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Peripheral arterial occlusive disease (PAOD) of the lower extremities is becoming more prevalent worldwide. Nonsurgical treatment options provide the foundation for management. Lifestyle and risk factor modification should be emphasized in this patient population because of the associated adverse cardiovascular events. This includes implementation of a regular walking and smoking-cessation programs, aggressive control of hyperlipidemia, hypertension and diabetes mellitus, and treatment of hyperhomocysteinemia. Antiplatelet agents such as aspirin (acetylsalicylic acid) or clopidogrel are not specifically indicated for claudication but these drugs should be used in all patients with PAOD to prevent secondary ischemic events. Currently, cilostazol is the only US FDA approved agent that appears effective for the treatment of claudication symptoms. Several agents have been used with success outside of the US and others are still undergoing testing. Definitive recommendations cannot be made on the use of these drugs until further evaluation is completed. Ongoing research with new strategies for angiogenesis and the use of progenitor cells has yielded encouraging results, particularly for patients with critical limb ischemia and limited options. Advances in endovascular technology over the last several years have greatly enhanced the ability to diagnose and treat specific anatomic lesions that previously would have required open surgical correction. The use of percutaneous transluminal angioplasty and stents in the lower extremities has had considerable success when following specific guidelines such as those set forth by the TransAtlantic Inter-Society Consensus Working Group.
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PMID:Current management of peripheral arterial occlusive disease: a review of pharmacologic agents and other interventions. 1735 66

Ocular vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration, whose population increases along with aging, have become leading causes of severe visual disturbance. Macular edema and serous retinal detachment are associated with abnormal vascular leakage and tractional retinal detachment, and neovascular glaucoma is caused by retinal neovascularization. Such ocular vascular diseases are caused by vascular cell aging and vascular damage associated with lifestyle-related diseases including diabetes mellitus, hypertension, hyperlipidemia, and obesity. In the present study, we investigated molecular mechanisms in such vascular deficiencies using vascular cell biology methodology, and we propose novel strategies for the treatment of such vascular diseases. Along with aging, oxidative stress and physical stress, such as mechanical stretch, continuously and directly insult vascular cells. Such stress induces apoptosis by intracellular signaling through stress kinases in cultured retinal vascular cells. Inhibition of such stress kinases could be an effective treatment to protect the vascular cells against age-related damage. In a retinal vascular developmental model, pericyte loss causes pathology mimicking macular edema and proliferative diabetic retinopathy. Angiopoietin 1 (Ang 1) secreted by pericytes suppresses oxidative stress-induced intracellular signaling through stress kinases linked to cell apoptosis and normalizes such retinal pathology. This suggests that the paracrine action of Ang 1 in the pericytes is necessary to sustain normal retinal vasculature, and that Ang 1-triggered intracellular signaling is useful for the treatment of vascular cell pathology associated with pericyte loss. In diabetic retinopathy and retinal vein occlusion, retinal vessels regress along with retinal vascular cell apoptosis, and the retina becomes ischemic followed by pathological retinal neovascularization. VEGF has been recognized as a predominant factor to induce the ischemic retinal neovascularization. We found that retinal vascular cells have a characteristic pattern in VEGF receptor expression, which causes vascular pathology more frequently in the retina than in other organs. Neuropilin 1 (NRP 1), which enhances VEGF receptor function, is abundantly expressed in the retinal endothelial cells and is upregulated by VEGF itself and by hypoxia to regulate a positive feedback mechanism in retinal neovascularization. This receptor could be a unique target for retina-specific therapy. Lifestyle-related diseases increase along with aging and have further increased due to changes in Japanese lifestyle imitating that of Western countries. We found that the renin-angiotensin system which regulates hypertension and cardiovascular diseases, and adipocytokines which are abnormally secreted in obesity, act as proangiogenic factors. Regulation of such lifestyle-related disease factors is important for the treatment of retinal vascular diseases. Finally, we found that erythropoietin is an ischemia-induced angiogenic factor that acts independently and as potently as VEGF in proliferative diabetic retinopathy (PDR). Our study utilizing human vitreous samples demonstrates that the VEGF level is particularly high and strongly associated with angiogenic activity in PDR patients. The potential of VEGF inhibitors has recently been recognized in clinical applications. The manipulation of each angiogenic factor and adipocytokine that we report here could become potential therapy in the near future.
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PMID:[Aging and retinal vascular diseases]. 1740 63

In our aging population, primary major amputations (AMP, below-knee or above-knee) continue to be performed despite advances in revascularization. We hypothesized that not only patient comorbidities but also the system of health-care delivery affected the treatment of patients with critical limb ischemia (CLI). A prospective analysis of patients presenting with CLI was undertaken to determine whether patient-specific factors or healthcare delivery factors (system-related) influenced treatment with primary AMP versus lower extremity revascularization (LER). The patient-specific factors age, gender, race/ethnicity, presence of coronary artery disease, cerebrovascular disease, tobacco use, diabetes mellitus (DM), dialysis dependence (end-stage renal disease, ESRD), hypertension, hyperlipidemia, stage of CLI (rest pain, minor or major tissue loss), history of revascularization, and functional status (living situation and ambulatory status) were recorded. The system-related factors time from onset of CLI to vascular surgery evaluation and type of insurance (managed care/other insurance) were also noted. The influence of patient-specific and system-related factors on the primary treatment modality (AMP versus LER) was determined with univariate and multivariate analyses. A total of 224 patients presented with CLI between March 1, 2001, and March 1, 2005. Patients were treated with primary major AMP in 97 cases (43%) and revascularization in 127 cases (57%). On univariate analysis, nonwhite race/ethnicity, DM, ESRD, major tissue loss, dependent living situation, and nonambulatory status were all significant predictors of AMP versus LER (all P < 0.01). On multivariate analysis, major tissue loss, ESRD, DM, and nonambulatory status remained independent predictors of AMP versus LER (all P < 0.05). The system-related factors of time to vascular surgery evaluation (mean 8.6 weeks, 7.1 vs. 9.3 weeks AMP versus LER, P = 0.60) and type of insurance (managed care, 17% vs. 24% AMP vs. LER, P = 0.15) had no influence on treatment. Fifty-four percent of all primary major AMPs were performed due to extensive gangrene or infection present at initial vascular evaluation which precluded limb salvage. Major tissue loss, ESRD, DM, and nonambulatory status are all independent predictors of treatment with primary AMP as opposed to revascularization. Treatment of CLI is determined by patient-specific factors and does not appear to be adversely influenced by system-related factors. Efforts toward improving limb salvage may be best directed at aggressive treatment of medical comorbidities to prevent the late complications of CLI. Earlier recognition of tissue loss and referral to the vascular specialist may lead to improved limb salvage.
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PMID:A prospective analysis of critical limb ischemia: factors leading to major primary amputation versus revascularization. 1749 67

The absence of coronary artery calcium (CAC) is associated with minimal atherosclerosis. Nonetheless, morbid and mortal cardiovascular events occur in patients with low CAC. This study attempts to identify whether calcific deposits outside the coronary arteries or traditional cardiovascular risk variables are associated with myocardial ischemia in patients with low CAC scores. From 1998 to 2006, a total of 605 patients with an Agatston CAC score of 0 to 10 were referred for stress echocardiography or myocardial perfusion imaging. There was a low rate (1.2%) of myocardial ischemia. Seven of 303 patients (2.3%) had ischemia on perfusion imaging. Zero of 302 stress echocardiograms were abnormal. Traditional risk-factor analysis did not predict the presence of ischemia. No differences in age, gender, or self-reported hyperlipidemia, diabetes mellitus, tobacco use, hypertension, or family history of premature heart disease were noted. Contrary to previous belief, patients with myocardial ischemia were not younger or female. Aortic valve calcium (AVC) was associated with ischemia (p = 0.02), with a >10-fold likelihood of having ischemia detected by MPS versus those without AVC (20.0% vs 1.7%). In conclusion, a CAC score <10 is associated with a low rate of myocardial ischemia. AVC may identify a subset of patients who may be at higher risk.
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PMID:Relation of aortic valve calcium to myocardial ischemic perfusion in individuals with a low coronary artery calcium score. 1753 76

Peripheral arterial disease (PAD) includes a wide range of manifestations in the lower limb, from asymptomatic to symptomatic disease ranging from intermittent claudication to critical limb ischemia, with ulcers, rest pain, or gangrene. It is manifestation of generalized atherosclerosis and this is clearly shown by the high prevalence of coexistence coronary and cerebral arterial disease in these patients. The cumulative findings on molecular and cellular biology have dramatically changed our concept of atherosclerotic disease. Recently, it has become clear that inflammation is fundamental to the process of atherosclerosis. Although the relation between inflammation and PAD is not well characterized, the emerging data demonstrated that PAD is a common manifestation of atherosclerosis that is associated with a systemic inflammation. The most important risk factors for PAD are similar to those of atherosclerotic disease elsewhere: age, male sex, diabetes mellitus, smoking, hypertension, hyperlipidemia, and hereditary factors. Serum levels of inflammatory markers, especially after exercise, have been found to be higher in patients with PAD than in controls, and associated with prognosis as well as restenosis in patients with PAD after revascularization. In the general United States adult population, inflammation is independently associated with PAD in a cross-sectional, nationally large representative sample. All of those evidences indicate that PAD is one aspect of atherosclerosis, a disease rationally connects with inflammation, which may further change our preventive and therapeutic strategies.
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PMID:A rational connection of inflammation with peripheral arterial disease. 1755 83

Diabetes mellitus (DM) is an important cardiovascular risk factor and is associated with abnormalities in endothelial and vascular smooth muscle cell function, evoked by chronic hyperglycemia and hyperlipidemia. Chronic insulin deficiency or resistance is marked by decreases in the intensity of glucose transport, glucose phosphorylation, and glucose oxidation, plus decreases in ATP levels in cardiac myocytes. It is important to search for new agents that promote glucose consumption in the heart and partially inhibit extensive fatty acid beta-oxidation observed in diabetic, ischemia. When the oxygen supply for myocardium is decreased, the heart accumulates potentially toxic intermediates of fatty acid beta-oxidation, that is, long-chain acylcarnitine and long-chain acyl-CoA metabolites. Exogenous glucose and heart glycogen become an important compensatory source of energy. Therefore we studied the effect of the antidiabetic 1,4-dihydropyridine compound cerebrocrast at concentrations from 10(-10) M to 10(-7) M on isolated rat hearts using the method of Langendorff, on physiological parameters and energy metabolism. Cerebrocrast at concentrations from 10(-10) M to 10(-7) M has a negative inotropic effect on the rat heart. It inhibits L-type Ca(2+)channels thereby diminishing the cellular Ca(2+) supply, reducing contractile activity, and oxygen consumption, that normally favors enhanced glucose uptake, metabolism, and production of high-energy phosphates (ATP content) in myocardium. Cerebrocrast decreases heart rate and left ventricular (LV) systolic pressure; at concentrations of 10(-10) M and 10(-9) M it evokes short-term vasodilatation of coronary arteries. Increase of ATP content in the myocytes induced by cerebrocrast has a ubiquitous role. It can preserve the integrity of the cell plasma membranes, maintain normal cellular function, and inhibit release of lactate dehydrogenase (LDH) from cells that is associated with diabetes and heart ischemia. Administration of cerebrocrast together with insulin shows that both compounds only slightly enhance glucose uptake in myocardium, but significantly normalize the rate of contraction and relaxation ( +/- dp/dt). The effect of insulin on coronary flow is more pronounced by administration of insulin together with cerebrocrast at a concentration of 10(-7) M. Cerebrocrast may promote a shift of glucose consumption from aerobic to anerobic conditions (through the negative inotropic properties), and may be very significant in prevention of cardiac ischemic episodes.
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PMID:Acute effect of antidiabetic 1,4-dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heart. 1799 Feb 88

Fenofibrate, a fibric acid derivative, is used to treat diabetic dyslipidemia, hypertriglyceridemia, and combined hyperlipidemia alone or in combination with statins. Rhabdomyolysis is defined as a pathological condition of skeletal muscle cell damage leading to the release of toxic intracellular material into the circulation. Its major causes include trauma, ischemia, toxins, metabolic disorders, infections, and drugs. Rhabdomyolysis associated with fenofibrate is extremely rare. In nearly all of the presented cases, there was a predisposing factor for rhabdomyolysis such as diabetes, older age, renal insufficiency, and hypothyroidism. Here, we report a nondiabetic, nonhypothyroidic young female patient without any known prior renal disease presenting with acute renal failure developing after fenofibrate treatment.
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PMID:Acute renal failure secondary to fenofibrate monotherapy-induced rhabdomyolysis. 1799 63

Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.
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PMID:Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. 1804 61

Therapy for atherosclerotic occlusive subclavian arterial disease is undergoing a paradigm shift from open to endoluminal therapy. The aim of this study was to review the changing patterns of presentation and clinical outcomes based on presenting symptoms of subclavian artery revascularization. We performed a retrospective analysis of consecutive patients treated for symptomatic atherosclerotic occlusive subclavian arterial disease from 1992 through 2006. Mean follow-up was 4 years. One hundred fourteen patients with a mean age of 63 years (range 33-89, 61% female) underwent 137 procedures. Of these, 89% had hypertension, 32% were diabetic, 69% had hyperlipidemia, and 13% had chronic renal insufficiency. Sixty-seven primary stent attempts (five technical failures) and 70 open (64 carotid-subclavian bypasses, six subclavian-carotid transpositions) were performed. No deaths occurred within the 30-day perioperative period. Fifty-seven percent of the patients presented with symptoms of arm ischemia: exertional pain (84%), rest pain (12%), and ulceration (4%). The assisted primary patency was 81 +/- 7% and 80 +/- 10% at 5 and 10 years, respectively. Symptoms resolved in all patients, and none required major or minor amputations. Freedom from recurrent arm symptoms was 71 +/- 8% and 71 +/- 10% at 5 and 10 years, respectively. Twenty-five percent of the patients presented with a cardiac indication: preparation for a left internal mammary artery (IMA) bypass in 61% and recurrent cardiac ischemia in the remainder. The assisted primary patency was 97 +/- 6% at 5 years. No IMAs were abandoned in this group, and the freedom from recurrent cardiac symptoms related to IMA distribution was 79 +/- 10% at 5 years. Eighteen percent of patients presented with posterior circulation symptoms secondary to vertebrobasilar disease. The assisted primary patency was 100 +/- 0% and 100 +/- 0% at 5 and 10 years, respectively. Freedom from recurrent vertebrobasilar symptoms was 95 +/- 6% and 95 +/- 10% at 5 and 10 years, respectively. Subclavian artery revascularization is safe and effective, but long-term outcomes are determined by the presenting symptomatology.
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PMID:Subclavian artery revascularization: an outcome analysis based on mode of therapy and presenting symptoms. 1808 31

Pseudocarcinomatous epithelial hyperplasia in the bladder is a little known phenomenon, recognized to be associated with prior irradiation and/or chemotherapy. Whether this process can occur outside of this setting has not been studied. We identified 8 of these cases mimicking invasive urothelial carcinoma from our consultation files from 07/04 to 07/06 with no prior history of radiation or chemotherapy. The mean age at diagnosis was 65 years (range, 42 to 81 y), with 5 of the 8 males. Seven patients had a potential etiology for these changes that could either have resulted in localized ischemia or injury to the urothelium. These included case 1: atrial fibrillation, hypertension, congestive heart failure, gastrointestinal bleeding, and coronary artery vascular disease; case 2: coronary angioplasty, atrial fibrillation, hyperlipidemia, and amputation of arm for ischemia; case 3: hypertension, uncontrolled diabetes, hyperlipidemia, and atrial fibrillation; case 4: underlying arteriovenous malformation of the bladder; cases 5 to 6: history of indwelling Foley catheter; and case 7: history of radical prostatectomy for prostate cancer but no radiation. One patient had no potential contributing factors. All 8 patients presented with gross hematuria. At cystoscopy, 7 patients had polypoid lesions with 1 appearing nonpolypoid. Histologically, all cases showed epithelial proliferation of urothelium with cells having prominent eosinophilic cytoplasm. This process that mimicked invasive cancer within the lamina propria was marked in 3 cases (38%). Moderate nuclear pleomorphism was seen in 6 cases (75%). Only 1 case revealed mitotic figures. Ulceration was seen in 1 case. All cases showed some degree of hemorrhage with hemosiderin deposition identified in 3 cases (38%). Fibrin deposition was present in 1 case within the stroma, 3 cases in the vessels, and 4 cases in both. Five cases show stromal fibrosis. Edema and vascular congestion were common features (90% and 100%, respectively). Six out of 8 cases were accompanied by moderate to marked acute and chronic inflammation. The original diagnosis included nested variant urothelial carcinoma (1 case), atypical suspicious for invasive carcinoma (5 cases), hemangioma (1 case), and eosinophilic cystitis (1 case). Patients were followed for a mean of 16.5 months (range, 10 to 34 mo), and none developed bladder cancer. As a rare response to ischemia and chronic irritation, pseudocarcinomatous epithelial proliferations in the bladder may be confused with invasive urothelial carcinoma. Pathologists must be aware of the histologic changes mimicking cancer, and recognize that it can occur outside of the setting of prior irradiation or chemotherapy.
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PMID:Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy. 1816 75


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