Postinfarction Day Research Articles

PO-05-082 ANTITACHYCARDIA PACING IS MORE EFFECTIVE WHEN DELIVERED TO THE LEFT BUNDLE BRANCH COMPARED TO THE RIGHT VENTRICLE IN A CANINE ISCHEMIC VENTRICULAR TACHYCARDIA MODEL

Implantable cardioverter-defibrillators (ICDs) can terminate ventricular tachycardia (VT) with Antitachycardia pacing (ATP) delivered to a right ventricular (RV) pacing lead, thereby avoiding painful and damaging high-energy shocks. However, ATP efficacy is limited for fast VT, and ATP can accelerate VT or convert VT to ventricular fibrillation (VF). Physiological pacing delivered to the left bundle branch (LBB) has emerged as a clinically relevant target to minimize ventricular dyssynchrony and pacing-induced heart failure. ATP efficacy and safety delivered to the LBB are yet to be investigated. Evaluate the therapeutic efficacy and safety of ATP delivered to an LBB lead compared to ATP delivered to a conventional RV lead. In 6 anesthetized dogs, pacing leads from two ICDs (CobaltTM XT DR, Medtronic, Inc) were implanted at the RV apex (6947 Sprint Quattro SecureTM, Medtronic, Inc) and the LBB (3830 SelectSecureTM, Medtronic, Inc). A lateral thoracotomy procedure was performed, and a two-hour lateral anterior descending artery ischemia-reperfusion injury was caused. The thoracotomy was closed and on post-infarct day 4, dogs were anesthetized, and sustained VT episodes were induced by programmed electrical stimulation. ATP (up to 5 trains of 8 pulses at approximately 88% of the VT cycle length) was delivered to either the LBB or RV pacing site in a randomized fashion. The success rate of ATP in terminating the VT episodes and the rate of VT acceleration and degeneration into VF from both pacing locations were evaluated. In our canine ischemic VT model, VT was induced 80 times, with a mean VT cycle length of 178±35 ms. ATP was delivered and tested for each episode. For ATP delivered to the RV, the success rate for terminating VT was 54%. The success rate for terminating VT for ATP delivered to the LBB was 73% (Fig. A, p < 0.05). ATP resulted in VT acceleration for 10% and 5% of ATP attempts delivered to the RV and LV, respectively (Fig. B, p = Not Significant, NS). Degeneration to VF occurred for 5% of all ATP attempts delivered to the RV, and there was no such incident for ATP delivered to the LBB (Fig. B). Higher efficacy and lower incidence of VT acceleration were observed with ATP delivered to LBB compared to ATP delivered to the RV in this canine ischemic VT model. Improved performance of ATP delivered to LBB compared to RV provides additional incentive for expanded use of LBB leads for pacing and therapy delivery.

Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction.

Acute occlusion of a coronary artery results in swift tissue necrosis. Bordering areas of the infarcted myocardium can also experience impaired blood supply and reduced oxygen delivery, leading to altered metabolic and mechanical processes. Although transcriptional changes in hypoxic cardiomyocytes are well studied, little is known about the proteins that are actively secreted from these cells. We established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Further functional validation experiments included ELISA measurement of human samples, murine left anterior descending coronary artery ligation, and adeno-associated virus 9-mediated in vivo overexpression in mice. The presented approach is feasible for analysis of the secretome of primary cardiomyocytes without serum starvation. A total of 1026 proteins were identified to be secreted within 24 hours, indicating a 5-fold increase in detection compared with former approaches. Among them, a variety of proteins have not yet been explored in the context of cardiovascular pathologies. One of the secreted factors most strongly upregulated upon hypoxia was PCSK6 (proprotein convertase subtilisin/kexin type 6). Validation experiments revealed an increase of PCSK6 on mRNA and protein level in hypoxic cardiomyocytes. PCSK6 expression was elevated in hearts of mice after 3 days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements in human serum also indicate distinct kinetics for PCSK6 in patients with acute myocardial infarction, with a peak on postinfarction day 3. Transfer of PCSK6-depleted cardiomyocyte secretome resulted in decreased expression of collagen I and III in fibroblasts compared with control treated cells, and small interfering RNA-mediated knockdown of PCSK6 in cardiomyocytes impacted transforming growth factor-β activation and SMAD3 (mothers against decapentaplegic homolog 3) translocation in fibroblasts. An adeno-associated virus 9-mediated, cardiomyocyte-specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis, as well as decreased left ventricular function, after myocardial infarction. A novel mass spectrometry-based approach allows investigation of the secretome of primary cardiomyocytes. Analysis of hypoxia-induced secretion led to the identification of PCSK6 as being crucially involved in cardiac remodeling after acute myocardial infarction.

Abstract 12354: Cardiac STAT3 Activation in Subacute Phase of Myocardial Infarction was Required for the Suppression of Adverse Cardiac Remodeling

Backgroud: Cardiac STAT3 plays crucial roles in cardioprotection against acute injury after MI. However, mutated gp130-induced continuous STAT3 activation resulted in serious cardiac damage in the subacute phase of MI. Here, we examined the biological significance of intrinsic cardiac STAT3 during subacute/chronic phase of MI in a time specific manner using tamoxifen inducible cardiac specific STAT3 knockout mice (iCKO). Methods and Results: MI was generated by ligating the left coronary artery in mice. Immunoblotting revealed that STAT3 was rapidly activated in the myocardium, and that its activation was sustained to subacute phase after MI. To clarify the impact of cardiac STAT3 in subacute phase of MI, STAT3 gene was ablated by administering tamoxifen to α-MHC-MerCreMer/STAT3 flox/flox for 14 consecutive days from post-infarct day 11. As control mice, α-MHC-MerCreMer/STAT3 wild/wild mice were used. Importantly, MI-induced cardiac STAT3 activation was significantly decreased in iCKO mice at day 24. Intriguingly, the mortality was accelerated in iCKO mice compared with control mice, coincident with increased heart weight/body weight. Masson’s trichrome staining demonstrated that cardiac STAT3 ablation resulted in severe fibrosis (iCKO; 58.3±6.7%, control; 40.8±9.3%, p &lt;0.01, n=7 for control, n=8 for iCKO). Moreover, Echocardiography clarified that cardiac function was deteriorated in iCKO mice (FS: iCKO; 20.6±4.1%, control; 29.1±6.0%, p &lt;0.05, n=10 for control, n=11 for iCKO). In border area, marked myocardial injuries, including ROS production and hypertrophy, were observed in iCKO mice. Finally, immunohistochemistry revealed that capillary density was decreased in iCKO mice (iCKO; 1724.2±119.4 capillaries/mm 2 , control; 2110.5±77.7 capillaries/mm 2 , p &lt;0.01, n=30 fields from 5 mice for each). Conclusions: Cardiac STAT3 ablation in subacute phase of MI aggravated cardiac remodeling. The augmentation of STAT3 activity could be a therapeutic strategy for the prevention from the onset of chronic heart failure.

Effects of postinfarct myelin-associated glycoprotein antibody treatment on motor recovery and motor map plasticity in squirrel monkeys.

New insights into the brain's ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin-associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage. Using a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to determine changes in spared motor representations. All monkeys recovered to baseline motor performance levels by postinfarct day 16. Functional recovery in the experimental group was significantly facilitated on the primary end point, albeit using slower movements. At 7 weeks post infarct, motor maps in the spared ventral premotor cortex in the experimental group decreased in area compared with the control group. GSK249320, initiated 24 hours after a focal cortical ischemic infarct, facilitated functional recovery. Together with the neurophysiological data, these results suggest that GSK249320 has a substantial biological effect on spared cortical tissue. However, its mechanisms of action may be widespread and not strictly limited to peri-infarct cortex and nearby premotor areas.

Paradoxical Procoagulant Effect of Early Doses of Warfarin: Possible Role of Non-Vitamin K Oral Anticoagulant in Patients with Atrial Fibrillation-Related Stroke

Paradoxical Procoagulant Effect of Early Doses of Warfarin: Possible Role of Non-Vitamin K Oral Anticoagulant in Patients with Atrial Fibrillation-Related Stroke

Intramyocardial thrombin promotes angiogenesis and improves cardiac function in an experimental rabbit model of acute myocardial infarction

Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by indirectly regulating and organizing a network of angiogenic molecules. On the basis of these reports, we investigated the angiogenic action of thrombin in a rabbit model of acute myocardial infarction. A rabbit model of acute myocardial infarction was established by ligation of the left anterior descending coronary branch. Subjects were then divided into 2 groups and treated with intramyocardial administration of thrombin (2500 IU; n=13) or an equal volume of normal saline (n=13). Four weeks later, animals were euthanized and histopathologic analysis, immunohistochemical staining for endothelial markers CD31 and vascular endothelial growth factor-A, and electron microscopy examination were performed on excised hearts. Electrocardiography, cardiac enzymes, and assessment of cardiac function by measuring left ventricular end-diastolic pressure and ejection fraction were recorded before and after myocardial infarction, and both left ventricular end-diastolic pressure and ejection fraction were further measured on the day of euthanasia (n=5-8 in each case). Increased levels of troponin, ST elevation, and histopathologically confirmed myocardial infarction were observed in all animals. A significant increase of microvessel density at the infarct border zone, as evaluated by CD31 immunohistochemistry, was observed in the thrombin-treated group compared with the control group (30.3 ± 12.8 vs 12.6 ± 4.8, P=.0065). A significantly higher number of vascular endothelial growth factor-A-positive vessels at the infarct border zone was observed in the thrombin-treated animals compared with the control group (21.8 ± 8.9 vs 5.6 ± 4.4; P=.0009). The thrombin-treated animals showed a statistically significant reduction in left ventricular end-diastolic pressure values (6.9 ± 1.8 mm Hg vs 12.7 ± 2.2 mm Hg, P=.0002) and significant improvement in left ventricular ejection fraction (59.8% ± 3.1% vs 42.2% ± 6.14%, P=.002) on the day of euthanasia compared with the post-infarct day, reflecting significantly improved cardiac function compared with control subjects that showed no significant change. Intramyocardial administration of thrombin seems to promote angiogenesis and improve cardiac function of the ischemic myocardium, which may provide a new therapeutic approach in patients with myocardial ischemia.

Isolated right coronary lesion and anterolateral papillary muscle rupture - case report and review of the literature

Ischemic rupture of the anterolateral papillary muscle is uncommon due to its dual blood supply. It usually follows an ischemic event involving branches of the left circumflex or left anterior descending arteries. We present a case of a patient admitted with an acute inferior wall myocardial infarction and an isolated distal right coronary artery occlusion. Acute mitral regurgitation with rupture of the anterolateral papillary muscle was diagnosed on the fifth post-infarction day. The patient underwent mitral valve replacement and coronary artery bypass grafting to the posterior descending artery. We conclude that anterolateral papillary muscle rupture may also result from an isolated right coronary lesion.

A Single Injection of d-Amphetamine Facilitates Improvements in Motor Training Following a Focal Cortical Infarct in Squirrel Monkeys

Background. There is growing interest in the use of d-amphetamine (d-AMPH) as a pharmacological treatment to supplement rehabilitative therapy following stroke. Based on the success of earlier animal models, several clinical studies have demonstrated beneficial effects of applying physical rehabilitation while stroke patients are under the influence of d-AMPH. To begin to understand the neural mechanisms underlying this promising adjuvant therapy, the authors examined the effects of a single pairing of d-AMPH and rehabilitative training on motor performance after cortical infarct in squirrel monkeys. Methods. Microelectrode stimulation techniques were used to delineate hand movement areas in the primary motor cortex prior to delivering a unilateral infarct to the complete hand representation. Postinfarct recovery was assessed for 3 groups of monkeys: d-AMPH + training, saline + training, and spontaneous recovery (SR). Postinfarct training groups received 14 consecutive days of motor skill training on a reach and retrieval task. A single injection of d-AMPH (0.25 mg/kg) or saline was given only on the 1st day of training (postinfarct day 10). Monkeys in the SR group had only minimal exposure to the training task once per week to monitor recovery. Results. The results show that a single coupling of d-AMPH + training initiated 10 days after cortical infarct facilitated the rate of recovery and improved performance (68% improvement from 1st day of training) beyond the level achieved by the monkeys in the saline + training group (27% improved from 1st day of training). Conclusions. D-AMPH is a potent modulator of behavioral recovery following an ischemic infarct in nonhuman primates.

Cell‐Free DNA Levels as a Prognostic Marker in Acute Myocardial Infarction

Cell-free DNA that originates from cell death, circulates in peripheral blood. There are indications that the infarcted myocardium contributes to an increase of cell-free DNA levels. Our aims were to quantify levels of cell-free DNA in patients with acute myocardial infarction (AMI) and examine their correlation with myocardial markers and with postinfarction (PI) clinical course. Thirteen patients (age 57 +/- 16 year) admitted with AMI and who underwent thrombolysis with reteplase within 6 h from the onset of chest pain were studied. PB samples were collected on admission and for 5 consecutive days. Creatine kinase (CK) and troponin I (TnI) were measured on admission and every 8 h for 3 consecutive days. Clinical events were recorded throughout the hospitalization period. Cell-free DNA levels were also measured in 30 healthy controls. Log-transformed mean (+/-SE) of maximum free DNA values in patients higher than controls (6873 +/- 357 g.e./mL verses 4112 +/- 234 g.e./mL, P < 0.0001). Log-transformed maximum values of CK and TnI were correlated with log-transformed free DNA values of first (r = 0.62, P = 0.02/r = 0.68, P = 0.01) and second (r = 0.57, P = 0.04/r = 0.72, P = 0.0053) PI day. Nine patients (group A) had an uncomplicated PI clinical course and four patients (group B) had recorded events (three with angina and one death). Free DNA levels on the second PI day were higher in group B than group A (1298.0 +/- 796.0 g.e./mL verses 244.6 +/- 257.7 g.e./mL, P = 0.003). In conclusion, free DNA levels are significantly higher in patients with AMI than in controls and may play a role in the prognosis of these patients.

Influence of Angiotensin II receptors blocking on overall left ventricle’s performance of patients with acute myocardial infarction of limited extent. Echocardiographic assessment

Recent studies documented the beneficial effect of angiotensin-receptor blockers (ARBs) on patients (pts) with acute myocardial infarction (AMI) combined with left ventricle (LV) systolic dysfunction. The present study intended to assess the impact of the ARB irbesartan, on the overall LV performance in pts with uncomplicated AMI of limited extent. Forty consecutive pts with first inferior AMI (AMI-I) and preserved LV-systolic function were enrolled. They were allocated into two groups: (a) 20 pts received the conventional treatment of AMI-I and placebo (CT) and (b) 20 pts administered irbesartan additionally to the conventional treatment (IR). Twenty four healthy individuals of matching age and sex were recruited as control group (CG). Complete echocardiographic examination, Tei index of overall LV function and systolic blood pressure (SBP) were measured on the 8th post-infarct day. The Tei index of IR group (0.53+/-0.03) was significantly lower compared to that of CT group (0.78+/-0.05) (p<0.001) and was similar to that of CG (0.45+/-0.03)(p=NS). Irbesartan induced a considerable decrease in both isovolumic relaxation (115+/-7 ms vs 140+/-7 ms; p<0.01) and contraction time (52+/-2 ms vs 64+/-3 ms; p<0.01) and a significant increase in ejection time (279+/-6 ms vs 256+/-8 ms; p<0.05). SBP in pts of IR group was similar to that of CT group (112+/-3 mmHg vs 113+/-4 mmHg; p=NS). Therapy with Irbesartan improves overall LV function of pts with AMI-I. Irbesartan leads to acceleration of the LV relaxation, which possibly indirectly ameliorates LV systolic performance too. This beneficial influence is possible attributed to a direct tissue effect of the drug and not to its hemodynamic action.

Angiogenic growth factors and/or cellular therapy for myocardial regeneration: A comparative study

Background Locally delivered angiogenic growth factors and cell implantation have been proposed for patients with myocardial infarcts without a possibility of percutaneous or surgical revascularization. The goal of this study was to compare the effects of these techniques in an experimental model of myocardial infarct. Methods Left ventricular myocardial infarction was created in 27 sheep by ligation of 2 coronary arteries. Three weeks after creation of the infarct, animals were randomized into 4 groups. In group 1, sheep received a culture medium injection to the infarct area (control group); group 2 underwent autologous myoblast implantation; group 3 received vascular endothelial growth factor; and group 4 received injection of both vascular endothelial growth factor and myoblasts. Evaluation included serum troponin IC levels, echocardiography (2-dimensional and color kinesis), and immunohistologic studies for quantitative analysis of capillaries (3 months after surgery). Results Four animals died of refractory ventricular fibrillation during myocardial infarction; 2 died after surgery because of stroke and 2 because of infections. Serum troponin increased to 45.6 ± 4.7 ng/mL at postinfarction day 2. Echocardiography at 3 months showed a significant limitation of left ventricular dilation in the cell group (57 ± 11.1 mL) and in the cell plus vascular endothelial growth factor group (58.6 ± 6.6 mL: control group, 74.4 ± 11.2 mL; vascular endothelial growth factor group, 68.1 ± 3.4 mL). Color kinesis echography showed important improvements of regional fractional area change in the cell group (from 13.6% ± 0.8% to 21.1% ± 1.5%) and in the cell plus vascular endothelial growth factor group (from 12.8% ± 0.9% to 18.7% ± 2.3%). The number of capillaries increased in the peri-infarct region of the vascular endothelial growth factor group (1036 ± 75: control group, 785 ± 31; cell group, 830 ± 75; cell plus vascular endothelial growth factor group, 831 ± 83). Conclusions In the cell therapy groups, regional ventricular contractility improved and heart dilatation was limited compared with either vascular endothelial growth factor or control; thus, postischemic remodeling was reduced. Angiogenesis was demonstrated in the vascular endothelial growth factor group, without improvement of ventricular function and remodeling. To improve local conditions for cell survival, further studies are warranted on prevascularization of myocardial scars with angiogenic therapy.

Is the Tissue Affinity of ACE Inhibitors of Relevance for the Remodeling of the Left Ventricular Wall following Myocardial Infarction?

Background: Angiotensin-converting enzyme (ACE) inhibitors have been shown to be of value in the treatment of postinfarction remodeling. The question whether substances with a greater tissue affinity are associated with advantages for the acute and the chronic course is, however, still unclear. Aim: The aim of the present study was to investigate the influence of ACE inhibitors with differing tissue affinities on the remodeling of the left ventricular wall in patients recovering from myocardial infarction. Methods: 52 patients (17 women, aged 38–73 years) suffering their first acute myocardial infarction were randomized to receive a daily dose of either 25–75 mg captopril or 10–20 mg fosinopril, beginning on the 7th postinfarction day. 28 patients had an anterior wall infarction and 24 patients an inferior wall infarction. The size of the infarct was determined using the creatine kinase integral method. 50 patients were investigated by cine magnetic resonance imaging 1 and 26 weeks after the infarction. The following parameters were determined: infarct weight and diastolic diameter of the infarcted zone, systolic wall stress, muscle mass, diastolic and systolic diameters, systolic wall thickening, and motility of the noninfarcted myocardium. Results: The infarct weight increased under captopril by 5.7% (p < 0.05) and under fosinopril by 6.1% (p < 0.05). The diastolic diameter of the infarcted zone decreased by 12% under captopril (p < 0.001) and by 11% under fosinopril (p < 0.001). The systolic wall thickness increased by 12.1% (p < 0.001) and the muscle mass by 12.7% (p < 0.001) under captopril and by 15.4% (p < 0.001) and 9.6% (p < 0.01), respectively, under fosinopril. Under captopril, the diastolic diameter increased by 2.3% (p < 0.05) and the systolic diameter by 17.8% (p < 0.01) and under fosinopril by 2.8% (n.s.) and 17.5% (p < 0.001), respectively. The systolic wall thickening increased by 73.9% under captopril (p < 0.001) and by 129.4% under fosinopril (p < 0.001). The motility decreased by 13.8% (p < 0.05) under captopril and by 6.0% (n.s.) under fosinopril. For all parameters, the results seen in anterior wall infarction were appreciably poorer than those seen in inferior wall infarction. All the differences between captopril and fosinopril were not significant. Conclusions: Captopril and fosinopril show no major differences in their influence on left ventricular wall remodeling following myocardial infarction. On the basis of the present results, the tissue affinity of an ACE inhibitor does not appear to be of a significant relevance for postinfarction treatment.

Serum total and lipid-bound sialic acid levels following acute myocardial infarction.

Although serum total sialic acid has been shown to be a cardiovascular risk factor, with elevated levels associated with increased cardiovascular mortality and also with cerebrovascular disease, the reason for the elevation in serum sialic acid content remains obscure. It has been shown that an increased output of serum proteins by the liver due to some type of acute phase reaction may be one of the possible sources of an increased serum sialic acid concentration in patients with myocardial infarction. An increase in the activity of sialidase, which cleaves the terminal sialic acid residues from oligosaccharides, glycoproteins and gangliosides, may also play an important role in the elevation of serum total sialic acid in myocardial infarction. Elevated serum total sialic acid in the blood might result either from the shedding or secreting of sialic acid from the cell membrane surface, or releasing of cellular sialic acid from the cell into the bloodstream due to cell damage after myocardial infarction. The purpose of the present study is to investigate serum total and lipid-bound sialic acid and the enzymes serum lactate dehydrogenase, creatine kinase and aspartate aminotransferase in patients with acute myocardial infarction, at 24 h post-infarction (day 1), 48 h post-infarction (day 2) and 72 h post-infarction (day 3). A possible role of cell damage in the elevation of serum total and lipid-bound sialic acid levels in these patients was also evaluated. In this study, 40 patients with myocardial infarction ranging in age from 42 to 68 years, and 26 healthy volunteers ranging in age from 45 to 71 years were included. Serum total sialic acid determination was carried out by the thiobarbituric acid method of Warren and lipid-bound sialic acfd by the method of Katopodis. Our data shows that a) there is a gradual increase in the levels of serum total sialic acid and lipid-bound sialic acid during the first three days after the acute myocardial infarction and b) the elevation in serum total sialic acid levels correlates with the elevation in lactate dehydrogenase activity only on day 1 following infarction. Therefore, either the shedding or secreting of sialic acid from the cell or cell membrane surface may be partly responsible for an increased serum sialic acid concentration especially on day 1 following myocardial infarction.

Evaluation of the treadmill stress testing for risk stratification after acute myocardial infarction.

The recent decline in postinfarction mortality reflects the success of the most recent therapeutical proposals incorporated into clinical practice . Despite this evolutional enhancement, mostly due to the use of thrombolytic agents, an increase in the recurrence of thrombotic phenomena, such as reinfarction and unstable angina, has occurred creating the need for strategies that adequately identify the patients with higher probability of an unfavorable outcome . The current evolution of acute myocardial infarction has resulted in changes in the clinical characteristics of the patients referred for the provocative tests for ischemia. These clinical characteristics were clearly identified by the professionals involved in treating acute myocardial infarction, who needed to reassess the previously existing concepts regarding these tests . This led to the spread of the routine performance of coronary angiography after acute myocardial infarction before hospital discharge . In 1987, research carried out among American cardiologists revealed that 86% of them had adopted this management in patients who had received thrombolytic agents . The TIMI II study 5 was designed to compare the routine use of coronary angiography prior to hospital discharge with the more conservative management of only those patients who had a clinical indication. All patients were treated during the acute phase with recombinant tissue plasminogen activator (r-TPA) within the first 4 hours of pain onset. In the group undergoing the invasive procedure, 1.636 patients underwent coronary angiography and prophylactic angioplasty when it was anatomically feasible 18 to 48 hours after administration of the thrombolytic agent. In the group treated conservatively, 1.626 patients were clinically followed up and only those patients with signs of ischemia during hospital stay, either spontaneous or triggered by the treadmill stress test, were referred for coronary angiography. No statistically significant difference between the two groups was observed in regard to mortality or acute myocardial infarction and the ejection fraction at rest or during exercise on the 42 postinfarction day. In the oneyear evaluation, no difference in the rate of new infarction or mortality occurred between the groups . During this period of time, a larger number of hospital admissions due to cardiac events and coronary angiography was observed in those patients undergoing the conservative treatment, but the total number of coronary angiographies was still 40% smaller than that reported for the group undergoing the invasive treatment . Evidence obtained in the TIMI II study was fundamental in defining the results obtained in both managements, reducing the impulse to use invasive techniques in all patients.

Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency.

Left ventricular function after acute myocardial infarction (AMI) is determined by the expansion of the infarct zone and remodeling of the noninfarcted myocardium. An occluded infarct-related artery (IRA) is an independent risk factor for remodeling. Changes in myocardial collagen metabolism were evaluated in 36 patients with suspected AMI. The plasma creatine kinase MB fraction and myoglobin release curves were analyzed for assessment of early reperfusion and infarct size. Collagen scar formation was evaluated by measurement of serum concentrations of the aminoterminal propeptide of type III procollagen (PIIINP), the aminoterminal propeptide of type I procollagen (intact PINP), and the carboxyterminal propeptide of type I procollagen (PICP). Plasma renin activity and urine excretion of cortisol and aldosterone were also measured. Coronary angiography and left ventricular cineangiography were performed during early hospitalization. The serum concentration of PIIINP increased from 3.50+/-0.20 to a maximum of 5.08+/-0.36 microg/L (n=32) in the patients with AMI, whereas the concentrations of intact PINP and PICP tended to decrease. The area under the curve (AUC) of PIIINP during the first 10 postinfarction days was larger in patients with severe heart failure or ejection fractions < or = 40% than in those with no heart failure or with an ejection fraction > 40% (P<.05 and P<.01, respectively), and it was also larger in the patients with TIMI grade 0 to 2 flows than in those with TIMI 3 flows (P<.05), despite similar enzymatically determined infarct sizes. No significant correlations between PIIINP and neurohumoral parameters were observed. The AUC of PIIINP and the change in PIIINP during the first 4 days were significantly correlated with indices of cardiac function. Collagen scar formation after AMI can be quantified by measurement of serum PIIINP concentrations. Scar formation is more prominent in large infarctions causing left ventricular dysfunction and in patients with occluded IRAs.

Angiotensin-converting enzyme inhibition limits dysfunction in adjacent noninfarcted regions during left ventricular remodeling

We hypothesized that angiotensin-converting enzyme inhibitors would limit dysfunction in the first 8 weeks after transmural infarction in adjacent noninfarcted regions, as well as attenuate left ventricular remodeling. Angiotensin-converting enzyme inhibition limits ventricular dilation and hypertrophy and improves survival after anterior infarction, but its effect on regional function during remodeling is not well characterized. Thirteen sheep underwent coronary ligation to create an anteroapical infarction. At postinfarction day 2, eight sheep were randomized to therapy with the angiotensin-converting enzyme inhibitor ramipril, and five sheep received no therapy. Animals were studied with magnetic resonance myocardial tagging before and 8 weeks after infarction. Left ventricular volume, mass and ejection fraction were measured, as were changes in percent circumferential shortening within the subendocardium and subepicardium of infarcted and noninfarcted myocardium, both adjacent to and remote from the infarction. Angiotensin-converting enzyme inhibition limited the increase in end-diastolic volume from a mean (+/- SD) of +1.5 +/- 0.7 ml/kg in control animals to +0.5 +/- 0.8 ml/kg in the treated group (p < 0.04). Segmental function within infarcted and remote noninfarcted tissue did not differ between groups. However, angiotensin-converting enzyme inhibition limited the decline in function in the adjacent noninfarcted region 8 weeks after infarction. Percent circumferential shortening in the subendocardium decreased by -13 +/- 5% in the control group compared with -5 +/- 5% in the treated group (p < 0.03). In concert with a reduction in left ventricular remodeling after anterior infarction, angiotensin-converting enzyme inhibition limits the decline in function in the adjacent noninfarcted region. Dysfunction in adjacent noninfarcted regions may be an important determinant of left ventricular remodeling after infarction.

Changes in interstitial collagen metabolism during acute myocardial infarction treated with streptokinase or tissue plasminogen activator

Collagen plays a specific role in the maintenance of vascular integrity and in the thrombosis and scar formation processes. Therefore we found it interesting to study the changes in interstitial collagen metabolism during acute myocardial infarction treated with thrombolytic agents. Changes in collagen synthesis were evaluated by obtaining assays of the serum concentrations of the carboxyterminal propeptide of type I procollagen. Except fibrin plasmin is capable of degrading extracellular matrix components including collagen, and this capability was evaluated by monitoring the serum concentrations of the aminoterminal propeptide of type III procollagen. Twenty-four patients with suspected acute myocardial infarction and indications for thrombolytic therapy were randomized to receive either streptokinase ( n = 11) or tissue plasminogen activator ( n = 13). The patient groups were identical in their clinical characteristics. Serum levels of the aminoterminal propeptide of type III collagen increased rapidly on infusion of the thrombolytic agents, with the maximal mean increases of 44% and 16% in the streptokinase and TPA-treated groups, respectively. Levels of the carboxyterminal propeptide of type I collagen did not change during the thrombolytic therapy. A transient decrease occurred in the type I propeptide concentration at postinfarction day 2, and this decrease was followed by a secondary increase at days 4 to 6 in both patient groups studied. We conclude that thrombolytic agents stimulate the breakdown of interstitial collagen and that the collagen-degrading activity of TPA is lower than that of streptokinase. This factor may contribute to the relatively higher rethrombosis rate seen after TPA, because exposed collagen in the affected vascular wall stimulates thrombosis formation. On the other hand, increased collagen degradation followed by inhibition of collagen synthesis in the infarcted myocardium might increase the risk for cardiac rupture, especially after streptokinase treatment.

Systolic time intervals after phenylephrine administration for early stratification of patients after acute myocardial infarction

This study was designed to assess the usefulness of the changes in left ventricular (LV) systolic time intervals after phenylephrine administration for detecting hightisk patients soon after acute myocardial infarction by correlation with the angiographic and ventriculogmphic findings. The procedure was performed in 76 consecutive patients (group I) on the fourth postinfarction day and in 12 normal subjects (group II) free of coronary artery disease. In 20 patients with LV ejection fraction ≤ 40% (subgroup IA) the preejection period (PEP)/LV ejection time (ET) ratio increased from 0.410 ± 0.107 to 0.535 ± 0.102 (p = 0.01) after phenylephrine, whereas in the remaining 56 patients (subgroup IB) with LV ejection fraction >40% and in the 12 normal subjects the PEP/LVET increased nonsignificantly. Of patients with LV ejection fraction >40% a subset of 20 patients was distinguished with proximal stenosis in both left anterior descending and either a dominant right or left circumflex coronary artery (subset IB-a). In these the PEP/LVET increased from 0.347 ± 0.056 to 0.445 ± 0.019 (p = 0.0001) after phenylephrine, whereas in the remaining 36 patients (subset IB-b) without proximal lesions in 2 main arteries the PEP/LVET increased nonsignificantly. In conclusion, the PEP/LVET response to phenylephrine administration early after acute myocardial infarction is a precise, safe, noninvasive bedside method for early stratification of these patients.

Clinical Recovery and Sleep Architecture Degradation

We achieved a unique and timely recording of cerebral activity in a 70 year old woman immediately pre- and post-stroke, while studying the effect of acute cerebral infarction on sleep-electroencephalogram (EEG) patterns. Normal patterns, except for increased wakefulness, were recorded during two pre-infarct polysomnograms. Immediately following cerebral infarction increased delta activity was recorded from the infarcted hemisphere only. Initially, REM sleep could not be recorded from either side; however, on the third post infarct day REM sleep returned. Background EEG levels from both hemispheres became progressively slower, flatter and simpler. In addition, sleep spindles and the distinctive saw-tooth wave forms of sleep almost disappeared. At one year post-stroke sleep-EEG rhythm recordings from both hemispheres became more similar except for persisting delta activity from the left hemisphere. Unexpected deterioration of sleep-EEG pattern recordings from the undamaged hemisphere taken during the patient's clinical recovery remains unexplained. Serial sleep recording may facilitate the study of brain recovery, activity and reorganization following stroke.

Sensory-motor deficit and recovery from thrombotic infarction of the vibrissal barrel-field cortex

The present studies were undertaken to examine: (1) whether thrombotic infarction of the vibrissal cortical barrel-fields of the primary somatosensory cortex would produce behavioral consequences reflecting a sensory-motor deficit; and (2) whether there was any recovery of function up to two months after infarction. Specifically, in two different learning tasks requiring sensory-motor integration, rats were trained to perform a motor response consequent to the detection of vibrissal cues derived from either active exploration or from passive detection of vibrissal deflection. Once training was complete, unilateral, bilateral or sham-infarction restricted to the region of the primary somatosensory cortex was produced by a non-invasive photochemical technique, which induces platelet-activated vascular occlusion combined with blood-brain barrier changes and subsequent cell death. The results demonstrated that, regardless of the active or passive sensory characteristics of the task, unilateral and bilateral infarction resulted in a reliable performance deficit, which was not present in sham-operated control animals. Thus, the infarct disrupted the ability to integrate passively received or actively acquired vibrissal sensory information with a previously associated motor response. However, unlike the bilaterally infarcted animals, who displayed no recovery of performance level throughout the postinfarction testing sessions, the unilaterally infarcted animals exhibited a gradual improvement in performance beginning in the second or third week postinfarction and recovering to within 10–20% of preinfarction levels between postinfarction days 46–61. The similarity of the temporal pattern of behavioral recovery in the unilateral groups, despite large differences in the sensory-motor demands of the two tasks, may reflect several common underlying mechanisms of recovery. Since similar sensory-motor behavioral deficits and recovery have been described with human stroke, the present model incorporates many of the pathophysiological and behavioral properties present in the clinical situation and may be useful for future investigation of therapeutic intervention.