), respectively; normal level, 0.14+/-0.02 ms(2)). MNSA was increased in frequency (61 bursts per minute; normal level, 34+/-18 bursts per minute), and the burst amplitude was not inversely related to diastolic BP. BP and MNSA responses to cold pressor and isometric handgrip stimuli were intact. CONCLUSIONS: Extensive unilateral infarction of the brain stem in the region of the nucleus tractus solitarius may result in partial baroreflex dysfunction, increased sympathetic activity, and neurogenic paroxysmal hypertension.

Baroreceptor denervation presenting as part of a vagal mononeuropathy.

A 48-year-old woman presented with a history of progressive cough, dysphonia, dysphagia, and postural symptoms. Subsequent neurological investigations were consistent with a bilateral vagal mononeuropathy, and neurosarcoidosis was diagnosed after scalene node biopsy. Autonomic investigations including microneurography, neurohormones, and heart rate variability demonstrated arterial and cardiopulmonary baroreflex failure. In addition, parasympathetic control of heart rate was absent and consistent with a bilateral, nonselective lesion in the proximal vagus.

Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.

BACKGROUND: Plasma neurohormones were analyzed for prediction of adverse outcomes and response to treatment in 415 patients with ischemic left ventricular dysfunction randomly assigned to receive carvedilol or placebo. METHODS AND RESULTS: Atrial natriuretic peptide, brain natriuretic peptide (BNP), or norepinephrine (NE) levels above the group median were associated with increased mortality rates and heart failure. On multivariate analysis, both BNP and NE interacted with treatment to predict death or heart failure independent of age, New York Heart Association class, and left ventricular ejection fraction. For placebo, supramedian levels of BNP were associated with 3-fold the mortality rate of inframedian levels (20/104; 19% vs 6/99; 6%; P<0.01). For carvedilol, mortality rate was comparable in these 2 subgroups (12/109; 11% vs 8/94; 9%; NS). Corresponding rates for heart failure were 29/104 (28%) versus 3/99 (3%; P<0.001) for placebo and 16/109 (15%) versus 7/94 (7%; NS) for carvedilol. High NE levels did not predict additional benefit from carvedilol, which significantly reduced heart failure admissions only in those with NE levels below the median (13.1% to 4. 0%; P<0.01). In the 23% of the study population with supramedian BNP but inframedian levels of NE, carvedilol reduced hospital admission with heart failure by >90% (P<0.001). CONCLUSIONS: Carvedilol reduced mortality rates and heart failure in those with higher pretreatment BNP levels but lesser activation of plasma NE. Neurohumoral profiling may guide introduction of beta-blockade in heart failure.

Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group.

OBJECTIVE: To determine the relations of plasma levels of brain natriuretic peptide (BNP), atrial natriuretic factor (ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate (cGMP; the cardiac peptide second messenger), and plasma catecholamines to left ventricular function and to prognosis in patients admitted with acute myocardial infarction. DESIGN: Plasma hormones and ventricular function (radionuclide ventriculography) were measured 1-4 days after myocardial infarction in 220 patients admitted to a single coronary care unit. Radionuclide scanning was repeated 3-5 months after infarction. Clinical events were recorded over a mean period of 14 months. RESULTS: Both early and late left ventricular ejection fraction (LVEF) were most closely related to plasma BNP (r = -0.60, n = 220, p < 0.001; and r = -0.53, n = 192, p < 0.001, respectively), followed by ANF, N-ANF, cGMP, and the plasma catecholamines. Early plasma BNP concentrations less than twofold the upper limit of normal (20 pmol/l) had 100% negative predictive value for LVEF < 40% at 3-5 months after infarction. In multivariate analysis incorporating all the neurohormonal factors, only BNP remained independently predictive of LVEF < 40% (p < 0.005). Survival analysis by median levels of candidate predictors identified BNP as the most powerful discriminator for death (p < 0.0001). No early deaths (within 4 months) occurred in patients with plasma BNP concentrations below the group median (27 pmol/l), and over follow up only three of 26 deaths occurred in this subgroup. Of all episodes of left ventricular failure, 85% occurred in patients with plasma BNP above the median (p < 0.001). In multivariate analyses, BNP alone gave additional predictive information beyond sex, age, clinical history, LVEF, and plasma noradrenaline for both subsequent onset of LVF and death. CONCLUSIONS: Plasma BNP measured within 1-4 days of acute myocardial infarction is a powerful independent predictor of left ventricular function, heart failure, or death over the subsequent 14 months, and superior to ANF, N-ANF, cGMP, and plasma catecholamines.

Arginine vasopressin V1-receptor antagonism in an ovine model of acute myocardial infarction.

Arginine vasopressin (AVP) has an uncertain role in the pathogenesis of increased myocardial and other regional vascular resistance after cardiac injury. The extreme increase in plasma AVP levels observed in some individuals after myocardial infarction potentially exacerbates already compromised myocardial perfusion. We assessed whether blockade of AVP, by administration of the specific V1-receptor antagonist OPC-21268, can reduce the severity of myocardial injury after embolization in our ovine model of acute myocardial infarction. Embolizations resulted in a pattern of changes in ECG and cardiac enzymes consistent with moderate to severe acute myocardial infarction, resulting in left ventricular dysfunction [left ventricular ejection fraction (LVEF) reduced from 52-53% to 38%]. However, no statistically significant differences were observed between groups in hemodynamic or neurohumoral indices of myocardial damage. By contrast, the hypothalamus-pituitary-adrenal (HPA) response [including plasma AVP (p < 0.01), adrenocorticotropic hormone (ACTH; p < 0.01), and cortisol (p < 0.01)) to embolizations was significantly increased in the sheep infused with OPC-21268. In conclusion, whereas plasma HPA responses differed between the two groups, the similar responses in cardiac enzymes, LVEF, and hemodynamic and neurohumoral factors in both groups does not support a role of V1 receptor-mediated exacerbation of myocardial injury in this model of myocardial infarction. Assessment of different receptor antagonists or examination of other models of cardiac injury may further clarify the role of the markedly increased AVP levels that can occur in myocardial infarction.

Regional plasma levels of cardiac peptides and their response to acute neutral endopeptidase inhibition in man.

1. The cardiac natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide, are degraded via clearance receptors and the enzyme neutral endopeptidase (EC 3.4.24.11). We studied the regional plasma concentrations of these peptides and their response to acute neutral endopeptidase inhibition in a consecutive series of patients with a broad spectrum of severity of cardiac dysfunction who were undergoing diagnostic right and left heart catheterization (24 patients, mean age 62.6 years).2. Baseline blood samples were obtained for hormone analysis from femoral artery, femoral vein, renal vein, hepatic vein, superior vena cava, coronary sinus and pulmonary artery, and initial haemodynamic measurements were made. Twelve patients then received a neutral endopeptidase inhibitor (SCH 32615, 200 mg intravenously) and 12 received vehicle alone. The cardiac catheterization procedure was then completed and haemodynamic and hormone measurements were repeated.3.Haemodynamic status was similar at baseline in both groups, and at repeated measurement (post-procedure after placebo or active drugs) haemodynamic variables were not significantly different from baseline values. Plasma levels of atrial and brain natriuretic peptides exhibited an arteriovenous increment (344% and 124% respectively) across the heart (femoral artery to coronary sinus) and decrement (by 28-54% and 9-16% respectively) across all other tissue beds (P<0.05 for all) except the lung (no change). Final levels of atrial natriuretic peptide rose above initial levels at all sites in both groups (P<0.05) except coronary sinus levels in the vehicle group (no change). The increase was consistently greater in the inhibitor group at all sites (P<0.05 versus placebo). Levels of brain natriuretic peptide rose at all sites in the inhibitor group only (P<0.05). The transcardiac step-up in atrial natriuretic peptide was markedly augmented after the administration of neutral endopeptidase inhibitor. Other tissue gradients were not significantly altered by neutral endopeptidase inhibitor.4. Atrial and brain natriuretic peptides in plasma are degraded by a number of tissues, and respond differently to cardiac catheterization. Neutral endopeptidase has a significant role in determining plasma levels of natriuretic peptides, in part perhaps by influencing the amount of intact peptide reaching the circulation after secretion from the heart.

Autonomic control of vasovagal syncope.

In the pathophysiological study of vasovagal syncope, the nature of the interaction between baroreceptor sensitivity (BS), sympathetic withdrawal, and parasympathetic activity has yet to be ascertained. Altered BS may predispose toward abnormal sympathetic and parasympathetic responses to orthostasis, causing hypotension that may progress to syncope if there is sympathetic withdrawal. To examine this hypothesis, we monitored blood pressure (BP), heart rate (HR), BS, forearm blood flow, and muscle nerve sympathetic activity (MNSA) continuously in 18 vasovagal patients during 60 degrees head-up tilt, syncope, and recovery. Results were compared with those of 17 patients who were able to tolerate tilt for 45 min. During early tilt, BP was maintained in both groups by an increase in HR and MNSA from baseline (P < 0.01), but BS decreased more in the syncopal group (P < 0.05). At the start of presyncope (mean 2.7 +/- 0.2 min before syncope and 15.2 +/- 12 min after tilt), when BP fell, HR and sympathetic activity remained increased from baseline (P < 0.01). Thereafter, BP and HR correlated directly with sympathetic activity and regressed in linear fashion until syncope (P < 0.001), whereas BS increased to baseline. At syncope, BP, HR, and sympathetic activity fell below baseline (P < 0.01, P < 0.05, and P < 0.01, respectively), but BS did not increase. During recovery, sympathetic activity increased to baseline and BS increased (P < 0.05), whereas HR and BP remained low (P < 0.01 and P < 0.05, respectively). The mechanism for the initiation of hypotension during presyncope remains unknown, but BS may contribute. Vasodilatation and bradycardia during presyncope appear to be more closely related to withdrawal of sympathetic activity than to increased parasympathetic cardiac activity.

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction.

BACKGROUND: Newly discovered circulating peptides, N-terminal pro-brain natriuretic peptide (N-BNP) and adrenomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction. METHODS AND RESULTS: The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (r=-.63, P<.0001) and 3 to 5 months (r=-.58, P<.0001) after infarction was comparable to that for C-terminal BNP and far stronger than for ADM (r=-.26, P<.01), N-terminal atrial natriuretic peptide (N-ANP), C-terminal ANP, cGMP, or plasma catecholamine concentrations. For prediction of death over 24 months of follow-up, an early postinfarction N-BNP level > or = 160 pmol/L had sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 72%, 39%, and 97%, respectively, and was superior to any other neurohormone measured and to LVEF. Only 1 of 21 deaths occurred in a patient with an N-BNP level below the group median (Kaplan-Meier survival analysis, P<.00001). For prediction of heart failure (left ventricular failure), plasma N-BNP > or = 145 pmol/L had sensitivity (85%) and negative predictive value (91%) comparable to the other cardiac peptides and was superior to ADM, plasma catecholamines, and LVEF. By multivariate analysis, N-BNP but not ADM provided predictive information for death and left ventricular failure independent of patient age, sex, LVEF, levels of other hormones, and previous history of heart failure, myocardial infarction, hypertension, or diabetes. CONCLUSIONS: Plasma N-BNP measured 2 to 4 days after myocardial infarction independently predicted left ventricular function and 2-year survival. Stratification of patients into low- and high-risk groups can be facilitated by plasma N-BNP or BNP measurements, and one of these could reasonably be included in the routine clinical workup of patients after myocardial infarction.

The effects of pathophysiological increments in brain natriuretic peptide in left ventricular systolic dysfunction.

Plasma levels of brain natriuretic peptide (BNP) are raised in patients with left ventricular impairment and may play a role in the adaptation to left ventricular impairment. Manipulation of BNP levels may have therapeutic potential. The effects of BNP have not been well studied in patients with left ventricular impairment. We studied the effects of low-dose BNP infusion, reproducing the increment in plasma BNP seen with progression from mild to severe heart failure in patients with impaired left ventricular systolic function. BNP was infused in a placebo-controlled, single-blind, crossover design at a rate of 3.3 pmol x kg(-1) x min(-1) over 4 hours to 8 patients with a history of congestive heart failure and persistent impairment of left ventricular systolic function (left ventricular ejection fraction <35%). Endocrine, renal, and hemodynamic effects were measured. Compared with time-matched placebo-control, BNP infusion decreased mean systemic arterial pressure (peak decrease, 17.1 mm Hg; P=.04), mean pulmonary artery pressure (peak decrease, 6.1 mm Hg; P=.007), mean pulmonary capillary wedge pressure (peak decrease, 5.5 mm Hg; P=.04), and systemic vascular resistance (peak decrease, 1400 dyne s(-1) cm(-5); P=.015), but cardiac output and heart rate were unchanged. Urinary volume and urinary excretion of sodium and potassium were not altered. BNP infusion increased plasma cGMP (2.3-fold change, P=.002). Plasma atrial natriuretic peptide levels were increased for the first hour of BNP infusion (peak increase, 11.5 pmol/L; P=.005). Plasma aldosterone levels were unchanged during but increased over time-matched control levels after the end of the BNP infusion (peak increase, 90 pmol/L; P=.02). Plasma renin activity and cortisol and catecholamine levels were unchanged. Low-dose infusion of BNP causes favorable hemodynamic changes and relative neurohormonal suppression but has attenuated renal effects in patients with impaired left ventricular systolic function.

An ovine model of acute myocardial infarction and chronic left ventricular dysfunction.

In order to develop and validate an ovine model of myocardial infarction with subsequent impairement of left ventricular function, 15 instrumented sheep underwent selective microembolization of the left coronary arteries with 0.5 mL 90 microns polystyrene beads. Hemodynamics and plasma hormones were measured preembolization (baseline) and then at hours 2, 4, 6, and 12 and days 1, 2, 3, 5 and 7 postembolization. Of the 15 sheep studied, 2 (13%) died on the day of embolization from arrhythmias. In the remaining sheep, left ventricular systolic pressure and stroke work (both P < 0.001) were reduced promptly and remained below basal levels. Mean arterial pressure (P < 0.001) increased initially, then decreased to below basal levels by hour 6. Heart rate (P < 0.001) and left atrial pressure (P < 0.05) were increased while cardiac output was decreased (P < 0.05). Left ventricular ejection fraction at day 7 was reduced (38.8 +/- 3.5 vs 46.0 +/- 3.9% preembolization; P < 0.05). The cardiac enzymes creatine kinase (P < 0.001) and troponin-T (P < 0.001) were increased following microembolization and returned to basal levels by days 2 and 5 respectively. Plasma atrial and brain natriuretic peptides (both P < 0.001) and plasma renin activity (P < 0.005) were all increased following embolization. This ovine model mimics the hemodynamic and neurohumoral features of acute myocardial infarction, resulting in left ventricular dysfunction, and should prove suitable for the study of interventions in a number of these conditions.

Neurohormonal response to head-up tilt and its role in vasovagal syncope.

In a controlled study, 26 patients with a history of recurrent syncope were found to have increased arginine vasopressin, corticotrophin, and atrial natriuretic factor levels after 5 minutes of 60 degrees head-up tilt, long before they became hypotensive. The exaggerated neurohormonal response in these patients may indicate a greater sensitivity to central hypovolemia which may predispose to vasovagal syncope, mediated by the vasodilatory effects of atrial natriuretic factor or the sensitization of mechanoreceptors by arginine vasopressin.

Hypothalamo-pituitary-adrenal axis response to coronary artery embolization: an ovine model of acute myocardial infarction.

Although previous studies have described the hypothalamo-pituitary-adrenal (HPA) response to the stress of acute myocardial infarction, it is not possible to study the hormone changes immediately after infarction in humans. Accordingly, we have examined the HPA response to microembolization of coronary arteries in 13 sheep compared with 5 sham control sheep. Plasma vasopressin (AVP; P < 0.001), ACTH (P = 0.005) and cortisol (P = 0.005) were all increased 2 h (first sample time) after embolization. Plasma ACTH and cortisol levels returned to baseline levels by 6 h but plasma AVP levels did not return to baseline levels until more than 12 h after embolization. Plasma corticotrophin-releasing hormone (CRH) showed no significant change in response to embolization. In a subset of six animals which were sampled more frequently, the peak responses for plasma AVP, ACTH and cortisol occurred at 40 min after embolization. The maximum responses in any individual sheep observed at this time point were 744 pmol/l for AVP, 144 pmol/l for ACTH and 492 nmol/l for cortisol. CRH levels tended to increase across the first hour but these changes were not statistically significant. In conclusion, the stress hormone responses to microembolization of the coronary arteries have been defined in an ovine model of myocardial infarction. This model is suitable for studying the effects of novel treatments to reduce the stress of myocardial infarction.