Left Anterior Descending Region Research Articles

The effect of bifurcation angulation on flow characteristics and hemodynamic indicators in an idealized left coronary artery

Atherosclerosis is a pathological condition characterized by inflammation in the main arteries, which serves as the primary factor for the development of cardiovascular disease. This condition represents the prevailing medical and surgical issue. Clinically, consequences of this condition might include stroke, coronary artery and heart disease, or peripheral vascular disease. In this study, the hemodynamic effect of three different angulations is numerically analyzed on left coronary artery and constant degree of stenosis (DoS) which equals to 50 % is implemented on each branch of three models to create stenotic arteries. The idealized left main coronary artery (LM) is modeled with its primary branches, namely left anterior descending (LAD) and left circumflex (LCx). The bifurcation angulations between LAD and LCx are considered 30°, 75° and 120°. All numerical analyses are carried out in transient regime, blood is considered as a non-Newtonian fluid and the Carreau viscosity model is selected to describe the viscosity variation of blood. The outcomes of all numerical analyses revealed that the blood flow across the branches is closely related to bifurcation angle. Recirculation is vital in the post-stenotic regions of LAD and LCx, and velocity enhances its breadth. WSS is highest in the stenosis and carina regions. OSI values are greater in the post-stenotic LAD and LCx regions where recirculation and plaque development are more likely. Helical flow appears in the post-stenotic region of the LM when velocity is lowest and in the stenotic area when velocity is highest.

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

P864Histopathological damages in the epicardial coronary artery after ischemia and reperfusion injury in swine

Abstract Background The microscopic consequences in the myocardial capillaries after myocardial infarction (MI) have been widely addressed, but little attention has been paid to epicardial coronary arteries. Since epicardial circulation is responsible for providing blood flow to the heart, understanding the microscopical changes on the epicardial artery after MI becomes also crucial. Purpose To evaluate the dynamics of the microscopic damages in the coronary arteries post-MI in swine model of reperfused MI. Methods MI was induced in swine by transient 90-min coronary occlusion of the left anterior descending (LAD) coronary artery using angioplasty balloons. One control group and four MI groups were defined: 1) without reperfusion, and 2) 1-min, 3) 1-week, and 4) 1-month reperfusion (n=3, each). In each group, LAD (infarct-related artery) and the right coronary artery (RCA) were isolated. Taking as reference the region in which balloon was inflated, we also separated samples from two different regions: proximal and distal LAD. Histological stainings (HE, Masson's trichromic, and orcein) and immunohistochemistry against CD31 (endothelial cells), a-smooth muscle cells, and CD45 (total leukocytes) were performed. Results Abnormalities in the endothelial monolayer of the LAD artery started even before reperfusion (during ischemia). This damage dramatically increased after reperfusion, observing an almost absence of CD31+ cells in the tunica intima and some breaks in the internal elastic layer from the 1-min and 1-week reperfusion groups. No irregularities were found in the tunica media from the no reperfusion group, whereas an increased in its thickness was detected soon after reperfusion. In the 1-week reperfusion group, larger thickness, a desorganized muscular cells distribution, and oedema were found. The damage in the tunica intima and media was more pronounced in the region distal to the angioplasty balloon compared to the proximal region, whereas no changes were detected in the RCA. In the tunica adventitia, vasa vasorum density was reduced during the ischemic phase, remaining low in the 1-min and 1-week reperfusion group, while being restored after 1-month reperfusion. This dynamics was similar in both LAD regions, while no changes in the RCA were found. After coronary reperfusion, a higher leukocyte adhesion to the endothelium from the LAD artery, mainly in the region proximal to the balloon inflation, was observed. The process evolves, resulting in a massive presence of CD45+ cells not only in the tunica intima, but also in the media and the adventitia monolayer isolated from the 1-week reperfusion group. Conclusions The microscopic structure of the infarct-related coronary artery was compromised after MI. This damage started during ischemia and boosted after reperfusion, becoming more pronounced in the region distal to balloon inflation. Exploring these damages will be important for a better understanding of the pathophysiology of MI. Acknowledgement/Funding This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (PIE15/00013, PI17/01836, and CIBERCV16/11

Deep inspiration breath-hold intensity modulated radiation therapy in a large clinical series of 239 left-sided breast cancer patients: a dosimetric analysis of organs at risk doses and clinical feasibility from a single center experience.

To evaluate dose to organs at risk, target coverage and treatment compliance in left-sided breast cancer patients (LSBCP) treated with deep inspiration breath-hold (DIBH) and intensity modulated radiation therapy (IMRT) technique in a contest of daily clinical practice. A total of 280 consecutive LSBCP referred for adjuvant radiotherapy were systematically screened for suitability of DIBH technique. 239 were able to comply with the requirement for DIBH. Whole breast or chest wall were irradiated in DIBH, monitored by Varian RPM™ Respiratory Gating System, and two tangential inverse-planned beams with dynamic dose delivery. Dose prescription was 42.4 Gy/16 fractions in 205 patients and 50 Gy/25 fractions in 34. 23 patients received local and nodal treatment. Boost to tumor bed, of 10 Gy/5 fractions was used in 135 patients. Relevant dose metrics for heart, left anterior descending (LAD) coronary artery, lungs, contralateral breast and planning target volume were retrospectively analyzed. The average mean heart dose (MHD) for all patients was 0.94 Gy and mean maximum LAD dose was 13.82 Gy. MHD and LAD maximum dose were significantly higher in patients treated with conventional fractionation whether expressed in absolute dose (1.44 vs 0.85 Gy, p < 0.0005 and 20.78 vs 12.45 Gy, p < 0.0005 respectively) or in equivalent doses of 2 Gy fractionation (0.88 vs 0.52 Gy, p =< 0.0005 and 17.68 vs 10.63 Gy, p = 0.0002 respectively). In 57 patients (23.8%) the maximum LAD dose was >20 Gy. Mean V20 ipsilateral lung dose was 8.5%. Mean doses of contralateral breast and lung were 0.13 Gy and 0.09 Gy respectively. Mean planning target volume V95% coverage was 96.1%. Compliance rate of DIBH technique was 84.5% (239/280). DIBH and IMRT in daily clinical practice are feasible in high percentage of unselected patients and allows low levels of irradiation of organs at risk without compromising target coverage. However, despite low MHD a significant proportion of patients receives a maximum LAD dose superior to 20 Gy. The value of MHD used exclusively is not able to describe entirely the risk of late heart toxicity, which can be better evaluated with the joint analysis of the maximum dose to LAD region. The vast majority of LSBCP referred to adjuvant radiotherapy in the setting of routine practice are able to comply with the requirement of DIBH.

Targeted Delivery and Controlled Release of a Small Molecule Matrix Metalloproteinase Inhibitor Using a Self-Assembling Hydrogel Following Myocardial Infarction

Background Strategic delivery of biomaterials to the newly formed myocardial infarction (MI) continues to be an area of active investigation and offers the opportunity to reappraise the use of small molecule therapeutics that hold high target specificity but are problematic when systemically delivered. The goal of this study was to examine the effects of late post-MI delivery (3 days post-MI) of a self-assembling hydrogel (SAgel), which had been loaded with a previously characterized matrix metalloproteinase inhibitor (MMPi). Hypothesis Using a minimally invasive (mini-thoracotomy) and an SAgel allowing for targeted myocardial injection array within the MI region of a large animal model as well as localized release of an MMPi, improved LV function and geometry would be demonstrated up to 28 days post-MI. Methods and Results MI was induced in adult pigs (25 kg) by left anterior descending (LAD) catheter balloon occlusion (90 min/then reperfusion) and at 3 days post-MI randomized to MI-SAgel/SD7300 (500 μg/mL; n=7) or saline (MI saline; n=8), whereby the injections were performed in a 9 point 100 uL array within the targeted LAD region. The SAgel adapts fluid-like properties to flow through the syringe (21 Gauge) due to shear forces during injection and rapidly reassembles with encapsulated SD7300 following injection into the MI region. LV ejection fraction (LVEF) and end-diastolic volume (LVEDV) were measured at Baseline (pre-MI) and at 14 and 28 days post-MI by echocardiography. LVEF fell post-MI but was significantly attenuated by SAgel/SD7300 injections. LVEDV increased from Baseline (35±2 mL) in the MI-saline (84+6) and MI-SAgel/SD7300 (64+4 mL groups at 28 days post-MI (p Conclusions This is the first study to demonstrate the feasibility of targeted delivery of a self-assembling injectable gel using a minimally invasive surgical approach at a relevant post-MI time point. Second, targeted delivery of this gel containing an MMPi for sustained local release demonstrated sustained beneficial effects on post-MI remodeling.

Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery.

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

Anomalous origin of right coronary artery from mid-left anterior descending artery leading to coronary steal phenomenon and ischemia.

Coronary anomalies are usually diagnosed incidentally during coronary angiography. Anomalous origin of the right coronary artery (RCA) from the left anterior descending (LAD) is a rare clinical entity [1, 2]. Noninvasive anatomic assessment by coronary computed tomography (CT) angiography has evolved to become a highly accurate method in the diagnosis of coronary artery disease (CAD), comparable to conventional invasive coronary angiography [3]. We report a case of anomalous RCA originating from the mid-LAD leading to exertional dyspnea. A 50-year-old woman was admitted to our cardiology outpatient clinic with the complaint of exertional dyspnea and atypical chest pain. The patient was not eligible for the treadmill stress test due to congenital hip dislocation. Therefore, we scheduled myocardial perfusion scintigraphy, and hypoperfusion was detected in the mid and basal segments of the anterior region of the heart (Figure 1). These changes were interpreted as mild ischemia. As further investigation, coronary CT angiography was scheduled for the patient. Coronary CT angiography demonstrated a single coronary artery from the left Valsalva sinus. An anomalous RCA originated from the mid-LAD, after the first diagonal branch, coursing to the right, anterior to the pulmonary artery, then trajecting downward into the right atrioventricular groove (Figures 2–4). Figure 1 Tomographic scans during stress myocardial scintigraphy. Perfusion defects in the mid and basal anterior segments in the short-axis (SAX) and vertical long-axis (VLA) views. The resting SAX and VLA views show the normal perfusion Figure 2 Coronary computed tomography angiography image showing an anomalous RCA originating from the mid-LAD and coursing anterior of the aorta and the pulmonary trunk Figure 4 Anatomical course of the anomalous RCA Figure 3 Overview of coronary vessel course in relation to the great arterial vessels aorta and pulmonary trunk Anomalies of the RCA are observed to a relatively lesser extent. Yamanaka and Hobbs [4] reported anomalous RCA at the rate of 0.26% in a series of 126,595 patients. Turkmen et al. reported the incidence of single coronary artery anomaly as 0.031% in a series of 215,140 patients who underwent routine coronary angiography [5]. Although anomalous coronary artery is considered to be a benign entity, it may cause myocardial ischemia and even sudden cardiac death. Most of these patients are asymptomatic and have normal electrocardiograms at rest. However, ischemia may be precipitated by strenuous, prolonged physical activity. Our patient's symptoms emerged only with exercise. Myocardial ischemia should be excluded before a coronary anomaly is considered as benign. Myocardial perfusion scintigraphy is a useful and widespread method for indicating the presence of ischemia. Also, coronary CT angiography may be beneficial in the diagnosis of CAD and coronary anomalies. Coronary tomputed angiography demonstrated a single coronary artery anomaly in our patient (Figures 2–4). The coronary tree was free of significant intraluminal narrowing, atherosclerosis, unusual angling or any compression sign which may explain ischemia. In our case, exertional dyspnea may be partly secondary to the myocardial ischemia, which could result from the steal phenomenon due to single coronary artery anomaly. To the best of our knowledge, this is the first case that shows myocardial ischemia in the LAD region in single coronary artery anomaly despite absence of any significant narrowing in the coronary arteries.

Progressively heterogeneous mismatch of regional oxygen delivery to consumption during graded coronary stenosis in pig left ventricle.

In normal hearts, myocardial perfusion is fairly well matched to regional metabolic demand, although both are distributed heterogeneously. Nonuniform regional metabolic vulnerability during coronary stenosis would help to explain nonuniform necrosis during myocardial infarction. In the present study, we investigated whether metabolism-perfusion correlation diminishes during coronary stenosis, indicating increasing mismatch of regional oxygen supply to demand. Thirty anesthetized male pigs were studied: controls without coronary stenosis (n = 11); group I, left anterior descending (LAD) coronary stenosis leading to coronary perfusion pressure reduction to 70 mmHg (n = 6); group II, stenosis with perfusion pressure of about 35 mmHg (n = 6); and group III, stenosis with perfusion pressure of 45 mmHg combined with adenosine infusion (n = 7). [2-(13)C]- and [1,2-(13)C]acetate infusion was used to calculate regional O2 consumption from glutamate NMR spectra measured for multiple tissue samples of about 100 mg dry mass in the LAD region. Blood flow was measured with microspheres in the same regions. In control hearts without stenosis, regional oxygen extraction did not correlate with basal blood flow. Average myocardial O2 delivery and consumption decreased during coronary stenosis, but vasodilation with adenosine counteracted this. Regional oxygen extraction was on average decreased during stenosis, suggesting adaptation of metabolism to lower oxygen supply after half an hour of ischemia. Whereas regional O2 delivery correlated with O2 consumption in controls, this relation was progressively lost with graded coronary hypotension but partially reestablished by adenosine infusion. Therefore, coronary stenosis leads to heterogeneous metabolic stress indicated by decreasing regional O2 supply to demand matching in myocardium during partial coronary obstruction.

Mitochondrial fusion proteins in revascularized hibernating hearts

BackgroundHibernating myocardium is characterized by viable yet dysfunctional myocardium secondary to chronic ischemia, with studies demonstrating incomplete early recovery after coronary artery bypass graft (CABG). We tested whether mitochondrial fusion proteins, an indicator of mitochondrial biogenesis, are increased in hibernating myocardium post-CABG. MethodsA constrictor was placed on the left anterior descending (LAD) artery of nine pigs. Four of these pigs additionally underwent CABG 12 wk later with a left internal mammary artery graft to the LAD distal to the constrictor. Five pigs had a constrictor placed but did not undergo CABG (Hib). Five pigs did not have a constrictor placed (control). Computerized tomography angiography was used to confirm stenosis at the site of constrictor placement and patency of left internal mammary artery grafts. Regional blood flows were determined at baseline and during 40 μg/kg/min dobutamine infusion. Mitochondrial proteins were quantified by Western blot. ResultsBlood flow in the LAD region after CABG was lower than remote regions during dobutamine infusion (2.54 ± 0.24 versus 3.46 ± 0.33 mL/min/g; P < 0.05). Electron transport chain proteins were ∼70% lower in Hib compared with those in control and failed to normalize after CABG. Post-CABG, PGC1α nuclear-bound content was increased compared with Hib (9.02 ± 0.48 versus 5.54 ± 0.98 arbitrary units, respectively; P < 0.05), and expression of mitofusins-1 and 2 and optic atrophy-1 more than doubled. ConclusionsPGC1α and mitochondrial fusion proteins are increased 4 wk post-CABG in hibernating hearts, indicating mitochondrial fusion has begun to occur and signaling early mitochondrial recovery. Future studies should address changes in maximal myocardial oxygen consumption relative to mitochondrial protein expression.

Abstract 185: Global Infusion of Allogeneic Cardiosphere-Derived Cells Proportionally Stimulates Angiogenesis and Myocyte Regeneration in Swine With Chronic Myocardial Infarction

Background: Previously we reported that global infusion of CDCs in infarcted and non-infarcted remote regions improved LV function in swine with chronic myocardial infarction. The effect of global infusion of CDCs on angiogenesis and myocyte regeneration in infarcted and non-infarcted remote regions is unknown. Methods: Swine (n=11) with chronic infarction in the left anterior descending (LAD) coronary artery region were studied 8 weeks after microsphere embolization (1x10^6 particles, 45μm diameter). CDCs were isolated from myocardial atrium and 20 x 10^6 CDCs were infused into the 3 major coronary distributions after cyclosporine (100mg/day) immunosuppression. Data were compared to untreated animals. To assess the factors related to angiogenesis, VEGF and SDF-1 expression on cultured CDCs were quantified by RT-PCR. Angiogenesis was quantified by assessing capillary density (von Willebrand Factor) with immunohistochemistry. Myocyte regeneration was quantified by assessing myocyte nuclear density. The ratio of capillary density to myocyte nuclear density was evaluated. Results: icCDCs improved infarcted LAD (13±6 vs. 36±6%, p&lt;0.05) and remote (47±8 vs. 99±10%, p&lt;0.05) wall thickening with increased ejection fraction (32±3 vs. 45±4%, p&lt;0.05) compared to untreated. RT- PCR from cultured CDCs showed VEGF expression and to a less extent SDF-1 expression. icCDCs increased capillary density and myocyte nuclear density in infarcted LAD and remote regions by 40% (Table). Thus, the ratio of capillary density to myocyte nuclear density was maintained in untreated and icCDCs animals. Conclusion: These data indicate that in a model of infarction, global infusion of icCDCs stimulates angiogenesis and myocyte regeneration to the same extent in infarcted and non-infarcted regions resulting in improved global function. Thus, global infusion of icCDCs may afford a widely available approach to regenerate myocardium in patients with ischemic cardiomyopathy.

EComment. Does off-pump coronary endarterectomy improve long-term outcomes?

The publication by Takahashi et al. highlights an area with limited data [1]. They successfully performed off-pump coronary endarterectomy to the left anterior descending (LAD) artery in 12 patients. We congratulate the authors for their effort and successful results. In this report, there are a few topics we would like to discuss. The study population belonged to a consecutive series of 232 off-pump cases performed by a single surgeon. We believe that the surgeon's preference and experience played major role on the outcomes of coronary artery bypass grafting (CABG), particularly on graft patency. The ROOBY trial, which represents the largest randomized controlled study on off-pump versus on-pump CABG to date, documented that graft patency was significantly and consistently lower in the off-pump group. The results were consistent with 3 major coronary regions, including the LAD. The graft patency rates in the LAD region were 89.0% in the off-pump group and 93.2% in the on-pump group (P = 0.01) on 1-year angiograms. Moreover, the effective revascularization rate was lower in the off-pump group (50.1% vs 63.9%; P = 0.001) [2]. In on-pump coronary endarterectomy cases propensity-matched to CABG alone, Lapar et al. documented comparable operative mortality, major complication and long-term survival rates [3]. Similarly, Schwann et al. reported survival benefits in on-pump CABG patients with endarterectomy similar to that described in isolated CABG patients with the use of multiple arterial grafts [4]. There are no studies documenting this relation between off-pump endarterectomy and isolated CABG. Due to the abovementioned facts, we do not think that patients will really benefit from off-pump endarterectomy. Conflict of interest: none declared

Abstract 5696: Dynamic Alterations in Ventricular Repolarization in Pigs with Hibernatimg Myocardium and a Chronic LAD Stenosis

Altered ventricular repolarization manifested as QT-RR hysteresis occurs in Long QT Syndrome and with acute ischemia. We hypothesized that this might identify risk of sudden cardiac death (SCD) associated with chronic coronary disease. Pigs were chronically instrumented with a left anterior descending (LAD) coronary stenosis to produce hibernating myocardium (n=11). This model develops frequent, spontaneous SCD due to ventricular tachycardia degenerating into ventricular fibrillation, in the absence of infarction. As compared to 13 Controls there was reduced LAD wall-thickening (25±2 vs 54±9%, p&lt;0.001) and flow reserve (1.4±0.3 vs 2.7±0.5, p&lt;0.05), with preserved ejection fraction (63±3 vs 71±4%, p=0.09), and minimal necrosis (0.4±0.2% of LV). Regional electrograms were obtained from subendocardial piezoelectric crystals. Baseline QT intervals from the LAD region were similar in both groups (Hibernating – 354±13 vs. 356±15 ms in Controls, p=0.93). The QT intervals shortened to a similar extent during atrial pacing (Hibernating – 247±8 vs. 249±10 ms, p=0.92), stellate ganglion stimulation (Hibernating – 259±16 vs. 242±11 ms, p=0.37), and intravenous epinephrine infusion (Hibernating – 255±16 vs. 237±9 ms, p=0.31), with no differences between groups. In contrast, the LAD region QT-RR relationships during epinephrine stimulation were altered in pigs with hibernating myocardium, resulting in greater hysteresis loop areas as compared to Controls (7247±2334 vs 1927±943 ms 2 , p&lt;0.05). Interestingly, this did not reflect stress-induced ischemia since pigs with hibernating myocardium also had greater hysteresis loop areas in the remote normally-perfused regions (9295±1319 ms 2 , p=0.40 vs LAD). There were no significant regional differences in either group. Hibernating myocardium in pigs is associated with altered ventricular repolarization hysteresis. This abnormality is global, and thus dissociated from regional dysfunction, reduced flow reserve and the propensity to develop acute ischemia. Thus, dynamic alterations in ventricular repolarization may be a substrate for SCD in patients with ischemic heart disease and chronic remodeling from hibernating myocardium.

Arterial coronary–coronary conduit over single, distal left anterior descending coronary artery lesion: 3.5 years afterward

Arterial coronary–coronary conduit over single, distal left anterior descending coronary artery lesion: 3.5 years afterward

Thromboxane induced‐vasoconstriction in coronary resistance arteries: Effects of age and ovarian hormone status

Both age and ovarian hormones are known to influence coronary vascular function; however, little is known of the influence of ovarian hormones on coronary vascular reactivity in aged females. Therefore, the purpose of this study was to examine the effects of age and ovarian hormones on vasoconstrictor responses to U46619, a thromboxane A2 agonist. Coronary resistance arteries were isolated from the Left Anterior Descending (LAD) and Septal Artery distributions (SA) from young (6 mo), and old (24 mo) control (CON) and ovariectomized (OVEX) female Fischer-344 rats. In intact female rats, U46619-induced constriction was preserved with age in both LAD (6 mo: 31.6 ± 5.7 %; 24 mo: 32.7 ± 7.5%) and SA (6 mo: 27.6 ± 5.7 %; 24 mo: 20.0 ± 6.1%) regions. Ovariectomy increased U46619-induced constriction in resistance arteries from the LAD and SA regions in old but not young rats. Furthermore, the magnitude of the increase in constriction that occurred following ovariectomy in old rats was greater in LAD (OVEX: 75.0 ± 6.1% vs. 32.7%) resistance arteries as compared to SA (OVEX: 35.1 ± 6.6% vs. 20.0 ± 6.1%) resistance arteries. These data indicate that modulation of arteriolar function by ovarian hormones is heterogeneous in the coronary circulation and increases with advancing age. Funded by NIH grant HL077224.

Treating metabolic impairment and myocardial stunning with phosphodiesterase inhibitor type III, milrinone, administered prior to coronary artery occlusion in the presence of calcium channel blockade in pigs

This study examined milrinone effects on ischaemic myocardial metabolism and function with calcium blockade. We studied 15 pigs in 3 groups: group C received no drugs; group D received diltiazem 5 mg bolus followed by infusion; group D+M received diltiazem and milrinone (50microg/Kg). The left anterior descending (LAD) artery was then occluded for 15 minutes. Left ventricular (LV) function data obtained included rate, pressures, output, Emax, and dP/dT. Blood lactate was obtained from the LAD and circumflex vessels at baseline, end of occlusion, early (15 min) and late (1 hour) reperfusion. In group D+M, less depression of LV function occurred during ischaemia and early reperfusion. Lactate extraction in the LAD region was less negative in D+M group than in the group without milrinone during ischaemia and late reperfusion. We conclude the preemptive administration of milrinone prior to ischaemia added to calcium blockade improved myocardialfunction and ischaemic metabolic effects.

Effect of Coronary Stenosis on Adjacent Bed Flow Reserve

During coronary stenosis, flow reserve in the adjacent nonstenotic bed decreases, but the microvascular mechanisms are unknown. Because myocardial contrast echocardiography (MCE) assesses microvascular physiology, we used it to relate flow reserve to intramyocardial blood volume in the adjacent bed. A noncritical left anterior descending (LAD) stenosis was created in 10 dogs. MCE was performed and myocardial blood flow was measured with neutron-activated microspheres and flow probes. Data were collected at baseline, hyperemia, and hyperemia and stenosis. Hyperemia was induced with an A2A receptor agonist. MCE acoustic intensity in the LAD and left circumflex (LCx) regions were fit to the following: y=A(1-e(-beta t)), where A, beta, and A x beta reflect intramyocardial blood volume, red cell velocity, and flow, respectively. During hyperemia alone, LCx probe and microsphere flows and MCE-derived red cell velocity increased from baseline (30+/-14 versus 125+/-62 mL/min, P<0.0005; 1.5+/-0.5 versus 6.6+/-2.0 mL x min(-1) x g(-1), P<0.0005; and 0.53+/-0.14 versus 0.96+/-0.45 second(-1), P=0.030, respectively); intramyocardial blood volume was unchanged. LAD stenosis during hyperemia decreased LCx probe flow (125+/-62 versus 110+/-57 mL/min; P<0.05), microsphere flow (6.6+/-2.0 versus 4.2+/-2.1 mL x min(-1) x g(-1); P<0.0005), and MCE-derived flow (0.57+/-0.29 versus 0.45+/-0.33 second(-1); P=0.032). LCx bed intramyocardial blood volume concurrently increased (0.61+/-0.14 versus 0.70+/-0.15; P<0.01). Coronary stenosis impairs flow reserve in the adjacent nonstenotic bed, in which intramyocardial blood volume increases. MCE suggests compensatory recruitment of microvascular anastomotic collateral networks that augment stenotic bed flow reserve, but at the expense of the adjacent bed. Adjacent bed collateral microcirculation thus participates in the regulation of collateral flow and appears functionally significant during coronary stenosis.

Mitochondrial adaptations within chronically ischemic swine myocardium

Experimental evidence has emerged that myocardial ischemic preconditioning can prime the mitochondria into a “stress-resistant state”, so that cell death is reduced following prolonged severe ischemia and reperfusion. Using a swine model of chronically ischemic myocardium, we tested the hypothesis that mitochondria within the ischemic territory have also acquired a protective phenotype. Eleven swine underwent a left thoracotomy with placement of an external constrictor around the proximal left anterior descending (LAD) artery. By 10 weeks, a severe stenosis of the LAD artery was documented by quantitative coronary angiography (92 ± 2%). Animals were sacrificed and myocardium was extracted from the LAD and remote regions. Mitochondria were isolated from subendocardium and subepicardium from LAD and remote regions and state 2 (substrate alone) and state 3 (+ADP) respiration were assessed with a Clark electrode. Within the LAD subendocardium, the respiratory control index was 2.68 ± 0.17 and was lower than the remote subendocardium (3.64 ± 0.08; P < 0.05). When exposed to 20 min anoxia with reoxygenation, the LAD region demonstrated a more preserved state 3 respiration compared with the remote region (99 ± 14 versus 65 ± 9 nmol O 2/mg, respectively; P < 0.05). In parallel mitochondrial experiments, chemiluminescence was detected with the probe coelenterazine and superoxide generation in the LAD region in the presence of antimycin A was 574 ± 108 RLU/30 s/μg and was nearly 50% lower than the remote region (979 ± 175 RLU/30 s/μg; P < 0.05). Within the mitochondria, the expression of uncoupling protein (UCP) 2 by western gels was 20% higher in the LAD region compared with the remote region ( P < 0.05) with no differences noted in UCP-3. In this swine model of chronic myocardial ischemia, isolated mitochondria from the ischemic tissue demonstrate preserved state 3 respiration following anoxia/reoxygenation, consistent with a stress-resistant state. This state is characterized by a mild degree of uncoupling under basal conditions and decreased superoxide generation. Uncoupling protein 2 expression is enhanced in the mitochondria, providing a potential mechanism for these favorable mitochondrial adaptations.

Hypertension and Smoking Are Associated With Reduced Regional Left Ventricular Function in Asymptomatic Individuals: The Multi-Ethnic Study of Atherosclerosis

This study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals. Coronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals. The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression. Higher diastolic blood pressure (DBP) was associated with lower Ecc (p < or = 0.002). The Ecc's in the LAD territory of participants with DBP <80, 80 to 84, 85 to 89, and > or =90 mm Hg were -15.6%, -14.8%, -14.2%, and -13.7%, respectively (p < 0.001). Similar results were documented in other territories and after multivariable analysis. Smokers had lower Ecc in the LAD and RCA regions compared with nonsmokers. Furthermore, dose response relationship between cigarette consumption measured in pack-years and regional LV dysfunction by Ecc was noted (p < or = 0.01 in LAD and RCA territories). Finally, combined diastolic hypertension and smoking was associated with a greater reduction of regional LV function. Higher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals.

Atrial natriuretic peptide reverses the negative functional effects of stunning in rabbit myocardium

We tested the hypothesis that atrial natriuretic peptide (ANP) would decrease both the effects of myocardial stunning and oxygen consumption in rabbit hearts. In two groups of anesthetized open-chest rabbits, myocardial stunning was produced by two 15 min occlusions of the left anterior descending (LAD) artery separated by 15 min of reperfusion. Either ANP (0.2 mg) or vehicle (lactated Ringers) was then injected into the affected area of the left ventricle. In a third group, ANP was injected into the LAD region of non-stunned rabbits. Hemodynamic (heart rate, aortic and left ventricular pressures) and functional (wall thickening (WT), delay of onset of WT, and rate of WT) parameters were measured. Coronary blood flow (microspheres) and O 2 extraction (microspectrophotometry) were used to determine myocardial O 2 consumption. Stunning was demonstrated by an increase in the time delay to contraction and depressed WT. In the control group, baseline delay to contraction was 25 ± 7 ms, and this increased to 84 ± 16 following stunning and vehicle administration. In the ANP group, baseline delay was 20 ± 6 at baseline and after stunning and ANP administration it was 30 ± 7. Wall thickening decreased by approximately 30% with stunning and vehicle but only 8% in the ANP treated hearts. Stunning did not affect regional O 2 consumption (6.0 ± 1.1 stunned vs. 7.4 ± 1.2 mlO 2/min/100g non-stunned). ANP administration did not affect O 2 consumption (7.3 ± 1.7 stunned vs. 6.4 ± 1.0 non-stunned). We therefore concluded that ANP administration reversed the effects of stunning without alteration in local O 2 consumption in stunned myocardium.

Intraluminal coronary shunting preserves regional myocardial perfusion and function.

Coronary artery hemostasis during offpump coronary artery bypass (OPCAB) may be achieved with extraluminal coronary occlusion or intraluminal coronary shunting. We sought to determine with a normal porcine beating-heart model whether coronary shunting preserves regional myocardial perfusion and function compared with coronary occlusion. Six pigs (50-60 kg) underwent sternotomy and instrumentation. Two pairs of ultrasonic crystals were placed in the distribution of t h e left anterior descending (LAD) and left circumflex (LCx) arteries for measurement of fractional change in area (FCA), an index of regional contractility. Regional myocardial blood flow (RMBF) was determined with radiolabeled microspheres. Data were recorded for each animal at baseline and after LAD arteriotomy and vascular control with (1) a 1.5-mm intraluminal shunt, (2) proximal occlusion, and (3) proximal and distal occlusion. One pig experienced ventricular fibrillation during LAD manipulation and was excluded from the study. Data were summarized for the remaining 5 animals. Coronary shunting maintained RMBF and function (FCA) compared with baseline. Proximal occlusion led to 50% (P =.05) and 47% (P =.04) decreases in RMBF and FCA, respectively, in the LAD region. Proximal and distal occlusion led to 55% (P =.03) and 51% (P = 02) decreases in RMBF and FCA, respectively, in the LAD region. There were no significant changes in RMBF or FCA in the LCx (control) region. Intraluminal coronary shunting is capable of preserving distal myocardial perfusion and function in a normal porcine heart. Coronary occlusion, in contrast, significantly reduces regional perfusion and function. More frequent use of intracoronary shunting may facilitate OPCAB by minimizing ischemia and hemodynamic compromise.