John S. MacGregor

Clinical Features of Acute Coronary Syndromes in Patients With Human Immunodeficiency Virus Infection

Background—Patients with HIV infection exhibit increased rates of coronary events; however, the clinical features of acute coronary syndromes (ACS) in HIV-infected patients have not been well defined. Methods and Results—Between 1993 and 2003, 68 HIV-infected patients were hospitalized with ACS. We compared the clinical features and outcome of these patients with those of 68 randomly selected control patients with ACS without HIV. HIV patients were on average more than a decade younger than controls and more likely to be male and current smokers and to have low HDL cholesterol. They were less likely than controls to have diabetes or hyperlipidemia, and their TIMI (Thrombolysis In Myocardial Infarction) risk scores on admission were significantly lower. At coronary angiography, the number of vessels with >50% stenosis was 1.3±1.0 in HIV patients and 1.9±1.2 in controls (P =0.007). Restenosis developed in 15 of 29 HIV patients who underwent percutaneous coronary intervention compared with 3 of 21 controls (52% versus 14%, P =0.006). Conclusions—HIV patients with ACS are younger and more likely to be males and current smokers and to have low HDL cholesterol levels compared with other ACS patients. Their TIMI risk scores are lower, and they are more likely to have single-vessel disease; however, their restenosis rates after percutaneous coronary intervention are unexpectedly high.

Assessment of coronary conductance and resistance vessel reactivity in response to nitroglycerin, ergonovine and adenosine: In vivo studies with simultaneous intravascular two-dimensional and Doppler ultrasound

OBJECTIVES The aim of this study was to determine the differential effects of nitroglycerin, ergonovine and adenosine on the resistance vessels in vivo by using a Doppler-tipped guide wire in combination with an ultrasound imaging catheter. BACKGROUND Catheter-based two-dimensional intravascular ultrasound yields images of the coronary arteries from which cross-sectional areas can be measured. Intravascular Doppler ultrasound techniques allow measurement of coronary blood flow velocity. The simultaneous use of the two techniques can yield anatomic and physiologic information on conductance and resistance vessels but has not been tried in the coronary arteries. METHODS In 15 dogs, we studied coronary flow and vascular reactivity in response to pharmacologic agents using two approaches: 1) a 30-MHz, 4.3F imaging catheter placed alongside a 0.018-in. (0.046 cm) Doppler wire in the circumflex or left anterior descending coronary artery (n = 5); 2) the ultrasound imaging catheter introduced directly over a 0.014-in. (0.036 cm) Doppler wire (n = 10). Vasodilator and vasoconstrictor responses were studied by using intracoronary nitroglycerin (50, 100 and 200 micrograms), ergonovine (200 micrograms) and adenosine (6 mg). RESULTS Nitroglycerin caused a dose-dependent increase in epicardial coronary artery cross-sectional area and, to a lesser extent, in average peak flow velocity, resulting in an increase in volumetric coronary blood flow of 39% and 50% at the doses of 100 and 200 micrograms, respectively. With these doses of nitroglycerin, the decrease in diastolic to systolic velocity ratio and the increased change in cross-sectional area from end-diastole to end-systole suggested an enhanced epicardial coronary artery compliance. With ergonovine, a 12% reduction in epicardial coronary artery cross-sectional area was seen, without a significant change in average peak velocity, resulting in a 15% decrease in volumetric coronary blood flow. Adenosine caused a 270% increase in average peak velocity but no change in epicardial coronary artery cross-sectional area, resulting in a 270% increase in volumetric blood flow. CONCLUSIONS This study demonstrates that nitroglycerin and ergonovine predominantly influence coronary conductance arteries whereas adenosine mainly dilates coronary resistance vessels. These findings also demonstrate that the combined use of a two-dimensional and a Doppler ultrasound transducer within one catheter assembly can provide information on the differential effects of vasoactive agents on the epicardial and microvascular coronary circulation.

Cyclosporine impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries.

BackgroundCyclosporin A is reported to impair endothelium-mediated vasorelaxation and induce endothelin release in some noncoronary vascular beds. We wished to determine whether acute cyclosporine administration induces endothelial dysfunction in coronary conductance or resistance arteries. Methods and ResultsWe examined the effect of intracoronary acetylcholine, N omega-nitro-L-arginine methyl ester (L- NAME), L-arginine, nitroglycerin, and adenosine before and after acute cyclosporine administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. Flow velocity was measured with a 0.014-in Doppler wire to assess resistance vessel responses, and epicardial coronary lumen area was simultaneously measured with a 4.3F, 30-MHz imaging catheter inserted over the Doppler wire. In 6 dogs, acetylcholine-induced increase in flow velocity was attenuated by cyclosporine in vehicle (137% to 55% at 10−5 mol/L, P < .001), as was acetylcholine- induced epicardial vasodilation (14.1% to 6.7% at 10−5 mol/L, P < .001). Vasodilation in response to intracoronary nitroglycerin (200 μg) and adenosine (6 mg) were unchanged by cyclosporine. Epicardial vasoconstriction with L-NAME (10−4 mol/L) was reduced by cyclosporine (Pre, 7.4 ± 0.9%; Post, 2.6 ± 1.2%; P = .04), but L- arginine (10−4 mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced vasodilatation to the same degree as cyclosporine in vehicle (Cremophor); vehicle infusion did not impair endothelial function. In 5 more dogs, cyclosporine did not increase either arterial or coronary sinus concentrations of endothelin-1. ConclusionsThe present study shows that cyclosporine acutely impairs release of endothelium-derived relaxing factor in canine conductance and resistance coronary arteries and provides evidence for decreased epicardial nitric oxide release after cyclosporine. The potential contribution of acute cyclosporine- induced coronary endothelial dysfunction to posttransplant vasculopathy needs further study.

Congenital anomalies of coronary arteries

After hypertrophic cardiomyopathy, coronary artery anomalies of origin from the wrong sinus of Valsalva are the second most common cause of sudden death on the athletic field in the USA. Although the right coronary artery arising from the left coronary sinus (ARCA) is four times as common as the left coronary artery arising from the anterior sinus (ALCA), it is the latter that is by far the more common cause of sudden death with or shortly after vigorous physical activity. Of the four types of ALCA, the interarterial type, where the left coronary artery passes anteriorly between the aorta and the right ventricular outflow tract, is the only type that places the patient at risk of sudden death. Another feature of this syndrome is the fact that sudden death occurs associated with or shortly after vigorous exercise and is very unusual after the patient is > 35 years of age. The mechanism by which there is sudden occlusion of the interarterial coronary artery is at present unknown, although there are a number of hypotheses involving the oblique passage of the vessel as it leaves the aorta. Sudden death is probably rare considering the number of people who have these anomalies.Symptoms premonitory to a fatal event such as exertional syncope, chest pain, or palpitations are probably common in patients at risk, and surgical correction is indicated in symptomatic patients at any age. In older asymptomatic patients, surgery is not recommended, since the incidence of sudden death in this age group is extremely small. In asymptomatic young patients, a stress test, preferably with radioisotope myocardial perfusion imaging or stress echocardiogram, should be done and surgical correction performed in those with ischemia provoked in the appropriate myocardial region. Since there is evidence that in patients who have survived a potentially fatal event, it is rare to be able to provoke ischemia with equal or greater exercise than had precipitated the malignant arrhythmia, the decision to surgically correct an asymptomatic young patient, serendipitously found to have ALCA, who has a negative exercise test, is debatable. Any decision for surgery in such patients should be made only after a full discussion of the risks pro and con surgery with the patient and the patient’s family.ZusammenfassungNach der hypertrophen Kardiomyopathie sind Koronaranomalien im Bereich des Sinus Valsalvae in den USA die zweithäufigste Ursache für den plötzlichen Herztod bei Athleten. Obwohl die rechte Koronararterie viermal häufiger aus dem linken Sinus Valsalvae (ARCA) entspringt als umgekehrt die linke Koronararterie aus dem rechten Sinus Valsalvae (ALCA), ist die letztere Variante bei Weitem die häufigere Ursache für einen plötzlichen Herztod kurz nach starker körperlicher Aktivität. Von den vier verschiedenen Typen einer ALCA ist der interarterielle Typ, bei dem die linke Koronararterie anterior zwischen der Aorta und dem rechten Ausflusstrakt verläuft, der einzige Typ, der das Risiko eines plötzlichen Herztods birgt. Zu den weiteren Besonderheiten dieses Syndroms gehört, dass der plötzliche Herztod immer während oder kurz nach einer starken Anstrengung und fast nie bei Patienten > 35 Jahre auftritt. Der Mechanismus, der zum plötzlichen Verschluss der interarteriellen Koronararterie führt, ist bis heute unbekannt, wenngleich es einige Hypothesen dazu gibt, etwa den schrägen Gefäßverlauf im Bereich des Austrittsort aus der Aorta. Im Vergleich zur Häufigkeit dieser Gefäßanomalie ist aber die Zahl der Todesfälle wahrscheinlich eher gering.Symptome, die ein solches Ereignis ankündigen, sind bei körperlicher Anstrengung auftretende Synkopen, Brustschmerzen oder Palpitationen. Bei solchen symptomatischen Patienten ist – unabhängig vom Alter – eine chirurgische Korrektur der Gefäßanomalie indiziert. Bei älteren asymptomatischen Patienten dagegen ist ein chirurgischer Eingriff nicht zu empfehlen, da in dieser Altersgruppe ein dadurch bedingter plötzlicher Herztod sehr selten ist. Bei asymptomatischen jüngeren Patienten sollte ein Stresstest, entweder eine Echokardiographie oder Myokardszintigraphie unter Belastung, durchgeführt werden; Patienten mit Ischämiezeichen in den entsprechenden Herzarealen sollten einer chirurgischen Intervention zugeführt werden. Allerdings ist es fraglich, ob jeder junge asymptomatische Patient, bei dem zufälligerweise eine ALCA gefunden wurde und dessen Stresstest negativ ausfällt, operiert werden muss, denn bei Patienten, die nach Anstrengung ein potentiell tödliches Ereignis überlebt hatten, konnte danach mit gleicher oder sogar stärkerer Belastung nur selten eine Ischämie provoziert werden. Deshalb sollte mit jungen asymptomatischen Patienten und deren Familien das Pro und Kontra eines chirurgischen Eingriffs sorgfältig abgewogen werden.

Congenital anomalies of coronary arteries: role in the pathogenesis of sudden cardiac death.

After hypertrophic cardiomyopathy, coronary artery anomalies of origin from the wrong sinus of Valsalva are the second most common cause of sudden death on the athletic field in the USA. Although the right coronary artery arising from the left coronary sinus (ARCA) is four times as common as the left coronary artery arising from the anterior sinus (ALCA), it is the latter that is by far the more common cause of sudden death with or shortly after vigorous physical activity. Of the four types of ALCA, the interarterial type, where the left coronary artery passes anteriorly between the aorta and the right ventricular outflow tract, is the only type that places the patient at risk of sudden death. Another feature of this syndrome is the fact that sudden death occurs associated with or shortly after vigorous exercise and is very unusual after the patient is > 35 years of age. The mechanism by which there is sudden occlusion of the interarterial coronary artery is at present unknown, although there are a number of hypotheses involving the oblique passage of the vessel as it leaves the aorta. Sudden death is probably rare considering the number of people who have these anomalies.Symptoms premonitory to a fatal event such as exertional syncope, chest pain, or palpitations are probably common in patients at risk, and surgical correction is indicated in symptomatic patients at any age. In older asymptomatic patients, surgery is not recommended, since the incidence of sudden death in this age group is extremely small. In asymptomatic young patients, a stress test, preferably with radioisotope myocardial perfusion imaging or stress echocardiogram, should be done and surgical correction performed in those with ischemia provoked in the appropriate myocardial region. Since there is evidence that in patients who have survived a potentially fatal event, it is rare to be able to provoke ischemia with equal or greater exercise than had precipitated the malignant arrhythmia, the decision to surgically correct an asymptomatic young patient, serendipitously found to have ALCA, who has a negative exercise test, is debatable. Any decision for surgery in such patients should be made only after a full discussion of the risks pro and con surgery with the patient and the patient’s family.ZusammenfassungNach der hypertrophen Kardiomyopathie sind Koronaranomalien im Bereich des Sinus Valsalvae in den USA die zweithäufigste Ursache für den plötzlichen Herztod bei Athleten. Obwohl die rechte Koronararterie viermal häufiger aus dem linken Sinus Valsalvae (ARCA) entspringt als umgekehrt die linke Koronararterie aus dem rechten Sinus Valsalvae (ALCA), ist die letztere Variante bei Weitem die häufigere Ursache für einen plötzlichen Herztod kurz nach starker körperlicher Aktivität. Von den vier verschiedenen Typen einer ALCA ist der interarterielle Typ, bei dem die linke Koronararterie anterior zwischen der Aorta und dem rechten Ausflusstrakt verläuft, der einzige Typ, der das Risiko eines plötzlichen Herztods birgt. Zu den weiteren Besonderheiten dieses Syndroms gehört, dass der plötzliche Herztod immer während oder kurz nach einer starken Anstrengung und fast nie bei Patienten > 35 Jahre auftritt. Der Mechanismus, der zum plötzlichen Verschluss der interarteriellen Koronararterie führt, ist bis heute unbekannt, wenngleich es einige Hypothesen dazu gibt, etwa den schrägen Gefäßverlauf im Bereich des Austrittsort aus der Aorta. Im Vergleich zur Häufigkeit dieser Gefäßanomalie ist aber die Zahl der Todesfälle wahrscheinlich eher gering.Symptome, die ein solches Ereignis ankündigen, sind bei körperlicher Anstrengung auftretende Synkopen, Brustschmerzen oder Palpitationen. Bei solchen symptomatischen Patienten ist – unabhängig vom Alter – eine chirurgische Korrektur der Gefäßanomalie indiziert. Bei älteren asymptomatischen Patienten dagegen ist ein chirurgischer Eingriff nicht zu empfehlen, da in dieser Altersgruppe ein dadurch bedingter plötzlicher Herztod sehr selten ist. Bei asymptomatischen jüngeren Patienten sollte ein Stresstest, entweder eine Echokardiographie oder Myokardszintigraphie unter Belastung, durchgeführt werden; Patienten mit Ischämiezeichen in den entsprechenden Herzarealen sollten einer chirurgischen Intervention zugeführt werden. Allerdings ist es fraglich, ob jeder junge asymptomatische Patient, bei dem zufälligerweise eine ALCA gefunden wurde und dessen Stresstest negativ ausfällt, operiert werden muss, denn bei Patienten, die nach Anstrengung ein potentiell tödliches Ereignis überlebt hatten, konnte danach mit gleicher oder sogar stärkerer Belastung nur selten eine Ischämie provoziert werden. Deshalb sollte mit jungen asymptomatischen Patienten und deren Familien das Pro und Kontra eines chirurgischen Eingriffs sorgfältig abgewogen werden.

Differential contribution of nitric oxide to regulation of vascular tone in coronary conductance and resistance arteries: Intravascular ultrasound studies

We examined the role of nitric oxide in the maintenance of coronary vascular tone in 15 dogs. A 0.014 inch Doppler wire was introduced into the midsegment of the circumflex coronary artery and a 4.3F, 30 MHz two-dimensional ultrasound imaging catheter was introduced over the Doppler wire. Acetylcholine caused a dose-dependent vasodilation in both epicardial and resistance coronary arteries. However, N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthetase caused a dose-dependent vasoconstriction mainly in the epicardial coronary arteries, partially reversed by L-arginine. The vasodilator response to acetylcholine was inhibited by L-NAME only in the epicardial circulation. Thus using combined intracoronary two-dimensional and Doppler ultrasound, we have demonstrated both basal and acetylcholine-induced release of nitric oxide in epicardial coronary arteries. The failure of L-NAME to decrease basal and acetylcholine-induced increases in flow velocity suggests that endothelium-dependent relaxation in coronary resistance vessels may not be mediated by nitric oxide alone.

Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection

Objective:To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH). Design:HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality. Methods:We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL-6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC. Results:Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 &mgr;mol/l, P = 0.0049 and 3.9% per doubling, P = 0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 &mgr;mol/l, P = 0.0014 and 5.8% per doubling, P = 0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio = 1.74, P = 0.029). Conclusion:Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH.

Doppler Echocardiography Does Not Accurately Estimate Pulmonary Artery Systolic Pressure in HIV-Infected Patients

Doppler echocardiography is used to screen for HIV-related pulmonary arterial hypertension (HRPAH). We studied patients with HIV infection to determine the accuracy of Doppler echocardiography-estimated pulmonary artery systolic pressure (PASP) compared with PASP measured during right heart catheterization. Doppler echocardiography-estimated PASP was inaccurate in 19.7% of cases. Using Doppler echocardiography-estimated PASP, one in three patients with HRPAH was missed. Doppler echocardiography estimates of PASP are not accurate in patients with HIV.

Contemporary clinical characteristics, treatment, and outcomes of angiographically confirmed coronary stent thrombosis: Results from a multicenter California registry†

Objectives: To describe the contemporary treatment and outcomes for patients with angiographically confirmed (definite) stent thrombosis (ST). Background: Limited data are available on contemporary treatment patterns and outcomes of patients with ST in the United States. Methods: In this multicenter California registry, consecutive cases of definite ST over 5 years were identified. Clinical characteristics, in‐hospital outcomes, and long‐term survival are reported. Results: One hundred and sixty five consecutive episodes of ST were identified in 153 patients from January 2005 to February 2010. The distribution of acute (≤24 hr), subacute (24 hr to 30 days), late (30 days to 1 year), and very late (≥1 year) ST was 3.9%, 21.8%, 17.6%, and 50.3%, respectively. Only 41.2% of patients were on dual antiplatelet therapy at the time of presentation, while 22.4% of patients were on none. Of the 61.4% of patients treated with restenting, 71.1% of them received a drug‐eluting stent. Procedural success was 88.1%, and in‐hospital death, stroke, and CABG occurred in 5.5%, 0.6%, and 6.1% of subjects, respectively. All‐cause mortality at 1 year was 14.3%. Although female gender, diabetes mellitus (DM), bifurcation disease, ejection fraction <40%, and cardiogenic shock at the time of presentation were associated with an increased risk of in‐hospital mortality, only DM (P = 0.047) and bifurcation disease (P = 0.027) remained independent predictors of in‐hospital death. Conclusion: In‐hospital mortality from definite ST is lower than previously reported, but long‐term mortality remains high. DM and bifurcation disease, but not type of percutaneous therapy, are independently associated with in‐hospital mortality.

Angiographically confirmed stent thrombosis in contemporary practice: Insights from intravascular ultrasound

Objective: We hypothesized that patients presenting with stent thrombosis (ST) have a high prevalence of stent underexpansion and malapposition when assessed by intravascular ultrasound (IVUS). Background: IVUS can provide mechanistic insight into mechanical factors, including stent underexpansion, malapposition, and fracture that may predispose to ST. Methods: All consecutive cases of angiographically confirmed ST from a multicenter registry (from 2005 to 2010) were reviewed. All IVUS images were reviewed off‐line for the presence of stent underexpansion, malapposition, and fracture. Kaplan–Meier analysis was used to determine whether use of IVUS at the time of ST was associated with long‐term mortality and major adverse cardiovascular events. Results: IVUS was performed in 32 of 173 subjects with ST (18%). Stent underexpansion was present in 82% of cases and in all cases of early ST, with a mean stent expansion of 0.7 ± 0.23 by MUSIC criteria. Stent malapposition was most frequently observed in very late ST (40%). In‐hospital mortality was similar between subjects who had IVUS performed at the time of ST when compared with the non‐IVUS group (3.2% vs. 4.3%, P = 0.8). Subjects who had IVUS performed at the time of ST had lower rates of mortality (HR 0.4, 95% CI 0.1‐1.6, P =0.2) and major adverse cardiovascular events (HR 0.5, 95% CI 0.2–1.4, P =0.2) at follow‐up, but these values were not statistically significant. Conclusions: There is a high prevalence of stent underexpansion in early ST, while the prevalence of malapposition is higher in very late ST. Use of IVUS during treatment for ST may identify mechanisms underlying the development of ST.