Patricia J.M. Best

Incidence and Prognostic Importance of Acute Renal Failure After Percutaneous Coronary Intervention

Background—In patients undergoing percutaneous coronary intervention (PCI) in the modern era, the incidence and prognostic implications of acute renal failure (ARF) are unknown. Methods and Results—With a retrospective analysis of the Mayo Clinic PCI registry, we determined the incidence of, risk factors for, and prognostic implications of ARF (defined as an increase in serum creatinine [Cr] >0.5 mg/dL from baseline) after PCI. Of 7586 patients, 254 (3.3%) experienced ARF. Among patients with baseline Cr <2.0, the risk of ARF was higher among diabetic than nondiabetic patients, whereas among those with a baseline Cr >2.0, all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum Cr, acute myocardial infarction, shock, and volume of contrast medium administered. Twenty-two percent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF (P <0.0001). After adjustment, ARF remained strongly associated with death. Among hospital survivors with ARF, 1- and 5-year estimated mortality rates were 12.1% and 44.6%, respectively, much greater than the 3.7% and 14.5% mortality rates in patients without ARF (P <0.0001). Conclusions—The overall incidence of ARF after PCI is low. Diabetic patients with baseline Cr values <2.0 mg/dL are at higher risk than nondiabetic patients, whereas all patients with a serum Cr >2.0 are at high risk for ARF. ARF was highly correlated with death during the index hospitalization and after dismissal.

The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions

OBJECTIVES We sought to determine the effect of varying degrees of renal insufficiency on death and cardiac events during and after a percutaneous coronary intervention (PCI). BACKGROUND Patients with end-stage renal disease have a high mortality from coronary artery disease. Little is known about the impact of mild and moderate renal insufficiency on clinical outcomes after PCI. METHODS Cardiac mortality and all-cause mortality were determined for 5,327 patients undergoing PCI from January 1, 1994, to August 31, 1999, at the Mayo Clinic, based on the estimated creatinine clearance or whether the patient was on dialysis. RESULTS In-hospital mortality was significantly associated with renal insufficiency (p = 0.001). Even after successful PCI, one-year mortality was 1.5% when the creatinine clearance was > or =70 ml/min (n = 2,558), 3.6% when it was 50 to 69 ml/min (n = 1,458), 7.8% when it was 30 to 49 ml/min (n = 828) and 18.3% when it was < 30 ml/min (n = 141). The 18.3% mortality rate for the group with < 30 ml/min creatinine clearance was similar to the 19.9% mortality rate in patients on dialysis (n = 46). The mortality risk was largely independent of all other factors. CONCLUSIONS Renal insufficiency is a strong predictor of death and subsequent cardiac events in a dose-dependent fashion during and after PCI. Patients with renal insufficiency have more baseline cardiovascular risk factors, but renal insufficiency is associated with an increased risk of death and other adverse cardiovascular events, independent of all other measured variables.

Clinical Features, Management, and Prognosis of Spontaneous Coronary Artery Dissection

Background— Spontaneous coronary artery dissection (SCAD) is an acute coronary event of uncertain origin. Clinical features and prognosis remain insufficiently characterized. Methods and Results— A retrospective single-center cohort study identified 87 patients with angiographically confirmed SCAD. Incidence, clinical characteristics, treatment modalities, in-hospital outcomes, and long-term risk of SCAD recurrence or major adverse cardiac events were evaluated. Mean age was 42.6 years; 82% were female. Extreme exertion at SCAD onset was more frequent in men (7 of 16 versus 2 of 71; P<0.001), and postpartum status was observed in 13 of 71 women (18%). Presentation was ST-elevation myocardial infarction in 49%. Multivessel SCAD was found in 23%. Initial conservative management (31 of 87) and coronary artery bypass grafting (7 of 87) were associated with an uncomplicated in-hospital course, whereas percutaneous coronary intervention was complicated by technical failure in 15 of 43 patients (35%) and 1 death. During a median follow-up of 47 months (interquartile range, 18–106 months), SCAD recurred in 15 patients, all female. Estimated 10-year rate of major adverse cardiac events (death, heart failure, myocardial infarction, and SCAD recurrence) was 47%. Fibromuscular dysplasia of the iliac artery was identified incidentally in 8 of 16 femoral angiograms (50%) undertaken before closure device placement and in the carotid arteries of 2 others with carotid dissection. Conclusions— SCAD affects a young, predominantly female population, frequently presenting as ST-elevation myocardial infarction. Although in-hospital mortality is low regardless of initial treatment, percutaneous coronary intervention is associated with high rates of complication. Risks of SCAD recurrence and major adverse cardiac events in the long term emphasize the need for close follow-up. Fibromuscular dysplasia is a novel association and potentially causative factor.

Outcomes of Patients With Chronic Renal Insufficiency in the Bypass Angioplasty Revascularization Investigation

Background—Although severe chronic kidney disease (CKD) is an independent predictor of mortality among patients with coronary artery disease, the impact of mild CKD on morbidity and mortality has not been fully defined. Methods and Results—Morbidity and mortality for the 3608 patients with multivessel coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation randomized trial and registry were compared on the basis of the presence and absence of CKD, defined as a preprocedure serum creatinine level of >1.5 mg/dL. Seventy-six patients had CKD. Patients with renal insufficiency were older and more likely to have a history of diabetes, hypertension, and other comorbidities. Among patients undergoing PTCA, patients with CKD had a greater frequency of in-hospital death and cardiogenic shock (P <0.05 and 0.01, respectively). There was a trend toward a larger proportion of patients with CKD experiencing angina at 5 years (P =0.079). Patients with CKD had more cardiac admissions (P =0.003 and <0.0001 for patients undergoing PTCA and CABG, respectively) and a shorter time to subsequent CABG after initial revascularization than patients without CKD (P =0.01). CKD was associated with a higher risk of death at 7 years, both of all causes (relative risk 2.2, P <0.001) and of cardiac causes (relative risk 2.8, P <0.001). Conclusions—CKD is associated with an increased risk of recurrent hospitalization, subsequent CABG, and mortality. This increased risk of death is independent of and additive to the risk associated with diabetes.

The Effect of Estrogen Replacement Therapy on Plasma Nitric Oxide and Endothelin-1 Levels in Postmenopausal Women

Cardiovascular disease is the leading cause of illness and death in women. Estrogen replacement therapy (ERT) in postmenopausal women decreases total mortality and cardiovascular mortality [1]. This therapy increases coronary vasodilatation in response to acetylcholine and decreases angiographically detectable coronary artery disease [2, 3]. Alterations in nitric oxide and endothelin-1 levels have been hypothesized to be one of the mechanisms by which ERT provides cardiovascular benefit [4]. Nitric oxide and endothelin-1 are endothelium-derived vasoactive factors that are important in cardiovascular disease [5, 6]. Nitric oxide causes vasodilatation, inhibits platelet aggregation, suppresses smooth-muscle proliferation, and acts as an anti-atherogenic factor [5, 7]. Continuous release of nitric oxide from the endothelium maintains basal vascular tone, and alterations in nitric oxide release allow autoregulation of blood flow [8]. Both endogenous substances and physical forces, such as shear stress, stimulate production of nitric oxide. Alternatively, endothelin-1 opposes the effects of nitric oxide. It causes potent vasoconstriction of the systemic and coronary vasculature through the endothelin receptors, increases monocyte adhesion, activates macrophages, and promotes vascular smooth-muscle cell proliferation and migration [9]. In addition to the opposing effects of nitric oxide and endothelin-1 on vascular tone and smooth-muscle cell proliferation, the regulatory mechanisms of these vasoactive factors interact. Nitric oxide inhibits the production of endothelin-1 and modulates both the number and affinity of the endothelin-A receptors. Nitric oxide synthase is functionally coupled to the endothelin-B receptor [10]. In such disease states as hypercholesterolemia, atherosclerosis, and congestive heart failure, imbalances between nitric oxide and endothelin-1 are detected and may contribute to both vasomotor abnormalities and vascular remodeling [9]. We tested the hypothesis that ERT increases the ratio between plasma total oxidized products of nitric oxide and circulating endothelin-1. Methods Participants After the institutional review board approved our study, participants were recruited by local announcements. All participants gave informed consent. Participants were healthy, ambulatory women who were 40 to 65 years of age, had no contraindications to ERT, had not undergone surgically induced menopause, had not had a menstrual period in the preceding year, and had a follicle-stimulating hormone level greater than 50 IU/L and a serum 17-estradiol level of 100 pmol/L or less. At the beginning of the study, a complete history, physical examination, laboratory evaluation (chemistry and hematology panel), and electrocardiography were done at the Mayo Clinic for each participant. Exclusion criteria were clinical or laboratory abnormalities that suggested cardiovascular, hepatic, or renal disorders; coagulopathy; use of oral or transdermal estrogen, progestin, androgen, or other steroids in the preceding year; smoking habit of more than 10 cigarettes per day; or therapy with cholesterol-lowering or cardiovascular medications. All patients agreed not to alter their diet and exercise regimens during the study period. Study Protocol All participants had a baseline cholesterol profile, and plasma nitric oxide and endothelin-1 were measured on samples obtained while participants were fasting to minimize dietary effects. Participants received estradiol-17, 2 mg daily for 6 months, and a 10-day course of methoxyprogesterone, 5 mg daily every 3 months. To minimize the effects of the methoxyprogesterone, repeated daily laboratory measurements were done before the second course of methoxyprogesterone on samples obtained while participants were fasting. Assays Plasma endothelin was measured by using an endothelin-1,2[I125] assay system (Nycomed Amersham, Bucks, United Kingdom) as described elsewhere [6]. Blood was drawn, and plasma was separated. The efficacy of the extraction procedure was 81%; interassay variations were 9%, and intra-assay variations were 5%. In this assay, cross-reactivities were less than 5% for endothelin-2, less than 3% for endothelin-3, and less than 37% for proendothelin [6]. Previously established normal values (SD) for plasma endothelin-1 are 7.1 0.1 pg/mL [11]. Nitric oxide was measured by chemiluminescence with a Sievers Nitric Oxide Analyzer, model 280 (Boulder, Colorado) [12]. Blood samples were centrifuged at 2500 rpm for 20 minutes at 10C. The supernatant was removed and stored at 70C.The nitric oxide assay was standardized by a calibration curve using known concentrations of nitrate (0.01 to 100 mol/L) obtained from sodium nitrate. For each measurement, a 4-L sample was placed in a reducing vessel with 5 mL of 0.1 mol of vanadium III chloride per L, 1 mol of hydrochloric acid per L, and 100 L of antifoaming agent (Sievers) at 90C. Each standard was analyzed three times, and each plasma sample was analyzed at least five times. The mean value was used for all subsequent analysis. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were measured in the Mayo Clinic ImmunoChemistry Laboratory (Roche Diagnostic Systems, Branchburg, New Jersey). Statistical Analysis Data are given as the mean SD with 95% CIs and ranges. Comparisons before and after ERT were based on paired sample t-tests. A P value of 0.05 or less was considered statistically significant. Correlations were determined by using the Pearson correlation equation. Results The mean age of the 15 women who received ERT was 53 years (range, 46 to 58 years). Two patients were current smokers of 10 cigarettes per day, 3 patients had a history of smoking, and 2 patients had a substantial family history of coronary artery disease. The mean baseline level of follicle-stimulating hormone was 79.1 21.0 IU/L (range, 43.8 to 120.0 IU/L). The data on nitric oxide, endothelin-1, and cholesterol are summarized in the Table 1, and individual patient data are shown in the (Figure 1). The mean nitric oxide level was 27.5 nmol/mL (range, 20.3 to 34.8 nmol/mL) at baseline; this increased by a mean of 7.2 nmol/mL (range, 0.2 to 14.1 nmol/mL) (P = 0.04) after 6 months of ERT. The mean plasma endothelin-1 level was 16.4 pg/mL (range, 12.0 to 20.8 pg/mL) at baseline; this decreased by 3.9 pg/mL (range, 0.4 to 7.8 pg/mL) (P = 0.04) after 6 months of ERT. Before ERT began, endothelin-1 levels were significantly higher than the control value of 7.1 0.1 pg/mL. With ERT, total and low-density lipoprotein cholesterol levels decreased (P = 0.005 and P = 0.004, respectively) and high-density lipoprotein cholesterol levels increased (P = 0.003). Use of ERT did not change systolic blood pressure, diastolic blood pressure, or heart rate (P < 0.2 for all comparisons). No correlation existed between estradiol levels and nitric oxide (r = 0.04) or endothelin-1 (r = 0.18)or between plasma nitric oxide and endothelin-1 concentrations (r = 0.05). The ratio of nitric oxide to endothelin-1 increased from 2.0 (range, 1.3 to 2.8) by a mean of 1.2 (range, 0.1 to 2.2) after ERT (P = 0.03). Table 1. Effects of Estrogen Replacement Therapy on Cholesterol, Estradiol, Oxidized Products of Nitric Oxide, and Endothelin-1 in 15 Postmenopausal Women* Figure 1. Individual patient data on plasma oxidized products of nitric oxide (left) and endothelin-1 (right) before and after 6 months of estrogen replacement therapy in 15 postmenopausal women. Discussion Our study shows that in postmenopausal women, ERT increases plasma nitric oxide levels and decreases plasma endothelin-1 levels, thereby increasing the ratio of nitric oxide to endothelin-1. A previous study by Roselli and coworkers [13] showed that ERT in postmenopausal women increases levels of circulating nitrate and nitrite. Ylikorkala and colleagues [14] reported that ERT in postmenopausal women decreases plasma endothelin-1 levels. Our study extends these observations and shows the effect of ERT on nitric oxide and endothelin-1 levels in the same study group. It also shows that these changes are associated with improvement in the lipid profile. However, a subset of patients in whom ERT does not increase the ratio of nitric oxide to endothelin-1 may exist. The therapy failed to improve the ratio of nitric oxide to endothelin-1 in two patients. Our results may be limited by the small sample size and the large variability in responses to ERT among study participants. Our study did not address the mechanism by which ERT alters these vasoactive substances, but we can suggest several possibilities. The therapy may regulate nitric oxide by increased production of nitric oxide synthase [15], and additional evidence suggests that estrogen can directly increase the release of nitric oxide [16]. Another possible mechanism for the increase in nitric oxide seen with ERT is the beneficial effects of estrogen on lipid metabolism. The therapy lowers total cholesterol and low-density lipoprotein cholesterol levels and increases high-density lipoprotein cholesterol levels; all of these reductions reduce the risk for cardiovascular events. Although the beneficial effects of estrogen on cardiovascular disease are mediated through this lipid-lowering effect, not all of the benefits of estrogen relate to cholesterol [17]. Because hypercholesterolemia is associated with impaired vascular tone (probably secondary to decreased bioavailability of nitric oxide), decreased cholesterol levels may increase vascular nitric oxide and may be another mechanism by which estrogen exerts its effect [18]. Through its antioxidant effects, estrogen may also decrease nitric oxide degradation. This potent inhibitor of lipid peroxidation may hinder the accelerated degradation of nitric oxide that results from the increased production of oxide free radicals associated with hypercholesterolemia [19]. Thus, estrog

Simvastatin Preserves Coronary Endothelial Function in Hypercholesterolemia in the Absence of Lipid Lowering

Abstract—Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3±1.2% versus 42.9±1.6%, respectively;P <0.0001). This attenuation was significantly reversed in the HC+S group (38.7±1.5%, P <0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5±11.9% versus 79.3±5.3%, respectively;P <0.05). This attenuated response was normalized in the HC+S group (74.9±4.1%, P <0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9±4.9% versus 96.8±1.34%, respectively;P <0.005). This was reversed in the HC+S group (98.4±0.6%, P <0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F2-isoprostanes and thiobarbituric acid–reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.

BACKGROUND Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD. METHODS Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]). RESULTS Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1). CONCLUSIONS Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD.

Spontaneous Coronary Artery Dissection Revascularization Versus Conservative Therapy

Background—Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic acute coronary syndrome for which optimal management remains undefined. Methods and Results—We performed a retrospective study of 189 patients presenting with a first SCAD episode. We evaluated outcomes according to initial management: (1) revascularization versus conservative therapy and (2) percutaneous coronary intervention (PCI) versus conservative therapy stratified by vessel flow at presentation. Demographics were similar in revascularization versus conservative (mean age, 44±9 years; women 92% both groups), but vessel occlusion was more frequent in revascularization (44/95 versus 18/94). There was 1 in-hospital death (revascularization) and 1 late death (conservative). Procedural failure rate was 53% in those managed with PCI. In the subgroup of patients presenting with preserved vessel flow, rates of PCI failure were similarly high (50%), and 6 (13%) required emergency coronary artery bypass grafting. In the conservative group, 85 of 94 (90%) had an uneventful in-hospital course, but 9 (10%) experienced early SCAD progression requiring revascularization. Kaplan–Meier estimated 5-year rates of target vessel revascularization and recurrent SCAD were no different in revascularization versus conservative therapy (30% versus 19%; P=0.06 and 23% versus 31%; P=0.7). Conclusions—PCI for SCAD is associated with high rates of technical failure even in those presenting with preserved vessel flow and does not protect against target vessel revascularization or recurrent SCAD. A strategy of conservative management with prolonged observation may be preferable.

Hydroxyurea-Induced Leg Ulceration in 14 Patients

Hydroxyurea therapy has been recognized as an effective treatment for cancer since 1960 [1]. The most common indications for this therapy are chronic myeloproliferative disorders and acute myelogenous leukemia. Hydroxyurea has also been used to treat various solid tumors, including primary brain tumors, head and neck cancers, renal cell carcinoma, and breast cancer [2]. Less commonly, it is used as a radiosensitizer, for the management of sickle-cell anemia, for the treatment of psoriasis, and to inhibit viral replication in HIV disease [3-6]. Dermatologic side effects of hydroxyurea are fairly common and include hyperpigmentation, scaling, erythema and desquamation of the face and hands, and partial alopecia [7]. A less well-described and less well-characterized complication is leg ulcers. We present clinical observations documenting a strong association between hydroxyurea therapy and cutaneous ulceration of the legs. Retrospective review of the medical records of patients registered at the Mayo Clinic, Rochester, Minnesota, identified 14 patients who had leg ulcers related to hydroxyurea therapy. Case Reports Patient 1 A 69-year-old man with a history of polycythemia vera and an associated transient ischemic attack received 1.5 g of hydroxyurea daily. After 3 years of continuous therapy, he developed a painful, indolent ulcer of the right posterior calf. Various topical wound dressings, enzymatic debridement, and oral antibiotics failed to heal the ulcer. When the hydroxyurea dosage was increased to 2 to 2.5 g/d, the ulcer increased in size to 3 3 cm. Hydroxyurea treatment was discontinued when its association with the ulcer was identified. The ulcer healed over the course of 3.5 months, and the patient had no further difficulties until 3 years later, when hydroxyurea treatment was restarted by a physician who was not convinced of the original diagnosis of hydroxyurea-induced cutaneous ulceration. Four months after therapy was reinitiated, the patient developed multiple painful ulcers on both ankles (Figure 1). Treatment was again discontinued, and the cutaneous ulcers completely resolved within 6 months. Figure 1. Hydroxyurea-induced ulcer. Top. Bottom. Patient 2 A 41-year-old woman with an undifferentiated myeloproliferative disorder and a history of portal venous thrombosis had received hydroxyurea therapy for 9 years without complications, but she developed an extremely painful ulcer over the left lateral malleolus while she was receiving 1.5 g of hydroxyurea daily. Treatment with pentoxifylline, aspirin, warfarin, and leg elevation was unsuccessful. Hydroxyurea therapy was subsequently discontinued, and anagrelide therapy was initiated. The ulcer resolved within 2 months. Several months later, hydroxyurea therapy was restarted at a dosage of 1.5 g/d because of gastrointestinal intolerance of anagrelide. Cutaneous ulcers developed within 4 months and persisted for the ensuing 4 years while the patient was receiving hydroxyurea therapy. Results Fourteen patients with hydroxyurea-induced leg ulcerations were identified through review of the medical records of 115 patients with various myeloproliferative diseases and leg ulcers who had been treated with hydroxyurea during the previous 16 years (1980 to 1995). This period extended back beyond the first report of hydroxyurea-associated leg ulcers, which was published in 1986 [8]. It would have been preferable to identify all patients treated with hydroxyurea at our institution, but this was not possible because our clinical database does not index patients by medication use. Detailed medical histories of 8 women and 6 men, including the 2 patients described above, were reviewed. The Table 1 summarizes the clinical and morphologic features and clinical course of hydroxyurea-related skin ulcers in these 14 patients. The average age of patients at diagnosis was 65 years (range, 41 to 74 years). Hydroxyurea was administered to treat polycythemia vera (5 patients), essential thrombocythemia (2 patients), agnogenic myelogenous metaplasia (2 patients), chronic granulocytic leukemia (4 patients), and an incompletely characterized myeloproliferative disorder (1 patient). One patient had diabetes mellitus, and 6 had hypertension. Noninvasive arterial and venous vascular studies were done in 7 patients, and no specific vascular causes were identified that might explain the persistent ulcers. Table 1. Clinical Findings in Hydroxyurea-Related Leg Ulcers in 14 Patients Cutaneous ulcers were typically located near the malleoli but were occasionally found over the tibia, on the dorsal aspect of the feet, and on the calves. Of the 18 malleolar ulcers in our 14 patients, 10 (55.6%) were over the medial malleolus and 8 (44.4%) were over the lateral malleolus. A representative cutaneous ulceration is shown in the top panel of the (Figure 1). The ulcers were usually extremely painful. Multiple ulcers were seen in 9 patients (64%). When treatment was discontinued, the hydroxyurea dosage ranged from 1 to 2.5 g/d. The average cumulative dose of hydroxyurea before ulcers developed was 3.2 kg (range, 1.4 to 5.5 kg). The duration of hydroxyurea treatment ranged from 2 to 15 years (mean, 6.1 years). The cutaneous ulcers completely resolved in 12 patients after cessation of hydroxyurea treatment. Two patients had skin grafting to expedite healing. Patient 4 had an indolent ulcer for 1 year, after which time the hydroxyurea dosage was decreased from 1.5 to 0.5 g/d. Ulcer healing ensued within 5 months. Patient 8 also had improvement after the hydroxyurea dosage was decreased from 2 to 1 g/d. However, this dosage was subsequently increased to 2.5 g/d. The original ulcer markedly worsened over the ensuing 4 months, and new ulcers appeared over both malleoli. Hydroxyurea treatment was discontinued. A fatal myocardial infarction that occurred 2 weeks later prevented further assessment. Discussion Hydroxyurea is typically well tolerated and has a relatively low toxicity profile [9]. However, substantial cutaneous side effects have been seen; these include diffuse hyperpigmentation, brown discoloration of nails, acral erythema, photosensitization, fixed drug eruption, alopecia, oral ulceration, and stomatitis [9]. A poikilodermatous dermatomyositis-like skin eruption with atrophy, erythema, and scaling has also been reported [7]. Another ill-defined dermatologic side effect is cutaneous ulceration during hydroxyurea administration. Montefusco and colleagues [8] described 17 patients who had hydroxyurea-related leg ulcers and found complete resolution (14 patients) or marked improvement (3 patients) after hydroxyurea therapy was discontinued. Another study [10] described 4 patients with hydroxyurea-induced skin ulcers that eventually resolved with diligent wound care. We describe 14 patients in whom cutaneous leg ulcers developed while the patients were receiving long-term treatment with hydroxyurea. Our findings indicate that even with meticulous wound care, resolution of the ulcers usually requires discontinuation of hydroxyurea treatment. Extensive attempts to initiate wound healing before discontinuation of treatment included the use of topical and systemic antibiotic therapy, pentoxifylline, hyperbaric oxygen, warfarin, prednisone, Unna vascular boots, and topical wound dressings. None offered significant clinical benefit. Several mechanisms of action have been described for hydroxyurea, including inactivation of the enzyme ribonucleotide reductase with subsequent inhibition of cellular DNA synthesis and cell death in S phase [11]. In the skin, basal keratinocytes are the most actively replicating cells of the epidermis, and damage to keratinocytes by cytotoxic chemotherapeutic agents is one of the most common pathologic alterations seen in chemotherapy-induced reactions [12]. With sustained damage to basal keratinocytes, epidermal atrophy may become prominent [7]. Hydroxyurea has other effects on mammalian cells, including damage due to free-radical nitroxide intermediates and inhibition of DNA repair [11]. Hydroxyurea-induced cutaneous ulcers often occur over the malleoli. One explanation for this localization may be mechanical injury and trauma. In addition, the latency to onset, indolent behavior, and eventual healing after therapy is discontinued all suggest that the mechanism for cutaneous toxicity involves chronic and progressive but reversible cytologic damage. Cellular injury accumulates to the extent that repair mechanisms can no longer regenerate viable, normal-functioning epidermis, stromal cells, or endothelium and tissue damage and ulcers therefore develop [11]. Histologic examination shows nondiagnostic changes. A typical histologic photomicrograph of a hydroxyurea-induced ulcer is shown in the bottom panel of the (Figure 1). At the ulcer border, pseudoepitheliomatous hyperplasia and epidermal spongiosis are seen. In the dermis, endothelial cell swelling, edema, and thickening of blood vessel walls are prominent. Perivascular lymphocytic inflammation without vasculitis is common. In chronic lesions, focal hyalinization of blood vessel walls and intraluminal deposition of fibrinoid material directly beneath the ulceration are seen. These findings resemble the cutaneous occlusive vasculopathy seen in livedoid vasculitis. At later stages, dermal fibrosis develops. No consistent correlation between the dose or duration of hydroxyurea therapy and the occurrence of ulcers has been reported previously [8]. On the other hand, although we observed the development of ulcers over a range of hydroxyurea dosages, the extent and size of the ulcers did correlate with the amount of hydroxyurea administered in two patients. One patient had resolution of the ulcers when the dosage was decreased to 500 mg/d. In addition, long-term hydroxyurea therapy lasting at least 2 to 3 years was generally required before the ulcers occurred. The clinical experience summarized here confirms and further cl

Apoptosis: Basic Concepts and Implications in Coronary Artery Disease

Apoptosis is an active form of cell death that is intricately regulated and distinct from necrosis. Data suggest that apoptosis may play a role in the pathophysiology of coronary atherosclerotic disease. Anatomic evidence of apoptosis has been observed in coronary atherosclerosis, restenosis, and transplant arteriopathy, accompanied by an increase in biochemical and genetic markers of apoptosis. Vasoactive substances such as nitric oxide and angiotensin II also regulate vascular smooth muscle cell apoptosis; vasodilating factors may induce apoptosis, whereas vasoconstricting factors may inhibit apoptosis. The aim of this article is to review key points regarding the detection of apoptosis, its regulation, and its possible role in the pathogenesis of coronary artery disease.