Large Coronary Vessels Research Articles

Perioperative Myocardial Infarction (PMI): A Never-ending Story

In Reply:—We thank Dr. Mollhoff et al. for addressing our article. 1We wish to offer clarification on their questions.We agree that the rate of perioperative myocardial infarction (PMI) may be underestimated in our study, as we acknowledged in our study limitations section. In the article, we listed four reasons: (1) perioperative surveillance for PMI was not done prospectively; (2) not all patients were monitored for PMI; (3) monitoring sometimes was not performed in a systematic manner; and (4) troponin concentrations were not assessed in any of the patients. As we have stated, we are confident that we reported all cases of clinically significant PMI, and it is possible that a certain number of silent PMIs were not diagnosed. It should be noted that, for another variable we studied, mortality after PMI (death is an unmistakable complication), the rate we reported (17%) is similar to the one reported by Badner et al. 2(20%).In our study, general anesthesia carried a higher risk of PMI than did neuraxial anesthesia (odds ratio, 3.25, P < 0.003). However, in the multivariate analysis, type of anesthesia did not play a significant role in PMI or cardiac mortality. We cannot comment about possible differences in perioperative pain management between the two groups because we did not analyze this variable.In our discussion, we suggested some of the explanations for why we think β blockade did not reduce the PMI rate in our population. First, patients to whom β blockers are administered are not absolutely protected against perioperative myocardial ischemia, and Slogoff and Keats 3demonstrated that patients with coronary artery disease who use β blockers may experience myocardial ischemia intraoperatively, despite better hemodynamic control. Second, β blockade in our patients was probably inadequate because we found no difference between the heart rates in the two groups. Third, β blockade may have been administered preferentially to the patients with more severe coronary artery disease, and it may be that the increased severity of disease was the reason why these particular patients had a higher incidence of PMI.The patients who had undergone percutaneous transluminal coronary angioplasty (PTCA) and subsequently experienced PMI had lower odds of cardiac death than did patients with PMI who had not undergone PTCA (the odds ratio of 0.32, however, was not statistically significant). Because we did not know the preoperative coronary artery anatomy (sites of stenoses) of our patients, we may postulate the following: PTCA is typically used to dilate stenotic lesions in larger coronary vessels, and, therefore, occlusions on smaller coronary artery branches may persist even after successful PTCA, but PMI that results from occlusion of these areas affects less cardiac muscle mass, with consequently lower mortality. Therefore, our finding has some logical explanation but needs to be further studied. We collected data on PTCA and categorized the procedures in four intervals: less than 3 months before surgery, 3–6 months previously, 7–12 months previously, and more than 12 months previously. In the PMI group, we had 12 patients: 3 underwent PTCA within 3 months before surgery, 4 underwent it 4–6 months before surgery, and 5 underwent it more than 12 months before surgery (1 of these 5 patients died). Although we have representative subjects in three of four categories, this is a small number of patients to make a definitive conclusion about the optimal timing of surgery after PTCA. In our previous (retrospective) study, we found very low cardiac morbidity in patients undergoing vascular surgery who underwent PTCA up to 18 months preoperatively. 4The retrospective study by Postner et al. 5did not provide one important piece of information for the patients who had PTCA and subsequent PMI: Did PMI develop in the area that was treated with PTCA or in some other area that was not originally amenable to treatment? It is moot to discuss the value of PTCA without this information. This issue may be resolved only by analyzing coronary angiograms in patients who underwent PTCA and consequently experienced PMI, and, to the best of our knowledge, this type of study does not exist.

Coronary microvasculature alteration in hypertensive rats. Effect of treatment with a diuretic and an ACE inhibitor

The development of hypertension is accompanied by rarefaction of arterioles and capillaries in both animal models and humans. Although many studies have examined the effects of antihypertensive therapies on hemodynamics, cardiac hypertrophy, and large vessel structure, the question of whether changes in microvascular density induced by hypertension can be restored by pharmacologic treatment has yet to be answered. We report a series of experiments performed in rats with renovascular hypertension induced by unilateral nephrectomy and renal artery stenosis (Goldblatt one-kidney, one-clip model). Animals were treated for 4 weeks, after renal artery clipping, either with an angiotensin converting enzyme inhibitor (perindopril [PER], 0.76 mg/kg/day), or with an indol derivative diuretic with specific vascular properties (indapamide [IDP], 0.24 mg/kg/day) or with the combination of both drugs at the same doses as during monotherapy. Coronary microvessel densities (arterioles and capillaries) were evaluated by double immunolabeling in nonserial cryostat sections of the left ventricular inner myocardium. After 4 weeks of hypertension (mean arterial pressure, 174 ± 11 v 124 ± 5 mm Hg in normotensive (NT) controls, P < .01), cardiac hypertrophy (+59%, P < .001) was associated with a significant increase in myocardial arteriolar density (+27%, P < .01), and a decrease in capillary density (−12%, P < .05). Treatment with PER prevented the increase in arterial pressure, heart weight, and arteriolar density, but did not significantly affect the low coronary capillary density in comparison with that measured in untreated hypertensive (HT) rats. Treatment with IDP preserved normal capillary myocardial density but did not significantly lower the blood pressure (BP) (169 ± 9 mm Hg) and only slightly reduced the cardiac ventricular hypertrophy: −14% v untreated HT ( P < .05) and +37% v NT ( P < .01). In the same way, IDP normalized the left ventricular capillary density in spontaneously HT rats (+18% v untreated rats, P < .01). The combination of both drugs, PER and IDP, at the same low doses as during monotherapy, resulted in normal levels of arterial pressure and complete normalization of cardiac hypertrophy and arteriolar and capillary myocardial densities. In conclusion, the results observed after PER suggest that blockade of the renin-angiotensin system could inhibit large coronary vessel growth but minimally affects the capillary density despite complete normalization of BP. Indapamide could have beneficial effect on myocardial capillary density. The combination of IDP and PER has additional effects and prevents the increase in BP and cardiac weight, and reverses microvascular rarefaction, specifically arteriolar and capillary densities.

Early Inhibition of heme oxygenase enzymatic activity precipitates xenograft rejection.

514 Introduction: We have recently demonstrated that endothelial cell (EC) expression of heme oxygenase-1 (HO-1) is essential to insure accommodation of mouse hearts transplanted into rats treated with the complement inhibitor cobra venom factor (CVF) and Cyclosporin A (CyA). This study aimed to analyze the mechanism by which HO-1 contributes to suppress xenograft rejection and to investigate at what time after transplantation the expression of HO-1 is imperative to insure xenograft survival Methods: BALB/c mouse hearts were transplanted into Lewis rats treated with CVF (60 U/kg one day before transplantation and 20 U/kg at the time of transplantation) and CyA (15 mg/kg/daily starting at the time of transplantation). HO activity was inhibited by administration of Tin Protoporphyrin (SnPP, 30μM/kg/daily). Iron protoporphyrin (FePP, 30μM/kg/daily) was used as a control treatment Result: All mouse hearts transplanted into rats treated with CVF plus CyA survived long-term. Inhibition of HO activity by SnPP given on day −2, −1 and 0 (the day of transplantation) to the donor, and daily on day 0 to the time of rejection to the recipient, led to xenograft rejection 3 to 7 days after transplantation (Table 1).Table 1HO inhibition by SnPP given daily to the recipient from day 2 resulted in xenograft rejection in 3 of 7 cases, while inhibition of HO activity starting at later time points no longer induced xenograft rejection. Xenograft rejection under SnPP treatment was very similar to that of HO-1 deficient (knock-out) hearts: rejection was characterized by thrombosis of large coronary vessels, extensive myocardial infarction, cardiomyocyte apoptosis and infiltration by host macrophages and neutrophils. Thrombosis was detected in the xenograft aorta by 24 hours after transplantation, indicating that the pathogenesis of rejection may involve thrombosis of large coronary arteries, a decreased blood supply to the heart, anoxia and infarction. Conclusion: Early expression of HO-1 in the xenograft prevents injury leading to thrombosis of large coronary vessels, thus avoiding subsequent myocardial infarction and xenograft rejection. Inhibition of HO activity starting on day 2 following transplantation no longer precipitates rejection in all grafts, and later administration of SnPP does not lead to rejection. It is attractive to think that other mechanisms, such as the expression of other protective genes, exist to promote xenograft survival at those later times.

Vasomotion of coronary arteries: from nitrates to nitric oxide.

The vascular endothelium is a source of substances particularly nitric oxide that act in a paracrine fashion either to contract or relax smooth muscle cells and this function is disturbed in atherosclerotic arteries. The endothelium derived nitric oxide contribute in the basal vasomotor tone of epicardial normal and atheromatous coronary coronary arteries, and of atheromatous coronary stenoses in patients with stable angina. Nitrates, by acting indirectly to increase cGMP in smooth muscle cells, dilate most coronary stenoses and normal coronary segments, decrease left ventricular afterload and diastolic filling pressure and improve the distribution of coronary flow to subendocardial zone. Large and small epicardial coronary vessels responded differently to endothelium-dependent and independent vasodilators.

Coronary stent implantation without preliminary dilatation

Extensive coronary dissections are rare but represent serious complications of percutaneous transluminal coronary angioplasty (PTCA). In order to prevent dissections in large coronary vessels (> or = 2.5 mm), we evaluated stent implantation without predilatation in 98 selected patients with favorable coronary anatomy and lesion morphology. Coronary stenting without predilatation was performed 41 times in the LAD, 41 times in the RCA, 11 times in the RCx, and 5 times in a vein graft. Mean diameter stenosis was 83 +/- 3%. Thirty-six patients had type A lesions and 62 patients type B lesions. Patients with type C lesions were excluded. Only premounted stents were used. The clinical situation was stable angina in 68 patients, unstable angina in 18, and acute myocardial infarction in 12. Stenting without predilatation was successful in 92 patients (94%). In 6 cases (6%) it was not possible to cross the lesion with the premounted stent, and predilatation was necessary prior to successful stent implantation. Two out of 11 RCx-related lesions (18%) could not be stented without predilatation. However, ultimate success of PTCA was 100%. No stent was lost. Mean remaining stenosis amounted to 3 +/- 6%. Minor angiographically detectable dissections after stent deployment were noted in 8 patients (8%). Inflation time (30 +/- 22 s) and fluoroscopic time (4.5 +/- 2.1 min) compared favorably to standard procedures. During 30 d follow-up no subacute stent thrombosis, but 2 non-Q-wave myocardial infarctions due to lost side branches were reported. Coronary stenting with premounted stents without predilation is feasible and safe in selected patients in order to reduce fluoroscopic and procedural time and to save costs. Furthermore, this procedure might reduce the risk of hazardous coronary dissections.

Preferential Effect of Nitroglycerin on Large Microvessels

In Response: We appreciate the valuable comments of Drs. Wang and Shernan. Because the purpose of our study [1] was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation, their comment does not affect our results. However, we believe that this letter raises an important point. In our study, using an in vivo technique, topically applied nitroglycerin produced a dose-dependent dilation of both large and small pial (cerebral) arterioles in normothermic conditions. Similar results of in vivo techniques have been reported by several authors [2]. Unfortunately, there have been no reports investigating the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin using an in vitro technique. In contrast, in vitro studies by Wang et al. [3] demonstrated that nitroglycerin caused preferential dilation of large porcine coronary arterioles and produced only minimal relaxation of small arterioles. These findings were confirmed by in vivo studies, which showed that nitroglycerin caused dilation of large coronary vessels without significantly affecting coronary blood flow [4]. Because most factors including in vivo or in vitro study, species, and different vascular beds are different, it is difficult to compare them simply. Further study is required regarding the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin. Masahiko Kawaguchi, MD Hitoshi Furuya, MD Department of Anesthesiology; Nara Medical University; Nara 634-8522, Japan

Preferential Effect of Nitroglycerin on Large Microvessels

In Response: We appreciate the valuable comments of Drs. Wang and Shernan. Because the purpose of our study [1] was to investigate the effect of mild hypothermia on nitroglycerin-induced vasodilation, their comment does not affect our results. However, we believe that this letter raises an important point. In our study, using an in vivo technique, topically applied nitroglycerin produced a dose-dependent dilation of both large and small pial (cerebral) arterioles in normothermic conditions. Similar results of in vivo techniques have been reported by several authors [2]. Unfortunately, there have been no reports investigating the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin using an in vitro technique. In contrast, in vitro studies by Wang et al. [3] demonstrated that nitroglycerin caused preferential dilation of large porcine coronary arterioles and produced only minimal relaxation of small arterioles. These findings were confirmed by in vivo studies, which showed that nitroglycerin caused dilation of large coronary vessels without significantly affecting coronary blood flow [4]. Because most factors including in vivo or in vitro study, species, and different vascular beds are different, it is difficult to compare them simply. Further study is required regarding the influence of vessel size on the sensitivity of cerebral microvessels to nitroglycerin. Masahiko Kawaguchi, MD Hitoshi Furuya, MD Department of Anesthesiology; Nara Medical University; Nara 634-8522, Japan

Coronary artery aneurysm: A review

Coronary artery aneurysm is defined as coronary dilatation which exceeds the diameter of normal adjacent segments or the diameter of the patient's largest coronary vessel by 1.5 times. This is an uncommon disease which has been diagnosed with increasing frequency since the advent of coronary angiography. The incidence varies from 1.5% to 5% with male dominance and a predilection for the right coronary artery. Atherosclerosis accounts for 50% of coronary aneurysms in adults. Reported complications include thrombosis and distal embolization, rupture and vasospasm. The natural history and prognosis remains obscure. Controversies persist regarding the use of surgical or medical management. The authors recommend surgery based on the severity of associated coronary stenosis rather than the mere presence of aneurysm. Medical therapy is indicated for the majority of patients and consists of antiplatelet and anticoagulant medication.

Blunted coronary reserve in myotonic dystrophy. An early and gene-related phenomenon.

In myotonic dystrophy (DM), striated muscle is involved in relation to the size of the DNA mutation. Smooth muscle may be similarly impaired at the level of the urinary and digestive apparatus and possibly at the level of small vessels, since microangiopathy has been described in the iris and digital capillaries. Our purpose was to study the function of the myocardial microvasculature in relation to the size of the mutation in DM patients without clinical cardiac involvement and with normal left ventricular dimensions and function and normal large coronary arteries. In 6 control subjects and 10 DM patients, we investigated the coronary blood flow reserve using positron emission tomography with 15O-labeled water. Global and regional flow reserves were obtained from myocardial regions of interest manually drawn on a static FDG image encompassing, respectively, the whole left ventricle and the anterior, septal, and lateral walls. The DNA mutation size was determined on circulating lymphocytes in each DM patient. Compared with control subjects, DM patients had decreased global (2.39 +/- 0.39 versus 4.00 +/- 0.67, P = .00003) and regional (anterior, 2.39 +/- 0.64 versus 3.87 +/- 0.92, P = .002; septal, 2.60 +/- 0.48 versus 4.00 +/- 0.70, P = .0003; lateral, 2.26 +/- 0.58 versus 4.16 +/- 1.11, P = .0005) coronary reserves. In DM patients, the coronary reserve correlated strongly and inversely with the DNA mutation size (r = -.77, P = .009). The study demonstrated that global and regional coronary reserves are impaired, in relation to the DNA mutation size, in symptom-free DM patients with normal ventricular dimensions and function and normal large coronary vessels. We suggest that a gene-related blunted coronary reserve resulting from an impairment of vascular smooth muscle is an early component of DM cardiomyopathy.

Left main coronary aneurysm and severe three-vessel disease with sparing of an isolated conus artery

Aneurysms of the left main coronary artery are very rare. 1 We report on a patient with critical stenosis and large aneurysm of the ]eft main coronary artery, critical three-vessel disease, and an aberrant conus artery without significant atherosclerotic changes rising from the right coronary ostium. A 59-year-old man with a 2-year history of stable angina pectoris was hospitalized with signs of anterolateral ischemia in the electrocardiogram and retrosternal pain that was unresponsive to nitroglycerin. There was no patient or family history of connective-tissue or infectious disease (endocarditis or mucocutaneous syndrome). Under standard therapy the pain was relieved, the electrocardiographic changes regressed, and creatine kinase (including MB fraction), aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels remained normal. Total cholesterol was 5 mmol/L (<5.2), high-density lipoprotein fraction 1 mmol/L, and triglycerides 3.8 mmol/L (normal <2.1). Because the patient had signs ofischemia on admission even though he was not taking chronic antianginal medication, he was given a cautious exercise test after administration of a p-blocker, a nitrate, and a platelet inhibitor to document ischemia and/or symptoms under therapy and thus the indication for catheterization. Left main or three-vessel disease was suspected because of early-onset angina pectoris, downsloping ST segment depression of up to 3.1 mm, and lack of increased blood pressure on exertion. The exercise test was immediately interrupted. At cardiac catheterization, left ventricular ejection fraction was 47%, with inferior akinesis and anterolateral hypokinesis. The abdominal and thoracic aorta showed severe diffuse atherosclerotic changes and moderate dilatation. The left main coronary artery showed critical stenosis and a huge fusiform aneurysm (Fig. 1, A), with proximal occlusion of the left anterior descending artery and critical stenosis and ectasia of the left circumflex coronary artery (Fig. 1, B). The right coronary artery showed severe diffuse atherosclerotic changes, with saccular aneurysms and critical stenoses of its proximal part and of the posterior descending and posterolateral branches (Fig. 1, C). A conus branch (Fig. 2) went off separately from the right coronary ostium and gave collaterals to the left anterior descending artery. This isolated conus branch showed kinking but no aneurysm formation or signifiCant stenosis. No significant dampening or ventricularization of the pressure waveform occurred during cannulation of the left main coronary. All laboratory parameters were normal, including blood count, electrolytes, creatinine, C-reactive protein, blood sedimentation rate, anti-DNA, antinuclear antibodies, antineutrophil cytoplasm antibody, viral and bacterial serologic (including Venereal Disease Research Laboratory). The chest x-ray, abdominal ultrasound, and lung function test results were normal. The patient underwent uneventful coronary artery bypass surgery (mammary artery graft to the left anterior descending artery, vein grafts to the left posterolateral artery on the right posterior descending artery and the right ventricular branches). With no clues in the patient's history or laboratory findings suggesting active vasculitis and endocarditis as the underlying disease, an atherosclerotic cause of the aneurysms seems most probable. Kawasaki disease and a burned out vasculitis are improbable, but cannot be completely excluded. This case presents three unusual features. First, although coronary artery aneurysms or ectasia are fairly common,2, 3 left main aneurysms are very rare. 1, 4 Defined as permanent luminal enlargement of the left main coronary artery greater than two times the diameter of the patient's largest coronary vessel or three times the diameter of a standard coronary catheter, aneurysms can be classified as saccular or fusiform. 1 Pseudo filling defects, either from true thrombus formation or, more commonly, swirling of contrast material in the aneurysmal structure leading to admixture with blood and dilution, can lead to poor lumen definition and misinterpretation of severity ofstenosis. Pseudo filling defects can be avoided by prolonged and forceful injection that adequately fills tile aneurysm and coronary artery. 1 The second unus'ual feature about this case is the aberrant conus branch rising from the right coronary ostium. The abnormal origin of the conus branch was recognized some time ago, 5 as was its importance as a collateral flow pathway in patients with total obstruction of the left anterior descending artery. ~ Third, this conus branch was the only coronary artery spared from significant atherosclerotic disease: because of the critical stenosis of all three coronary arteries and the main stem, it is possible that the patient owed survival to this aberrant conus branch, which efficiently collateralized the left anterior descending artery.

Anomalous first septal perforator artery: Anatomic‐clinical correlates

The interventricular septum is considered the most densely vascularized portion of the heart, containing important elements of the cardiac conduction system and providing mechanical support for both right and left ventricular function. Anatomically, this structure is perfused by the relatively small caliber anterior and posterior septal perforator branches arising from two large epicardial coronary vessels, the anterior interventricular (descending) branch of the left coronary artery and the posterior interventricular (descending) branch of the right coronary artery, respectively. In cases of significant atherosclerotic disease depriving flow in the major coronary vessels and their septal branches, an anomalous septal perforator artery can take over the task of supporting the function of the interventricular septum by supplementing essential collateral flow.

Ventricular tachyarrhythmias, myocardial ischemia, and sudden cardiac death in patients with hypertensive heart disease

Hypertensive heart disease is increasingly considered to be a strong and independent risk factor for sudden cardiac death. Ventricular tachyarrhythmias in these patients are common and mainly the result of electrophysiologic abnormalities and increased electrical vulnerability of the hypertrophic myocardium. However, proarrhythmia in the hypertrophic heart often is facilitated and aggravated by electrolyte disturbances, the sympathoadrenergic tone, transient blood pressure crisis, and especially by the occurrence of myocardial ischemia. Myocardial ischemia in the setting of hypertensive heart disease may result from stenotic lesions in large and/or small coronary artery vessels and, in the absence of both, will result from the altered cellular oxygen supply and consumption in the hypertrophic myocardium. Recent studies have shown that acute and transient myocardial ischemia are common in many hypertensives, often fail to be symptomatic, and that the dynamic interaction of left ventricular hypertrophy, transient myocardial ischemia, and ventricular tachyarrhythmias may provide a crucial link for the high incidence of sudden cardiac death in patients with hypertensive heart disease.

Peripheral arterial angioplasty balloons as adjuncts to percutaneous coronary revascularization

Although PTCA balloon technology has improved dramatically since the first catheters were introduced over a decade ago, some limitations remain. The largest conventional balloon size available is 4.0 mm diameter. Larger size balloons are sometimes necessary for saphenous vein graft dilatation or in very large native coronary arteries. Also, adjunctive balloon angioplasty is used frequently after atherectomy and other coronary device therapy. Current generation balloons are not always necessary in this setting, since a large lumen has already been established. Thus, it has become useful in our laboratory to use peripheral arterial angioplasty balloons for both large coronary vessel dilatation, and also for adjunctive dilatation after device use. We describe our initial experience with peripheral arterial angioplasty balloons as adjuncts to percutaneous coronary revascularization.

Influence of coronary vessel size on renarrowing process and late angiographic outcome after successful balloon angioplasty.

Although coronary angioplasty is increasingly applied in the treatment of multivessel disease and a broadening range of vessel size, the influence of vessel size itself on the late results of intervention is unresolved. An influence of vessel size on late outcome would carry implications for the application and evaluation of interventional devices, which are selectively used in larger or smaller vessels. The purpose of the present study was to investigate the influence of vessel size on both the restenosis process and late angiographic outcome in a large homogeneous patient group after successful percutaneous transluminal coronary angioplasty (PTCA). The study population comprised 3072 patients with 3736 successfully dilated native primary coronary artery lesions and satisfactory quantitative angiographic analysis in multiple identical projections before and after PTCA and at a 6-month follow-up. Late luminal loss, minimal luminal diameter (MLD) at follow-up, and net luminal gain, as well as percent diameter stenosis at follow-up, net gain in percent diameter stenosis, restenosis rates (according to three definitions), and net gain index, were all compared among nine equally sized groups (noniles) according to vessel size. A direct influence of vessel size on continuous measures of late result was also evaluated by linear regression. These evaluations provided conflicting information with no consistent influence of vessel size emerging. To elucidate the independent influence of vessel size on the restenosis process (late loss) and late angiographic outcome (MLD at follow-up), multiple linear regression analysis was performed taking into account luminal gain, preprocedural MLD, and lesion location. In this manner, vessel size was found to be exert a significantly positive influence on MLD at follow-up (P < .0001) and an equally negative effect on loss. Correcting for vessel size by using percent stenosis measurements led to an anticipated neutralization of this influence. Lesion location in the left anterior descending coronary artery was found to be independently associated with greater loss and smaller MLD at follow-up (P < .0001). Increasing coronary vessel size was found to be independently predictive of decreasing late luminal loss and increasing follow-up MLD after successful balloon angioplasty. Apparently superior or inferior late angiographic results of new interventional devices may thus be explained in part by preferential use in larger or smaller vessels, respectively. Devices that can safely optimize the short-term result of intervention may realize their ultimate long-term value in larger coronary vessels.

Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression.

Recently, we have shown that chronic exercise increases endothelium-derived relaxing factor (EDRF)/nitric oxide (NO)-mediated epicardial coronary artery dilation in response to brief occlusion and acetylcholine. This finding suggests that exercise can provide a stimulus for the enhanced production of EDRF/NO, thus possibly contributing to the beneficial effects of exercise on the cardiovascular system. Therefore, the purpose of the present study was to examine whether chronic exercise could influence the production of NO (measured as the stable degradation product, nitrite) and endothelial cell NO synthase (ECNOS) gene expression in vessels from dogs after chronic exercise. To this end, dogs were exercised by running on a treadmill (9.5 km/h for 1 hour, twice daily) for 10 days, and nitrite production in large coronary vessels and microvessels and ECNOS gene expression in aortic endothelial extracts were assessed. Acetylcholine (10(-7) to 10(-5) mol/L) dose-dependently increased the release of nitrite (inhibited by nitro-L-arginine) from coronary arteries and microvessels in control and exercised dogs. Moreover, acetylcholine-stimulated nitrite production was markedly enhanced in large coronary arteries and microvessels prepared from hearts of dogs after chronic exercise compared with hearts from control dogs. One potential mechanism that may contribute to the enhanced production of nitrite in vessels from exercised dogs may be the induction of the calcium-dependent ECNOS gene. Steady-state mRNA levels for ECNOS were significantly higher than mRNA levels for von Willebrand's factor (vWF, a specific endothelial cell marker) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, a constitutively expressed gene) in exercised dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

The molecular biology of heart failure

In the mammalian heart, the development of cardiac hypertrophy is a common feature that normally precedes all forms of heart failure. This adaptive process involves molecular changes in the myocardium, including the altered expression of several genes encoding proteins for contraction and relaxation. The expression of myosin heavy chain (MHC) and sarcomeric alpha-actin messenger ribonucleic acid (mRNA) changes qualitatively during cardiac hypertrophy; however, their accumulations are not coordinated. Skeletal alpha-actin transcripts accumulate throughout the ventricles and earlier than beta-MHC transcripts, which accumulate primarily around large coronary vessels. Skeletal alpha-actin transcripts also “hyperaccumulate” relative to cardiac alpha-actin mRNA, whose expression does not change. Expression of MHC isomRNA shows an inverse relation; as β-MHC accumulates, α-MHC decreases in abundance. From nuclear run-on assays, we present evidence that the accumulation of these gene products is at least under partial transcriptional control with developmental growth, suggesting that those changes that occur with hypertrophy and heart failure may be primarily transcriptionally regulated. The expression of the mRNA for the calcium-adenosine triphosphate (Ca2+-ATPase) of the sarcoplasmic reticulum changes quantitatively with cardiac hypertrophy without the reexpression of a different isoform. The relative mRNA and protein concentrations for this protein diminish with both cardiac hypertrophy and heart failure, a change that may partially explain the delayed relaxation rates seen in hypertrophied and failing hearts. Preliminary studies suggest that the transcriptional activity of this gene and that for phospholamban, a regulatory protein for the sarcoplasmic reticulum Ca2+-ATPase, can be assayed using the nuclear run-on assays. These studies will enable a more complete understanding of the processes that lead to quantitative and qualitative changes in gene expression with hypertrophy and failure and should in the future lead to the identification of genetic targets for new drugs.

The biophysics of radiofrequency catheter ablation in the heart: the importance of temperature monitoring.

Radiofrequency (RF) catheter ablation is a technique whereby high frequency alternating electrical current with frequencies of 350 kHz to 1 MHz is delivered through electrode catheters to myocardial tissue creating a thermal lesion. The mechanism by which RF current heats tissue is resistive (or ohmic) heating of a narrow rim (< 1 mm) of tissue that is in direct contact with the electrode. Deeper tissue planes are then heated by conduction from the small region of volume heating. Heat is dissipated from the region by further heat conduction into normothermic tissue, and by heat convection via the circulating blood pool and larger coronary vessels. The lesion size is proportional to the temperature at the electrode-tissue interface (which is also a function of power level if electrical factors remain constant), and to the size of the electrode. At temperatures above 100 degrees C, boiling occurs at the electrode-tissue contact point resulting in a rapid rise in electrical impedance. Therefore, a theoretical maximum lesion size exists for any given electrode geometry. Other factors that are important for RF lesion formation include electrode-tissue contact pressure and duration of RF delivery. Temperature rises monoexponentially, and duration of energy delivery should be at least 35 to 45 seconds to approach steady state.

Effect of K+ channel blockade with tetraethylammonium on anesthetic-induced relaxation in canine cerebral and coronary arteries.

The mechanism by which volatile anesthetics produce their direct effects on vascular smooth muscle remains unknown. The authors previously reported that volatile anesthetics decrease both Ca2+ and K+ currents, however the role of Ca(2+)-activated K+ channels during the vasorelaxation by anesthetics has not been investigated. The purpose of this study was to determine whether blockade of the K+ channel alters the response to volatile anesthetics. Responses were studied in canine middle cerebral arteries and proximal and distal canine coronary arteries. Vascular rings (2-mm length) were suspended in tissue baths, and isometric tension was recorded. Rings were constricted with 40 mM KCl and prostaglandin F2 alpha (middle cerebral arteries only) and subsequently exposed to enflurane (3.25%), halothane (1.35%), and isoflurane (2.1%). Volatile anesthetics produced vasorelaxation with relative potency in order: enflurane > halothane > isoflurane. The procedure was repeated in the presence of the K+ channel blocker tetraethylammonium chloride (TEA, 20 mM). In all groups of vessels TEA alone elicited either no increase or only a transient increase in tension, however constrictions to both agonists were augmented in the presence of TEA. The presence of TEA significantly augmented anesthetic-induced vasorelaxation in small and large coronary vessels and in middle cerebral arteries. However, this effect was more pronounced in the cerebral as compared to coronary arteries. Constrictions produced in cerebral vessels by 15 microM prostaglandin F2 alpha were comparable with constrictions produced by 5 microM prostaglandin F2 alpha in the presence of TEA. The subsequent relaxant response of these vessels to enflurane was also comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary occlusive disease and late graft failure after cardiac transplantation.

Coronary occlusive disease is the main cause of late mortality after cardiac transplantation. It has both similarities and differences compared with conventional atherosclerotic coronary disease. The pathophysiology of late graft failure from coronary occlusive disease is unclear at present. We reviewed the experience of this disorder in our cardiac transplant programme. A retrospective analysis of angiographic and pathological data. A regional cardiothoracic centre and transplant unit. Of a population of 383 orthotopic cardiac transplant recipients operated upon between January 1979 and June 1990, 447 coronary angiograms were available for review in 193 patients. Thirteen of a possible 18 results of post mortem examinations from patients dying from coronary occlusive disease were available. Coronary occlusive disease was defined as any evidence of disease on coronary angiography. Post mortem examinations were performed with standard techniques. The angiographic prevalence of coronary occlusive disease was 3% (1/32 patients) and 40% (19/47 patients) at one and five years respectively. Twenty six grafts failed due to coronary occlusive disease compared with 132 graft failures from all causes during this period. Acute thrombosis was present in a large vessel in seven of 13 fatal cases undergoing necropsy (54%). Noticeable large vessel involvement with disease in smaller distal vessels was present in four patients (31%). The remaining two patients (15%) had small vessel disease alone. Twelve of the 13 patients had significant cardiomegaly (cardiac weight > or = 400 g) with a mean weight of 510 (range 370-740) g. Coronary occlusive disease is the main late complication after cardiac transplantation. A combination of coronary thrombosis, ischaemia from stenoses of large and small coronary vessels, and cardiomegaly contribute to the graft failure of these patients.

Differential effects of nitrovasodilators, K(+)-channel openers, and nicorandil on large and small coronary arteries in conscious dogs.

When administered intravenously to conscious dogs, nicorandil, nitrovasodilators (nitroglycerin and SIN-1), and the K(+)-channel opener cromakalim exhibited marked differential effects on large epicardial and small resistance coronary arteries. Nitrovasodilators markedly increased the left circumflex coronary artery diameter at doses at which coronary resistance was not significantly decreased. In contrast, both cromakalim and nicorandil dilated large and small coronary arteries in the same conditions. When coronary blood flow was held to its control value by partial inflation of a hydraulic occluder implanted around the artery, the nitroglycerin- and nicorandil-induced increases in large coronary diameter remained unchanged whereas the response to cromakalim was reduced significantly. This coronary dynamic profile indicates that both nitrovasodilators and nicorandil directly dilate large coronary vessels, whereas the effect of cromakalim on these vessels is mediated partially through a flow-dependent mechanism. This suggests that nicorandil mainly dilates large coronary arteries through its nitroglycerin-like properties, whereas its ability to dilate coronary resistance vessels depends mainly on its K(+)-channel opener-like properties.