Subendocardial Flow Research Articles

Repetitive Preload Elevation and Stretch‐Induced Stiffening of Non‐Ischemic Myocardium in a Porcine Model of Multi‐Vessel Coronary Artery Disease

Objective We have recently shown that a transient elevation in left ventricular (LV) preload causes stretch-induced myocyte injury, with repetitive episodes resulting in interstitial fibrosis and reduced diastolic compliance. The present study was designed to test the hypothesis that this phenomenon contributes to stiffening of remote, non-ischemic myocardium that is subjected to repetitive preload elevation secondary to demand-induced ischemia in the setting of chronic multi-vessel coronary artery disease (CAD). Methods Swine (n=12) were instrumented with fixed 1.5 mm constrictors on the proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries. One month later, continuous ECG and LV pressure monitoring was initiated via implantable telemetry (PhysioTel Digital, DSI) to assess the frequency of preload elevation (LV end-diastolic pressure (EDP) > 30 mmHg) and tachycardia (heart rate > 170 beats/min). Serial physiological studies were performed for 3 months to assess stenosis severity (angiography), coronary flow reserve (fluorescent microspheres at rest and during adenosine vasodilation), and LV function (echocardiography). Circumferential diastolic stiffness was derived from stress-strain relationships obtained via speckle tracking echocardiography and invasive measurements of LV minimum pressure and EDP. Myocardial tissue samples were subsequently collected from the LAD (ischemic) and right coronary artery (RCA; non-ischemic) perfusion territories for post-mortem quantification of collagen content (hydroxyproline assay) and comparison to normal controls (n=8). Results By the end of the 3 month study period, animals exhibited severe LAD (93 ± 2 %) and LCx (91 ± 3 %) stenoses and significant reductions in subendocardial flow reserve (LAD: 1.4 ± 0.2; LCx: 1.3 ± 0.2) relative to the RCA territory (3.8 ± 0.6). Although LV EDP was only mildly elevated at rest (18 ± 2 mmHg), transient preload elevation occurred frequently (63 ± 10 episodes/day) and resulted in a total of 199 ± 45 min/day during which LV EDP exceeded 30 mmHg. Spontaneous tachycardia was also common (26 ± 5 episodes/day) and associated with transient elevations in LV EDP (28 ± 2 mmHg; p<0.05 vs. rest). Although LV ejection fraction was preserved (58 ± 3 %), radial and circumferential strain was depressed in ischemic and non-ischemic segments of the LV compared with controls (Table). Non-ischemic segments also exhibited increased diastolic stiffness, which coincided with a significant ~40% elevation in collagen content (0.31 ± 0.03 mg/g) vs. normal controls (0.22 ± 0.03 mg/g) that was comparable to that observed in the ischemic area of the LV (0.29 ± 0.02 mg/g). Conclusions Transient elevations in preload are common in swine with multi-vessel CAD and associated with interstitial fibrosis and myocardial stiffening in normally-perfused segments of the LV. Repetitive stretch-induced stiffening of remote myocardium may contribute to diastolic dysfunction and could explain the high prevalence of angiographically-significant CAD in patients with heart failure with preserved ejection fraction (HFpEF).

Transmural variation in microvascular remodeling following percutaneous revascularization of a chronic coronary stenosis in swine.

Remodeling of the coronary microcirculation is known to occur distal to a chronic coronary stenosis, but the reversibility of these changes and their functional significance on maximum myocardial perfusion before and after revascularization is unknown. Accordingly, swine instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium underwent percutaneous coronary intervention (PCI; n = 8) and were compared with animals with a persistent stenosis (n = 8), as well as sham controls (n = 6). Stenotic animals demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio (37.8 ± 3.3 vs. 28.3 ± 1.3% in sham, P = 0.04), reduced lumen area per arteriole (597 ± 88 vs. 927 ± 113 μm2, P = 0.04), and a compensatory increase in arteriolar density (9.4 ± 1.0 vs. 5.3 ± 0.4 arterioles/mm2, P < 0.01). As a result, vasodilated flow immediately after PCI was similar to normally perfused remote regions (5.1 ± 1.0 vs. 4.8 ± 0.9 ml·min-1·g-1, P = 0.87). When assessed 1-mo after PCI, increases in wall thickness-to-lumen diameter (42.2 ± 3.3%) and reductions in lumen area per arteriole (638 ± 59 μm2) remained unchanged, but arteriolar density returned to normal (5.2 ± 0.5 arterioles/mm2). As a result, maximum subendocardial flow during adenosine declined and was lower than remote regions (2.6 ± 0.3 vs. 5.9 ± 1.1 ml·min-1·g-1, P = 0.01). There was no microvascular remodeling in subepicardial arterioles, and maximum perfusion remained unchanged. These data demonstrate that subendocardial microvascular remodeling occurs distal to a chronic epicardial stenosis. The regression of arteriolar density without increases in luminal area may precipitate stress-induced subendocardial ischemia in the absence of a physiologically significant stenosis.NEW & NOTEWORTHY Swine with a chronic coronary stenosis exhibit subendocardial microvascular remodeling distal to a critical stenosis characterized by an increase in arteriolar wall thickness and reduction in lumen area with a compensatory increase in arteriolar density. The present study is the first to demonstrate that subendocardial arteriolar density normalizes 1-mo after revascularization, but the lumen area of individual arterioles remains reduced. This leads to a reduction in maximal subendocardial perfusion at this time point despite initial normalization of vasodilator reserve after revascularization. This pattern of chronic microvascular structural remodeling could contribute to recurrent subendocardial ischemia in the absence of coronary restenosis during tachycardia and increases in myocardial oxygen demand.

Central diastolic pressure exponential decay constant and subendocardial flow supply.

Central diastolic pressure exponential decay constant and subendocardial flow supply.

Comparison between Diastolic Subendocardial Tissue Pressures Measured Directly or Calculated from Pressure-Flow Relations

Changes in intramyocardial tissue pressure modulate the relationship between coronary pressure and flow during the cardiac cycle. The present study compared the relation between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero flow in anesthetized dogs after modulation of either coronary sinus (i.e. Fogarty catheter) or left ventricular intracavity (i.e. volume loading) pressure. Experiments were conducted in anesthetized, instrumented dogs; coronary pressure flow relations were constructed during pharmacologic vasodilatation and intramyocardial tissue pressure was measured using micromanometer pressure sensors. Elevated coronary sinus pressures did not affect subendocardial pressure-flow relations signifying that diastolic tissue pressure within this layer is the effective coronary back pressure. Higher left ventricular intracavity pressure did not affect either diastolic subendocardial tissue pressure or pressure flow relations within this layer. Results show a direct linear relation (y = 1.106x - 0.652; r2 = 0.59. P = 0.001) between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero-flow over a wide range of pressures after either LV systemic or coronary sinus pressure modulation. Knowledge of back pressure in the subendocardium is useful for the evaluation of efficacy of cardiac interventions on myocardial perfusion particularly at the level of the microcirculation.

New pharmacological approaches to ischemic heart disease

Major steps have been made in the treatment of ischemic heart disease from the discovery of nitrates as antianginal medication to the techniques of percutaneous angioplasty. This incredible therapeutic progress has resulted in a reduced incidence of ischemic heart disease and related mortality and morbidity. However, statistical and epidemiological data indicate that in ischemic heart disease, despite the achievement of great success, there is a necessity for a further step toward treatment, considering the fact that the characteristics of this population are changing (increased prevalence of subendocardial infarction compared with classic transmural infarction, especially in the elderly population). Furthermore, the need for alternative therapeutic approaches to traditional ones is recognized. Ranolazine is a selective inhibitor of Na channels that prevents pathological extension of late Na current developing in the ischemic myocardial cell. This current is responsible for calcium overload, with consequent impairment of diastolic relaxation. Ranolazine reduces Na overload induced by calcium and improves diastolic relaxation and coronary subendocardial flow, without affecting hemodynamic parameters such as blood pressure, heart rate, or inotropic state of the heart, avoiding undesirable side effects. Efficacy of ranolazine has been evaluated in several trials, using clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). Ivabradine acts through the inhibition of late Na current (also known as If), which controls the spontaneous diastolic depolarization of sinus node cells. The partial inhibition of these channels reduces the frequency of sinus node action potential initiation, resulting in decreased heart rate without effects on contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL trial has tested whether the effect of ivabradine in lowering heart rate is able to reduce mortality and cardiovascular morbidity in patients with coronary artery disease and left ventricular systolic dysfunction. The most significant results were obtained in the subgroup of patients with life-limiting exertional angina. In this group, ivabradine significantly reduced the primary endpoint, a composite of cardiovascular death, hospitalization for fatal and nonfatal acute myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm, hospitalizations for AMI and revascularization were reduced by 73% and 59%, respectively.

Arteriolar remodeling limits maximal perfusion after percutaneous revascularization of a chronic stenosis in pigs with hibernating myocardium

Chronic myocardial ischemia results in remodeling of the coronary microcirculation in hibernating myocardium but the reversibility of these changes is unknown. Accordingly, we evaluated parameters of arteriolar structure and measured transmural myocardial perfusion during adenosine vasodilation before and up to one month after percutaneous coronary intervention (PCI) of a chronic LAD stenosis in swine (n=12). Regional function was depressed at rest (LAD wall thickening 38.6±4.0 vs. 92.2±7.5%, p&lt;0.05). Immediately after PCI, subendocardial flow during adenosine vasodilation increased from 1.5±0.3 to 4.6±0.8 ml/min/g, but fell to 2.7±0.3 ml/min/g one month later without evidence of restenosis. Histological assessment of subendocardial resistance vessel remodeling is shown below: Group Subendocardial Arterioles Lumen Area (μm2) Density (arterioles/mm2) WT/Lumen Diameter (%) Hibernating (n=148) 721±67* 10.7±1.8* 37.3±1.5* Revascularized (n=54) 659±88* 5.8±0.4 40.3±2.2* Sham (n=54) 1184±173 6.2±0.3 28.7±1.3 Values are mean±SEM; n=total number of vessels analyzed; WT=wall thickness; p&lt;0.05 vs. Sham. These data indicate that there is subendocardial microvascular remodeling in hibernating myocardium with an increase in arteriolar density compensating for a reduction in arteriolar lumen area. After revascularization, arteriolar density returns to normal but lumen area remains reduced and decreases maximal perfusion. These chronic microvascular structural changes could precipitate subendocardial ischemia in the absence of coronary restenosis. Supported by NIH HL61610.

Acute Simvastatin Treatment Enhances the Efficacy of Rho Kinase Inhibitor Mediated Vasodilatation in Rat Caudal Arteries

these components currently exists. The aim of this study was to develop and verify a one-dimensional model of systemic and coronary arterial circulations incorporating ventricular pressure as the input via an aortic valve. The systemic circulation was modelled as a network of branching elastic vessels. The coronary circulation consisted of left and right coronary arteries which both branched into two ‘equivalent’ vessels to account for the lumped characteristics of subendocardial and subepicardial flows. A time-varying external pressure was applied to the subendocardial vessels to simulate myocardial compression. The aortic valve was modelled as a variable reflection coefficient for backward-running aortic waves, and a variable transmission coefficient for forwardrunning ventricular waves. To verify the model, simulations were performed with input parameters representing ‘at rest’ and exercise states, as well as two valve disease states (stenosis and incompetence). In accord with previous clinical and experimental observations, the model predicted increased cardiac output and CBF with exercise, but reduced output and CBF with both stenosis and incompetence. In addition, incompetence was associated with negative aortic flow throughout diastole, while stenosis produced high ventriculo-aortic pressure gradients. Conclusion: A newmodel incorporating systemic and coronary arterial circulations, ventricular pressure and aortic (p< 0.05). Simvastatin retained 80% of its vasodilator properties in the absence of an endothelium or in the presence of L-NAME. H-1152 relaxed U46619 and U46619/simvistatin constricted vessels in a concentrationdependent manner. The potency of H-1152 was increased in the presence of simvastatin. Conclusion: In the context of U46619 contraction, acute treatment with simvastatin increases vasorelaxation in both a nitric oxide-dependent and smooth muscledependent manner. Simvastatin treatment also increases the efficacy of direct Rho kinase inhibition on vasodilation, suggesting a therapeutic value of combined statin and low dose Rho kinase inhibitor therapy. doi:10.1016/j.hlc.2008.05.593

Microheterogeneity of regional myocardial blood flows in low-perfused rat hearts evaluated by double-tracer digital radiography

Using 3H- and 125I-labeled desmethylimipramine (DMI) for regional flow tracers, we established a two-time measurement method for the spatial pattern of myocardial perfusion in cross-circulated rat hearts. Myocardial extractions and retentions of these tracers were confirmed to be satisfactory; however, the latter were less than 90% after 3 min at a perfusion rate of 2.9 ml/min/g, limiting the present application to a short-time perfusion measurement. Distributions of myocardial depositions were separated by subtraction digital radiography with 400-μm pixel resolution. Its feasibility was examined by regression analysis between local deposition densities of 3H- and 125I-DMI injected simultaneously. The slope, y-intercept, and correlation coefficient ( r) of the regression line were 0.98±0.04, 0.02±0.04, and 0.95±0.03, respectively, indicating the validity of the present image subtraction technique. The spatial pattern of myocardial perfusion in response to flow reduction was evaluated by the injections of 3H- and 125I-DMI, respectively, before and after a nearly 70% flow reduction. A significant correlation between normalized density distributions of these tracers was found in both subepicardium ( r=0.77±0.12) and subendocardium ( r=0.73±0.20), indicating the stable pattern of myocardial perfusion. However, the coefficient of variation of tracer densities showed a decrease of subendocardial flow heterogeneity from 35±15% to 31±16%. Thus, flow differences between originally high- and low-flow regions in subendocardium were reduced on a relative basis during low perfusion.

Exercise Electrocardiogram Testing

Exercise testing remains the most widely accessible and relatively inexpensive method for initial evaluation of suspected coronary disease and for evaluation of its severity.1–3 Clinical usefulness has been limited, however, by poor sensitivity of standard ST-segment depression criteria for assessment of anatomic and functional coronary disease severity and for prediction of risk.1,2,4–6 Recent data make it clear that symptomatic obstructive plaques that typically result in exercise-mediated ischemia may be less relevant to infarction and sudden death than less obstructive unstable plaques.7 These limitations mandate a rethinking of the exercise ECG along 2 distinct lines: First, is it possible to improve the diagnostic value of the exercise ECG? Second, separate from its ability to diagnose obstructive coronary artery lesions, can the exercise test be used as a prognostic tool that can encourage effective prevention of premature deaths or coronary events? Both goals take us beyond the ST segment. Reversible ST-segment depression is the characteristic finding associated with exercise-induced, demand-driven ischemia in patients with significant coronary obstruction but no flow limitation at rest. This process differs from the flow-limited acute coronary syndromes because exercise-related ischemia is generally limited to the subendocardium and is proportional to increases in myocardial oxygen demand. Ventricular waveforms of the ECG can be related to the net uncanceled transmural gradients between endocardial and epicardial myocardium, as extrapolated from the work of Holland and Brooks, among others.8–10 Accordingly, isoelectric TQ and ST segments in normal and in nonischemic patients can be related to comparable resting membrane and action potential plateau voltages in endocardial and epicardial action potentials. During exercise, progressive ischemia results in changing endocardial action potentials during both diastole and systole. Less negative endocardial cell resting membrane potential leads to current flow across the ischemic boundary during diastole, leading to elevation of the TQ …

Myocardial protection in the failing heart: II. Effect of pulsatile cardioplegic perfusion under simulated left ventricular restoration

The open ventricle was studied in pacing-induced experimental heart failure to determine the extent of coronary perfusion and distribution during either continuous or pulsatile cardioplegic perfusion compared with whole blood in the beating heart. In 5 animals that underwent pacing-induced heart failure and in 6 control swine, regional coronary blood flows were measured on bypass in the open left ventricle (simulating exposure for left ventricle restoration) during (1) beating, (2) nonpulsatile cardioplegia, and (3) pulsatile cardioplegia modalities. Mean perfusion pressure was maintained at 80 mm Hg. Flow magnitude and distribution differed in control and failing hearts in the open left ventricle. In control hearts, transmural and endocardial cardioplegic flow of nonpulsatile and pulsatile flow (which were similar to each other) exceeded beating flow by 63% and 70%, respectively, in the open left ventricle condition. Transmural and subendocardial vascular resistance increased in failing hearts during cardioplegic delivery, resulting in lower subendocardial flow under nonpulsatile conditions for the same perfusion pressure. In failing hearts, subendocardial perfusion conditions did not change in the beating state (0.89 vs 0.78 mL/min/g in control and failing open beating states, respectively), but nonpulsatile cardioplegic flow was significantly reduced by 154%, and became lower than beating flow by 32.2% (0.78 vs 0.59 mL/min/g). Conversely, pulsatile cardioplegic delivery improved endocardial flow in the open failing hearts, as cardioplegic perfusion with pulsatility exceeded beating flow by 41%. In heart failure, pulsatility from either the beating heart, which causes extrinsic compression of coronary vessels, or intrinsic vessel distension during pulsatile cardioplegic perfusion preserved endocardial perfusion better than nonpulsatile cardioplegia at the same perfusion pressure. In the failing open ventricle (simulated geometry during ventricular restoration), subendocardial blood flow was maintained in the beating state, but decreased significantly from control values during nonpulsatile cardioplegic perfusion. Conversely, pulsatile cardioplegic delivery improved subendocardial perfusion of the open failing ventricle. These findings of improved subendocardial perfusion during pulsatile delivery (either during beating or cardioplegic perfusion) compared with nonpulsatile cardioplegic delivery may have important implications for myocardial protection in failing hearts.

Myocardial protection during surgical ventricular restoration☆

Ventricular restoration is a novel procedure for treating congestive heart failure (CHF). The two important features include a technically correct procedure and adequate myocardial protection. The two protective techniques include conventional cardioplegia and the beating heart. This report reviews a RESTORE clinical registry and summarizes background experimental work related to myocardial protection in failing dilated hearts. The RESTORE registry is reported, where protection is 55% with cardioplegia and 45% with beating heart. The beating method was used more frequently in patients with ejection fraction <30%, end systolic volume 80 ml/m2, NYHA class >III/IV. Overall survival results favored cardioplegia except for the first 30 days, but after matching patients on age, ejection fraction (EF) and NYHA the beating results and cardioplegic results were comparable. Experimental work evaluated the safety of the beating method in failing dilated ventricles under acute conditions. Supplemental coronary perfusion studies in chronically dilated hearts after tachycardia induced cardiomyopathy were analyzed to show that (a) there was vascular remodeling (less flow at the same pressure in failing hearts with cardioplegic, but not beating delivery; (b) in the open state (used during restoration) subendocardial flow increased in the beating heart, and fell after cardioplegia. These studies were done without ischemia. Cardioplegic delivery for protection is 'time dependent' (needing ischemic intervals) while beating nourishment is 'procedure dependent,' as continuous perfusion is provided throughout the procedure is suggested. The importance of maintaining high perfusion pressure is emphasized.

Investigation of the fluid dynamical properties of helical pipes from a mixing perspective

Ischemic heart disease is more apparent in the subendocardial than in subepicardial layers. We investigated coronary pressure–flow relations in layers of the isolated rat left ventricle, using 15 μm microspheres during diastolic and systolic arrest in the vasodilated coronary circulation. A special cannula allowed for selective determination of left main stem pressure–flow relations. Arterio-venous shunt flow was derived from microspheres in the venous effluent. We quantitatively investigated the pressure–flow relations in diastolic arrest (n=8), systolic arrest at normal contractility (n=8) and low contractility (n=6). In all three groups normal and large ventricular volume was studied. In diastolic arrest, at a perfusion pressure of 90 mmHg, subendocardial flow is larger than subepicardial flow, i.e., the endo/epi ratio is ∼1.2. In systolic arrest the endo/epi ratio is ∼0.3, and subendocardial flow and subepicardial flow are ∼12% and ∼55% of their values during diastolic arrest. The endo/epi ratio in diastolic arrest decreases with increasing perfusion pressure, while in systole the ratio increases. The slope of the pressure–flow relations, i.e., inverse of resistance, changes by a factor of ∼5.3 in the subendocardium and by a factor ∼2.2 in the subepicardium from diastole to systole. Lowering contractility affects subendocardial flow more than subepicardial flow, but both contractility and ventricular volume changes have only a limited effect on both subendocardial and subepicardial flow. The resistance (inverse of slope) of the total left main stem pressure–flow relation changes by a factor of ∼3.4 from diastolic to systolic arrest. The zero-flow pressure increases from diastole to systole. Thus, coronary perfusion flow in diastolic arrest is larger than systolic arrest, with the largest difference in the subendocardium, as a result of layer dependent increases in vascular resistance and intercept pressure. Shunt flow is larger in diastolic than in systolic arrest, and increases with perfusion pressure. We conclude that changes in contractility and ventricular volume have a smaller effect on pressure–flow relations than diastolic–systolic differences. A synthesis of models accounting for the effect of cardiac contraction on perfusion is suggested.

Diastolic time fraction as a determinant of subendocardial perfusion

Diastolic time fraction (DTF) has been recognized as an important determinant for subendocardial perfusion, but microsphere studies in which DTF was the independent variable are practically absent. In 21 anesthetized goats, the left coronary main stem was artificially perfused at controlled pressure. DTF was varied by pacing the heart, vagus stimulation, or administration of dobutamine. Regional coronary flow was measured with fluorescent microspheres under full adenosine dilation. Perfusion pressure (P(c)) was defined as mean coronary arterial pressure minus minimal left ventricular pressure. Regional flow conductances (flow/P(c)) were as follows: for the subendocardium, C(endo) = -0.103 + 0.197 DTF + 0.00074 P(c) (P < 0.001); for the midmyocardium, conductance = -0.048 + 0.126 DTF + 0.00049 P(c) (P < 0.001); and for the subepicardium, C(epi) was not significant. C(endo)-DTF relations demonstrated a finite value for DTF at which flow is zero, implying that, at physiological pressures, systolic subendocardial flow limitation extends into diastole. The DTF corresponding to an equal conductance in subendocardium and subepicardium (DTF1) was inversely related to P(c): DTF1 = 0.78 - 0.003 P(c) (P < 0.01). When heart rate and P(c) were held constant and dobutamine was administered (5 goats), contractility doubled and DTF increased by 39%, resulting in an increase of C(endo) of 40%. It is concluded that 1) DTF is a determinant of subendocardial perfusion, 2) systolic compression exerts a flow-limiting effect into diastole, and 3) corresponding to clinical findings on inducible ischemia we predict that, under hyperemic conditions, C(endo) < C(epi) if P(c) is lower than approximately 75% of a normal aortic pressure and heart rate >80 beats/min.

Dynamics of flow velocities in endocardial and epicardial coronary arterioles

The subendocardium is the most vulnerable area of the left ventricle to the effects of hypoperfusion and ischemia. Despite this well-acknowledged observation, the mechanisms underlying this susceptibility are not elucidated, although numerous explanations including differences in transmural distribution of hemodynamics, metabolism, and wall stresses have been proposed. Our goal was to make dynamic measurements of endocardial and epicardial flow velocities, which reflect hemodynamic and wall stresses, to approach this problem. We measured blood flow velocities in subendocardial and subepicardial coronary arterioles of in vivo beating canine hearts using a high-speed, charge-coupled device, intravital videomicroscope with a rod-probe lens. Subendocardial flow was characterized by remarkable systolic flow-velocity reversal (systolic slosh ratio, 84%; measurable velocity of retrograde flow, faster than -40 mm/s), which contrasted to predominant forward-flow velocity during systole in the subepicardial arterioles (systolic slosh ratio, 25%; maximum velocity, approximately -20 mm/s; P < 0.0005 and 0.05 vs. subendocardial arterioles, respectively). We speculate that this retrograde flow is "wasteful," because this volume must be refilled during the subsequent diastole, which thereby detracts from the net perfusion as well as the time for perfusion. Accordingly, we also believe that the retrograde systolic blood flow contributes to the vulnerability of the subendocardium to ischemia.

Women's Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2-4, 2002: Section 5: gender-related risk factors for ischemic heart disease.

The concomitant effects of aging, traditional risk factors, and a lack of endogenous estrogen promote the sequelae of arterial dysfunction, inflammation, and atheromatous plaque deposition in women. The challenges for improved diagnosis of coronary artery disease (CAD) in women include the more complex and multifactorial nature of the disease process; small artery size; and vascular and metabolic abnormalities that have yet to be thoroughly elucidated with existing imaging technology. Conditional risk markers, such as high-sensitivity C-reactive protein (hs-CRP), may provide greater insight into the arterial insult and underlying risk burden. Conventional ischemia testing, aimed primarily at detection of obstructive lesions, has provided disappointing results in women. Perhaps as a result of vascular remodeling, symptomatic women more often have nonobstructive atherosclerotic disease and, in some cases, evidence of metabolic or vascular dysfunction. Imaging accuracy in women is also hampered by technical problems and differences in body habitus. In addition, studies assessing diagnostic accuracy of imaging methods have often included small numbers of women subjects. In larger female samples, stress echocardiography and single photon emission computed tomography (SPECT) have yielded positive results in terms of estimating clinical outcomes. Newer technology, such as magnetic resonance spectroscopy (MRS) and perfusion imaging (MRI), has revealed intriguing findings indicating reductions in both subendocardial flow and high-energy phosphates that are suggestive of myocardial ischemia during stress testing in symptomatic women without obstructive CAD. This section reviews the evidence for gender differences in traditional and novel risk factors and explores the use of conventional and innovative myocardial methods to detect myocardial ischemia. ### Traditional Risk Factors The Atherosclerosis Risk In Communities (ARIC) study assessed traditional risks (age, cholesterol, blood pressure, smoking, and diabetes) for CAD events in 15 792 middle-aged, black and white women and men. These traditional risk factors can be integrated into a global risk score to predict 10-year risk …

Subendocardial and subepicardial pressure–flow relations in the rat heart in diastolic and systolic arrest

Ischemic heart disease is more apparent in the subendocardial than in subepicardial layers. We investigated coronary pressure–flow relations in layers of the isolated rat left ventricle, using 15 μm microspheres during diastolic and systolic arrest in the vasodilated coronary circulation. A special cannula allowed for selective determination of left main stem pressure–flow relations. Arterio-venous shunt flow was derived from microspheres in the venous effluent. We quantitatively investigated the pressure–flow relations in diastolic arrest ( n=8), systolic arrest at normal contractility ( n=8) and low contractility ( n=6). In all three groups normal and large ventricular volume was studied. In diastolic arrest, at a perfusion pressure of 90 mmHg, subendocardial flow is larger than subepicardial flow, i.e., the endo/epi ratio is ∼1.2. In systolic arrest the endo/epi ratio is ∼0.3, and subendocardial flow and subepicardial flow are ∼12% and ∼55% of their values during diastolic arrest. The endo/epi ratio in diastolic arrest decreases with increasing perfusion pressure, while in systole the ratio increases. The slope of the pressure–flow relations, i.e., inverse of resistance, changes by a factor of ∼5.3 in the subendocardium and by a factor ∼2.2 in the subepicardium from diastole to systole. Lowering contractility affects subendocardial flow more than subepicardial flow, but both contractility and ventricular volume changes have only a limited effect on both subendocardial and subepicardial flow. The resistance (inverse of slope) of the total left main stem pressure–flow relation changes by a factor of ∼3.4 from diastolic to systolic arrest. The zero-flow pressure increases from diastole to systole. Thus, coronary perfusion flow in diastolic arrest is larger than systolic arrest, with the largest difference in the subendocardium, as a result of layer dependent increases in vascular resistance and intercept pressure. Shunt flow is larger in diastolic than in systolic arrest, and increases with perfusion pressure. We conclude that changes in contractility and ventricular volume have a smaller effect on pressure–flow relations than diastolic–systolic differences. A synthesis of models accounting for the effect of cardiac contraction on perfusion is suggested.

Effect of steady versus oscillating flow on porcine coronary arterioles: involvement of NO and superoxide anion.

Coronary blood vessels are compressed by the contracting myocardium. This leads to oscillations in flow in especially the subendocardium. We examined the effects of steady and oscillating flow on isolated, cannulated subendocardial and subepicardial porcine arterioles. Steady flow-induced dilation in both vessel types, up to 12.9+/-0.8% of the passive diameter in subendocardials and 9.6+/-1.4% in subepicardials at 40 dyne/cm2. Dilation was completely abolished after treatment with 10 micromol/L L-NNA. Sinusoidal modulation of steady flow at 1.5 Hz and 50% to 200% amplitude did not affect dilation. Oscillating flow without a net forward component with peak-peak shear values up to 100 dyne/cm2 caused no dilation at all in these vessels. However, in the presence of 100 U/mL superoxide dismutase (SOD), oscillating flow induced dilation up to 19.5+/-2.3% in subendocardial vessels and 11.5+/-4.3% in subepicardials. LNNA (10 micromol/L) blocked this dilation by approximately 50%. SOD did not affect the magnitude of steady flow-induced dilation, but the response time after onset of steady flow shortened from 23.4+/-1.5 to 14.3+/-2.1 seconds. Diphenyleneiodinium, an inhibitor of NAD(P)H oxidase, uncovered dilation to oscillating flow in subendocardial vessels up to 9.5+/-1.6%. Flow causes production of both NO and O2-. During steady flow, the bioavailability of NO is sufficient to cause vasodilation. During oscillating flow, NO is quenched by the O2-, suppressing vasodilation. Considering the pulsatile nature of subendocardial flow and the vulnerability of this layer, pharmacological manipulation of the balance between NO and O2- may improve subendocardial perfusion.

Variability of contractile reserve in hibernating myocardium: dependence on the method of inotropic stimulation.

Contractile reserve during graded beta-adrenergic stimulation identifies viability in patients with left ventricular dysfunction. Nevertheless, contractile reserve is frequently absent in viable, chronically dysfunctional myocardium with reduced resting flow (hibernating myocardium). The goal of this study was to evaluate the mechanisms responsible for limited contractile reserve in hibernating myocardium. Pigs were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium; and regional flow, function and hemodynamics were assessed during graded beta-adrenergic stimulation (epinephrine). The chronic LAD stenosis produced a critical reduction in coronary flow reserve with regional reductions in resting subendocardial flow (0.69+/-0.05 vs. 1.03+/-0.11 ml/min/g in shams, P<0.05) and wall thickening (2.0+/-0.4 vs. 4.3+/-0.4 mm in shams, P<0.05), consistent with hibernating myocardium. In sham controls, LAD flow and function increased during graded, steady-state increases in epinephrine. Nevertheless, despite similar external determinants of demand in animals with hibernating myocardium, neither subendocardial flow (peak response: 0.66+/-0.14 and peak dose: 0.58+/-0.13 ml/min/g, respectively) nor wall thickening (3.0+/-0.5 and 2.5+/-0.6 mm, respectively) increased during graded epinephrine infusion. However, during a transient epinephrine infusion to the maximum dose used in the graded protocol, flow remained unchanged (0.80+/-0.06 to 0.85+/-0.08 ml/min/g) but wall thickening improved (2.3+/-0.4 to 4.1+/-0.6 mm, P<0.05). These data indicate that variability in contractile reserve in hibernating myocardium is at least partly related to the protocol used for beta-adrenergic stimulation. The blunted steady-state responses to beta-adrenergic stimulation raise the possibility that, like moderate supply-induced ischemia, an exquisite matching between flow and function develops during moderate demand-induced ischemia. This prevents metabolic deterioration in hibernating myocardium but limits contractile function during increases in the external determinants of myocardial metabolism.

Spatial inhomogeneity of sympathetic nerve function in hibernating myocardium.

Although humans and swine with hibernating myocardium have an increased risk of sudden death, the contribution of chronic alterations in sympathetic nerve function is unknown. Acute transmural ischemia causes inhomogeneity in sympathetic innervation that may lead to lethal arrhythmias, but it is unclear whether similar abnormalities develop in response to chronic reversible ischemia. Swine were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis that produced hibernating myocardium after 3 months. Resting subendocardial flow (LAD 0.75+/-0.14 versus 1.19+/-0.14 mL. min(-1) x g(-1), P<0.05) and wall thickening (LAD 15+/-3% versus 40+/-2%, P<0.05) were reduced compared with normal remote regions, without triphenyltetrazolium chloride evidence of necrosis. 131I-meta-iodobenzylguanidine (MIBG) was used to assess integrity of the norepinephrine uptake-1 mechanism, and the spatial and transmural distributions were quantified by ex vivo counting. In hibernating myocardium, MIBG deposition was decreased in each layer, with the greatest reduction in the subendocardium (LAD subendocardium 0.28+/-0.02 versus 0.42+/-0.04 mL x g(-1) x min(-1) in normal, P<0.05; LAD subepicardium 0.31+/-0.03 versus 0.38+/-0.04 mL x g(-1) x min(-1) in normal, P<0.05). In contrast, there were no spatial alterations of MIBG deposition in sham-instrumented animals. The sympathetic norepinephrine uptake-1 mechanism is impaired in hibernating myocardium. These findings raise the possibility that chronic alterations in sympathetic innervation contribute to the excess mortality seen in the setting of hibernating myocardium.

Nicorandil improves myocardial high-energy phosphates in postinfarction porcine hearts.

1. Nicorandil is a potent vasodilator combining the effects of a nitrate with an ATP-sensitive potassium channel (K(ATP)) opener. Because the postinfarct remodelled heart has increased vulnerability to subendocardial hypoperfusion, it is possible that the vasodilator effects of nicorandil could cause transmural redistribution of blood flow away from the subendocardium. Alternatively, the K(ATP) channel opening effects of nicorandil could exert a beneficial effect on mitochondrial respiration. Consequently, the present study was performed to examine the effect of nicorandil on energy metabolism in the postinfarct heart. 2. Studies were performed in swine in which myocardial infarction produced by proximal left circumflex coronary artery ligation had resulted in left ventricular remodeling. [(31)P] nuclear magnetic resonance spectroscopy (MRS) was used to examine the myocardial energy supply/demand relationship across the left ventricular wall while the transmural distribution of blood flow was examined with radioactive microspheres. Data were obtained during baseline conditions and during infusion of nicorandil (100 microg, i.v., followed an infusion of 25 microg/kg per min). 3. Nicorandil caused coronary vasodilation with a preferential increase in subepicardial flow; however, subendocardial flow also increased significantly. Nicorandil had no significant effect on the rate-pressure product or myocardial oxygen consumption. The ratio of phosphocreatine (PCr)/ATP determined with MRS was abnormally depressed in remodelled hearts (2.01 +/- 0.11, 1.85 +/- 0.10 and 1.59 +/- 0.11 for subepicardium, midwall and subendocardium, respectively) compared with normal (2.22 +/- 0.11, 2.01 +/- 0.15 and 1.80 +/- 0.09, respectively). Nicorandil had no effect on the high-energy phosphate content of normal hearts. However, nicorandil increased the PCr/ATP ratio in the subendocardium of remodelled hearts from 1.59 +/- 0.11 to 1.87 +/- 0.10 (P < 0.05). 4. Although nicorandil caused modest redistribution of blood flow away from the subendocardium of the postinfarct left ventricle, this was associated with an increase of the PCr/ATP ratio towards normal. These results suggest that nicorandil exerts a beneficial effect on energy metabolism in the subendocardium of the postinfarct remodelled left ventricle.