Mark W. Gorman

Recommendations for the Establishment of Stroke Systems of Care Recommendations From the American Stroke Association’s Task Force on the Development of Stroke Systems

Stroke continues to be a significant cause of morbidity and mortality in the United States. Approximately 700 000 Americans have a new or recurrent stroke each year, and stroke remains the third leading cause of death in the United States when considered independently from other cardiovascular diseases. Stroke also remains a leading cause of serious, long-term disability in the United States.1 Major advances have been made during the past several decades in stroke prevention, treatment, and rehabilitation. Despite successes in delivering effective new therapies, significant obstacles remain in ensuring that scientific advances are consistently translated into clinical practice. In many instances, these obstacles can be related to a fragmentation of stroke-related care caused by inadequate integration of the various facilities, agencies, and professionals that should closely collaborate in providing stroke care. There is increased emphasis on improving the components of stroke care, including recommendations from the Brain Attack Coalition for primary stroke centers and a formal process provided through the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) for the certification of primary stroke centers.2–4 It is critically important to look carefully at how the distinct components can be better integrated into systems of stroke care. The American Stroke Association (ASA), a division of the American Heart Association (AHA), is dedicated to improving stroke prevention, treatment, and rehabilitation through research, education, advocacy, and the development and application of scientifically based standards and guidelines. The ASA convened a multidisciplinary group, the Task Force on the Development of Stroke Systems, to describe the current fragmentation of stroke care, to define the key components of a stroke system, and to recommend methods for encouraging the implementation of stroke systems. The term “stroke system” is used in this article to avoid the corporate and financial connotations associated with the words “network” and …

Control of Coronary Blood Flow during Exercise

Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically Important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and Ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the medlator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K+ATP channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward ß-adrenoceptor coronary vasodilation that accounts for -25% of coronary vasodilation observed during exercise. There is also a feed-forward α-adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.

Role of Nitric Oxide and Adenosine in Control of Coronary Blood Flow in Exercising Dogs

BACKGROUND Inhibition of nitric oxide (NO) synthesis results in very little change in coronary blood flow, but this is thought to be because cardiac adenosine concentration increases to compensate for the loss of NO vasodilation. Accordingly, in the present study, adenosine measurements were made before and during NO synthesis inhibition during exercise. METHODS AND RESULTS Experiments were performed in chronically instrumented dogs at rest and during graded treadmill exercise before and during inhibition of NO synthesis with N(omega)-nitro-L-arginine (L-NNA, 35 mg/kg IV). Before inhibition of NO synthesis, myocardial oxygen consumption increased approximately 3.7-fold, and coronary blood flow increased approximately 3.2-fold from rest to the highest level of exercise, and this was not changed by NO synthesis inhibition. Coronary venous oxygen tension was modestly reduced by L-NNA at all levels of myocardial oxygen consumption. However, the slope of the relationship between myocardial oxygen consumption and coronary venous oxygen tension was not altered by L-NNA. Inhibition of NO synthesis did not increase coronary venous plasma or estimated interstitial adenosine concentration. During exercise, estimated interstitial adenosine remained well below the threshold concentration necessary for coronary vasodilation before or after L-NNA. CONCLUSIONS NO causes a modest coronary vasodilation at rest and during exercise but does not act as a local metabolic vasodilator. Adenosine does not mediate a compensatory local metabolic coronary vasodilation when NO synthesis is inhibited.

Adenine nucleotide control of coronary blood flow during exercise

The adenine nucleotide hypothesis postulates that the ATP released from red blood cells is broken down to ADP and AMP in coronary capillaries and that ATP, ADP, and AMP act on purinergic receptors on the surface of capillary endothelial cells. Purinergic receptor activation initiates a retrograde conducted vasodilator signal to the upstream arteriole that controls coronary blood flow in a negative feedback manner. A previous study (M. Farias 3rd, M. W. Gorman, M. V. Savage, and E. O. Feigl, Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005) demonstrated that coronary venous plasma ATP concentration increased during exercise and correlated with coronary blood flow. The present experiments test the adenine nucleotide hypothesis by examining the balance between oxygen delivery (via coronary blood flow) and myocardial oxygen consumption during exercise before and after purinergic receptor blockade. Dogs (n = 7) were chronically instrumented with catheters in the aorta and coronary sinus and a flow transducer around the circumflex coronary artery. During control treadmill exercise, myocardial oxygen consumption increased and the balance between oxygen delivery and myocardial oxygen consumption fell as indicated by a declining coronary venous oxygen tension. Blockade of P1 and P2Y(1) purinergic receptors combined with inhibition of nitric oxide synthesis significantly decreased the balance between oxygen delivery and myocardial oxygen consumption compared with control. The results support the hypothesis that ATP and its breakdown products ADP and AMP are part of a negative feedback control mechanism that matches coronary blood flow to myocardial oxygen consumption at rest and during exercise.

Role of K+ATP channels in local metabolic coronary vasodilation.

ATP-sensitive potassium ([Formula: see text]) channels have been shown to play a role in the maintenance of basal coronary vascular tone in vivo. [Formula: see text] channels are also involved in the coronary vasodilator response to adenosine. The aim of this study was to determine the role of[Formula: see text] channels in local metabolically mediated increases in coronary blood flow during cardiac electrical paired pacing without catecholamine effects. In 10 anesthetized closed-chest dogs, coronary blood flow was measured in the left circumflex coronary artery, and myocardial O2 consumption was calculated using the arteriovenous O2difference. Cardiac interstitial adenosine concentration was estimated from coronary venous and arterial plasma adenosine measurements using a previously described, multicompartmental, axially distributed, mathematical model. Paired stimulation increased heart rate from 57 to 120 beats/min, myocardial O2consumption 88%, and coronary blood flow 76%. During[Formula: see text] channel blockade with glibenclamide, baseline coronary blood flow decreased in relation to myocardial O2 consumption and thus coronary sinus O2 tension fell. Paired-pulse pacing with glibenclamide resulted in increases in myocardial O2 consumption and coronary blood flow similar to those during control pacing. Coronary venous and estimated interstitial adenosine concentration did not increase sufficiently to overcome the glibenclamide blockade. In conclusion, [Formula: see text] channels are not required for locally mediated metabolic increases in coronary blood flow that accompany myocardial O2consumption during pacing tachycardia without catecholamines, and adenosine levels do not increase sufficiently to overcome the glibenclamide blockade.

Open-loop (feed-forward) and feedback control of coronary blood flow during exercise, cardiac pacing, and pressure changes

A control system model was developed to analyze data on in vivo coronary blood flow regulation and to probe how different mechanisms work together to control coronary flow from rest to exercise, and under a variety of experimental conditions, including cardiac pacing and with changes in coronary arterial pressure (autoregulation). In the model coronary flow is determined by the combined action of a feedback pathway signal that is determined by the level of plasma ATP in coronary venous blood, an adrenergic open-loop (feed-forward) signal that increases with exercise, and a contribution of pressure-mediated myogenic control. The model was identified based on data from exercise experiments where myocardial oxygen extraction, coronary flow, cardiac interstitial norepinephrine concentration, and arterial and coronary venous plasma ATP concentrations were measured during control and during adrenergic and purinergic receptor blockade conditions. The identified model was used to quantify the relative contributions of open-loop and feedback pathways and to illustrate the degree of redundancy in the control of coronary flow. The results indicate that the adrenergic open-loop control component is responsible for most of the increase in coronary blood flow that occurs during high levels of exercise. However, the adenine nucleotide-mediated metabolic feedback control component is essential. The model was evaluated by predicting coronary flow in cardiac pacing and autoregulation experiments with reasonable fits to the data. The analysis shows that a model in which coronary venous plasma adenine nucleotides are a signal in local metabolic feedback control of coronary flow is consistent with the available data.

Distance from Home to Research Center: A Barrier to In-Person Visits but Not Treatment Adherence in a Stroke Trial

Background and Purpose: Clinical trials often seek to enroll patients from both urban and rural areas to safeguard the generalizability of results. However, maintaining contact with patients who live away from a recruitment site, including rural areas, can be challenging. In this research we examine the effect of distance between patient and study centers on treatment adherence and retention. Methods: Secondary analysis of 2,466 participants in the Insulin Resistance Intervention after Stroke trial who were enrolled from research sites in the United States. Driving distance between the zipcodes of patient’s reported place of residence and the study center was calculated. Outcome measures were loss to follow-up, completion of annual in-person visits, adherence to preventive therapy, and adherence to study drug in the first 3 years of participation. Logistic regression models were used to adjust for confounders. Results: Distance from residence to research center was not associated with loss to follow-up, adherence to study drug, or adherence to preventive therapy (p > 0.05 for each). However, patients who lived farther from the research center (>120 miles), compared to patients who lived closer (<60 miles), were less likely to complete the second annual in-person visit (62 vs. 81%; adjusted OR 0.48; 95% CI 0.31–0.75) and third visit (53 vs. 75%; adjusted OR 0.44; 95% CI 0.29–0.67). Conclusions: Distance between patient and study center was an independent predictor of missed in-person visits but not with adherence to study treatment or preventive care.

Evidence-Based Management of Stroke

Jose Biller, Jose M. Ferro, eds 334 pages. Shrewsbury, UK: tfm Publishing Ltd, 2011.

Contents Vol. 34, 2010

99.00. ISBN: 978-1-903378-76-2 Evidence-based medicine is the mantra of modern-day practice, the bedrock of todays clinical care. We feel justified, and to a certain degree protected, when we build our daily patient care decisions with randomized clinical trial data as the substratum for our house of informed management. When our patient happens to stray from this foundation slightly by not meeting the criteria of the original studies, we generalize with a mild degree of reticence. When the issue ventures out into unsupported territory, we rely on the joists of our own clinical judgment and experience, our understanding of the pathophysiology, and the expert opinion and guidelines put together by our professional organizations. Perhaps we, collectively, rest uneasy as we venture out into those areas. When examining the current state of our medical architecture, we might find it at once impressive in its scope but perhaps lacking in solidity. Todays practitioner of stroke medicine is constantly presented with patients and situations that challenge ones level and depth of understanding of the literature. The diagnosis and management of acute stroke involves a series of difficult decisions that must be rapidly executed. Some rest on solid experimental and theoretical ground, others do not. Guidelines for Food and Drug Administration–approved intravenous tissue-type plasminogen activator within 3 hours of stroke onset are straightforward, but many patients fall outside the recommendations. How does one calculate the risk-benefit ratio? How should these decisions be made? How should one manage blood pressure and …

Matching coronary blood flow to myocardial oxygen consumption

270 Regional North American Annual Meeting of the World Federation of Neurology – Research Group on Neuroepidemiology Editors: Marras, C. (Toronto); Louis, E. (New York, N.Y.); Leimpeter, A.; Van Den Eeden, S.K. (Oakland, Calif.) (only available online) 279 Author Index Vol. 34, 2010 280 Subject Index Vol. 34, 2010