CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 α Activation.

We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1α, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1α. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome.

Warfarin use and the risk of valvular calcification.

BACKGROUND: Warfarin affects the synthesis and function of the matrix Gla-protein, a vitamin K-dependent protein, which is a potent inhibitor of tissue calcification. OBJECTIVES: To investigate the incidence of mitral valve calcium (MVC), mitral annular calcium (MAC) and aortic valve calcium (AVC) in patients with non-valvular atrial fibrillation (AF) treated with warfarin vs. no warfarin. PATIENTS AND METHODS: Of 1155 patients, mean age 74 years, with AF, 725 (63%) were treated with warfarin and 430 (37%) without warfarin. The incidence of MVC, MAC and AVC was investigated in these 1155 patients with two-dimensional echocardiograms. Unadjusted logistic regression analysis was conducted to examine the association between the use of warfarin and the incidence of MVC, MAC or AVC. Logistic regression analyses were also conducted to investigate whether the relationship stands after adjustment for confounding risk factors such as age, sex, race, ejection fraction, smoking, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), glomerular filtration rate, calcium, phosphorus, calcium-phosphorus product, alkaline phosphatase, use of aspirin, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. RESULTS: There was a significant association between the use of warfarin and the risk of calcification [unadjusted odds ratio = 1.71, 95% CI = (1.34-2.18)]. The association still stands after adjustment for confounding risk factors. MVC, MAC or AVC was present in 473 of 725 patients (65%) on warfarin vs. 225 of 430 patients (52%) not on warfarin (P < 0.0001). Whether this is a causal relationship remains unknown. CONCLUSIONS: Use of warfarin in patients with AF is associated with an increased prevalence of MVC, MAC or AVC.

Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA(1)c.

AIMS/HYPOTHESIS: Patients with diabetes mellitus are well known to be at high risk for vascular disease. Circulating endothelial cells (CECs) have been reported to be an ex vivo indicator of vascular injury. We investigated the presence of CECs in the peripheral blood of 25 patients with diabetes mellitus and in nine non-diabetic control donors. METHODS: Endothelial cells were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads, and were stained with acridine orange dye and counted by fluorescence microscopy. The cells were also stained for von Willebrand factor and Ulex europaeus lectin 1. RESULTS: Patients with diabetes mellitus had an elevated number of CECs (mean 69+/-30 cells/ml, range 35-126) compared with healthy controls (mean 10+/-5 cells/ml, range 3-18) (p<0.001). The increase in CECs did not correlate with the levels of HbA(1)c. Circulating endothelial cell numbers were elevated regardless of glucose levels, suggesting that, even with control of glucose levels, there is increased endothelial cell sloughing. CONCLUSIONS: Our study suggests that the higher number of CECs in patients with type 2 diabetes may reflect ongoing vascular injury that is not directly dependent on glucose control.

Long-term clinical outcome of rescue balloon angioplasty compared with rescue stenting after failed thrombolysis.

Failed thrombolysis following acute myocardial infarction is associated with a poor prognosis. Balloon angioplasty with or without stenting is an established procedure in acute myocardial infarction and for failed thrombolysis (rescue percutaneous transluminal coronary angioplasty [PTCA]). Intracoronary stenting improves initial success rates, decreases incidence of abrupt closure, and reduces the rate of restenosis after angioplasty. The purpose of this study was to compare the effect of rescue PTCA with rescue stenting in the treatment of acute myocardial infarction after failed thrombolysis. Clinical data are from a retrospective review of 102 patients requiring rescue balloon angioplasty or stenting after failed thrombolysis for acute myocardial infarction. There was a greater incidence of recurrent angina in 11 patients (22%) in the rescue PTCA group versus 2 patients (4%) in the rescue stenting group. The in-hospital recurrent myocardial infarction rate was 14% in the rescue PTCA group versus 2% in the stented group. In the rescue PTCA cohort, 11 patients (22%) required in-hospital repeat revascularization versus 2 patients in the stented group. The in-hospital mortality rate was higher in the PTCA group (10%) versus that in the stent group (2%). There was no significant difference in the incidence of postdischarge deaths. Rescue stenting is superior to rescue angioplasty. The procedure is associated with lower in-hospital angina and recurrent myocardial infarction, and the need for fewer repeat revascularizations. Long-term patients treated with stents required fewer revascularization procedures. Overall, rescue stenting was associated with a significantly lower mortality.

Hypoxemia sans hypoxemia.

Acquired methemoglobinemia usually occurs during endoscopy after exposure to a variety of drugs commonly used in critical care units and in endoscopy suites. A rapid infusion of methylene blue can result in a complete recovery of patients with a favorable prognosis. The authors describe a case of 31-year-old woman in whom methemoglobinemia developed with the use of benzocaine, and who showed complete recovery after methylene blue infusion. Hence, the availability of methylene blue in these settings is advocated.

Evaluation of a medical ethics consultation service: opinions of patients and health care providers.

PURPOSE: To study the perceived effectiveness of bioethics consultation as evaluated by both professional staff and patients and their families. PATIENTS AND METHODS: An evaluation questionnaire was forwarded to physicians, nurses and patients or family members who were associated with 20 sequential cases referred for ethics consultation during a 2-year period. Respondents were asked to rate the consult as very helpful, somewhat helpful, or not helpful concerning a variety of issues related to the care of the patients. Responses were reviewed for agreement or disagreement between the three sample groups. RESULTS: Ninety-six percent of physicians and 95% of nurses sampled felt that the consult was helpful, compared with only 65% of the patient/family responses. Lack of communication between patients and staff was cited as a problem in all cases in which the consult was deemed unhelpful by patients and family. CONCLUSIONS: Patients or family members and professional staff have different perceptions regarding the value of bioethics consultation. When asked for comments, patients/family members cite lack of communication with professional staff as their primary reason for responding negatively. Earlier mobilization of consultative staff, rigorous training of consultants in techniques of conflict resolution, and education of primary caregivers regarding recognition of communication problems may serve to narrow this perceptual divergence.

Left circumflex coronary artery to left atrial fistula in a patient with mitral stenosis: invasive and noninvasive findings with pathophysiologic correlation.

We report a case of an angiographically documented fistula between the circumflex coronary artery and a left strial appendage thrombus in a patient with mitral stenosis, flow from which can be demonstrated solely by a color doppler transesophageal echocardiogram. Evaluation of catheter derived hemodynamics and angiographic flow patterns reveals a heretofore undescribed physiologic property of coronary to atrial shunts in patients with mitral stenosis.

Effect of New York State's do-not-resuscitate legislation on in-hospital cardiopulmonary resuscitation practice.

PURPOSE: On April 1, 1988, New York State enacted legislation governing the withholding of cardiopulmonary resuscitation (CPR). Suggestions that the mandated protocol for withholding CPR is too cumbersome and will result in an increase in CPR attempts led us to study the effect of the new law on in-hospital resuscitation practice. PATIENTS AND METHODS: We retrospectively reviewed the charts of 245 adult in-patients at a county teaching hospital who died during three-month periods before and after the law took effect. RESULTS: There was a statistically nonsignificant decline in the frequency of CPR attempts at the time of death, from 59 (50%) of 119 patients in 1987 to 57 (45%) of 126 patients in 1988. Use of explicit written "do-not-resuscitate" (DNR) orders increased significantly from 13 (22%) of 60 patients who died without CPR in 1987 to 64 (93%) of 69 patients in 1988. Patient and family involvement in decisions to withhold CPR was common before the law and did not change significantly. CONCLUSION: Although changing the way DNR decisions are documented, the legislation resulted in no significant change either in the frequency of CPR or in the degree to which patients are involved in these decisions.

Early postoperative spasm in left internal mammary artery bypass grafts.

Two patients with early postoperative spasm of a left internal mammary artery bypass graft are described. To our knowledge, this entity has not been reported previously. Both patients were characterized by vasomotor collapse secondary to intractable spasm responsive only to local application of vasodilator agents. Although the mechanism of graft spasm is not clear, prophylactic nifedipine therapy in appropriate dose may be of some value. The profound hemodynamic effect of internal mammary artery spasm in the immediate postoperative period may allow no time for anything other than emergency reoperation to assess the nature of the problem and treat it appropriately.

Coronary revascularization in young patients.

From 1978 to 1982, 92 of our 1704 patients undergoing coronary bypass surgery were 40 years of age or younger. Eighty-six were male and six were female. The main indications for surgery were refractory angina and unstable angina. A family history of heart disease, smoking, and hypertension were major risk factors. The majority of patients had triple vessel disease, and six had left main lesions. Left ventricular function was moderately or severely impaired in 24. Coronary revascularization was performed with internal mammary and saphenous vein conduits, with a mean of 3.7 grafts per patient (range, 1 to 7). There was no operative mortality, but one patient required an intraaortic balloon pump. Perioperative infarction determined by Q waves occurred in one patient, while eight had enzymatic evidence of infarction. Late follow-up to 60 months showed three late deaths of cardiac origin. Eighty-three survivors were greatly improved, and 50 were asymptomatic. Sixty-five patients returned to work. Seventy percent of smokers stopped smoking; half the patients exercised regularly, and half maintained dietary modifications. Coronary bypass grafting is an effective rehabilitation procedure in the young. Long-term attention to risk factors and life style is required to maintain a beneficial outcome.

IgA nephropathy occurring in the context of previous acute glomerulonephritis.

A 37-year-old female presented with acute onset of glomerulonephritis 10 days following an upper respiratory infection. Serum complement components were depressed and proteinuria exceeded 3.0 g daily. Renal biopsy revealed granular staining of IgG and C3 along the basement membrane as well as small amounts of IgA in a linear pattern. Gradual resolution of symptoms was followed by recrudescent proteinuria 2 years later. Renal biopsy at this time revealed large deposits of IgA in a mesangial staining pattern consistent with a diagnosis of IgA nephropathy. Possible mechanisms for this unusual morphologic transformation include enhanced mesangial permeability as well as mesangial sequestration of an exogenous antigen.

Prosthetic heart valves: a review.

There are a number of difficulties inherent in the analysis of such a large and diverse quantity of data. In a substantial number of clinical trials, there is no significant effort made to evaluate prosthetic performance as a function of preoperative cardiac anatomy. Hemodynamics have not been systematically studied in relation to preexisting left ventricular size, shape, or configuration, mitral annular orientation, or left atrial size. Postoperative anticoagulation protocols vary from one institution to another and occasionally within study groups themselves. Less tangible variables such as alteration in surgical technique over time and differential familiarity of cardiovascular surgeons with the prostheses employed are chronic problems in any study of this sort. Perhaps the greatest variable in evaluating the postoperative performance of valvular prostheses over the past 20 yr is the radical improvement in techniques of intraoperative myocardial preservation. Notwithstanding, comparisons are possible within the confines of certain criteria. The caged ball value remains in use after 20 years of clinical experience. It has sustained the greatest number of modifications, probably because it has been the most extensively studied. Hemodynamics are adequate although its centrally obstructed design is responsible for increased turbulence, hemolysis, and neointimal proliferation, particularly in the aortic position. The device has been shown to be durable with virtually no reports of ball variance since the alteration of the silicone curing procedure in 1965. Thromboembolic rates are acceptable in the anticoagulated patient while prosthetic thrombosis is not a grave threat in the non-close clearance device. Incidence of endocarditis is not particularly different from that associated with all nonbioprosthetic valves, although there is a much greater published volume of clinical experience concerning recognition and treatment of late prosthetic valve endocarditis in patients with caged ball valves than there is for any other replacement device. Perhaps the most serious disadvantage to caged ball design is its size. Its large spatial requirements have led to anatomic complications in patients with small aortic roots, isolated mitral stenosis, left ventricular hypertrophy, and double valve replacement, among others. Nevertheless, this is still the valve of choice in some centers.(ABSTRACT TRUNCATED AT 400 WORDS)

Results of combined valvular and myocardial revascularization operations.

A total of 105 patients underwent combined coronary artery and valvular operations. Sixty-six had combined coronary artery bypass grafting (CABG) and aortic valve replacement (AV), 28 had CABG and mitral valve operations (MV), and 11 patients had CABG and double or triple valve operations (DTV). An average of 3.0 bypasses was done, range one to seven. These patients were compared to a similar group of patients who underwent valve replacement(s) only, without CABG. Bypass time was increased for the combined groups, as was ischemic cross-clamp time. Early mortality was 3.0% AV, 3.5% MV, and 9.1% DTV in the combined groups and 1% in the valve only groups. The higher mortality for the combined groups was almost entirely due to the 23% mortality in women over 70 years of age. Perioperative myocardial infarction (MI) was higher in the combined groups (5% MI, 9% probable MI versus 2.9% MI, 4.1% probable MI). All survivors were in improved clinical condition and free of angina. Mortality and improvement were unrelated to perioperative infarction. The small increase in risk compared to the significant improvement from the combined approach has led to the following principles: coronary arteriography on all adult patients requiring valvular operations; bypass of all significant coronary lesions; restoration of valvular function and hemodynamics; and myocardial preservation with cold cardioplegia during a single period of cross clamping, topical cold, and systemic hypothermia.

Circulating immune complexes in patients with uncomplicated group A streptococcal pharyngitis and patients with acute poststreptococcal glomerulonephritis.

To investigate the role of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis (AGN), sera were obtained serially from 13 patients with biopsy-proven AGN, 16 patients with group A streptococcal infection, and 20 age- and sex-matched controls. Samples were analysed for Clq-binding activity (Clq-BA), levels of IgG, IgA, IgM, C3 and C4, and antibody titres to streptococcal enzymes. Significant elevation of Clq-BA was observed in 11 patients (84.5%) with AGN and 7 patients (44%) with streptococcal infection alone. The data suggest that CIC do not necessarily cause glomerular damage, but rather represent a systemic inflammatory response in patients with group A streptococcal infection.

Electromyographic verification of viable muscle tissue following a double-pendulum flap procedure for surgical repair of bilateral cleft lip.

Five patients were seen in an electromyographic study of the double pendulum flap method of bilateral cleft lip repair. All five patients displayed active orbicularis oris muscle tissue. By bringing lateral lip segments to the center of the cleft, the double pendulum flap method restores muscular function and improves cosmetic appearance. This surgical procedure may be modified to be performed on other anomalies resulting from a discontinuity of muscular tissue.

Electrophoretic microheterogeneity and subunit composition of the 13S coupling factors of oxidative and photosynthetic phosphorylation.

Two electrophoretically distinguishable species of the 13S coupling factor of oxidative phosphorylation from Alcaligenes faecalis are detectable by standard polyacrylamide gel electrophoresis in the absence of urea, detergents, or any other protein-denaturing reagents. The slower species (type IA) can be converted into the faster species (type IB) by treatment with ATP, and the fast form converts into the slow form when aged at 4 degrees. The enzyme undergoes these conversions both when it is free in solution and when it is membrane bound. The ATP analog adenylyl imidodiphosphate (AMP-PNP) gives the conversion without being hydrolyzed and without causing any apparent change in the mass of the protein, which suggests that the conversion may be a ligand-induced conformational change. Types IA and IB can convert into three other electrophoretically distinguishable species (types IIA, IIB, and III) if the purification procedure involves chromatography on a DEAE-Sephadex column equilibrated in phosphate buffer. These conversions can be prevented if the column is eluted in morpholinoethanesulfonic acid (Mes) buffer and KCl. Type IIA is convertible into type IIB by ATP treatment. Types IA and IB will also convert into types IIA and IIB and finally into type III when aged for extended periods of time at 4 degrees, without a detectable change in mass. Coupling factor activity is lost when type I enzyme converts into type II enzyme, as is the ability of the enzyme to bind to the membrane. However, ATPase activity does not change significantly. The mitochondrial 13S coupling factor shows up to three electrophoretically distinguishable species. The use of phosphate buffer during DEAE-Sephadex chromatography gives conversion of slower species into faster species. ATP treatment does not give interconversions, and aging at 4 degrees gives only a slow dissociation of the enzyme into subunits. The chloroplast 13S coupling factor also shows up to three electrophoretic species. Incubation with ATP does not give interconversions, but a temperature-dependent conversion of the major species into a faster species occurs upon aging. The subunit composition of the three 13S enzymes is very similar by polyacrylamide gel electrophoresis in sodium dodecyl sulfate, the major difference being in the number of classes of small polypeptides.