Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

beta-blocker use and diabetes symptom score: results from the GEMINI study.

AIM: The Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two beta-blockers in people with type 2 diabetes and hypertension treated with renin-angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two beta-blockers on commonly reported symptoms. METHODS: The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. RESULTS: Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (-0.08; 95% CI -0.15, -0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (-0.12; 95% CI -0.23, -0.02; p = 0.02) and hyperglycaemia symptoms (-0.16; 95% CI -0.27, -0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. CONCLUSION: Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated beta-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes.

Clinical adaptation of a high-performance liquid chromatographic method for the assay of pyridoxal 5'-phosphate in human plasma.

Vitamin B6, measured as pyridoxal 5'-phosphate (PLP), is a co-enzyme in the transsulfuration pathway of homocysteine metabolism. Since depletion of PLP has been suggested as an independent risk factor for coronary artery disease, PLP is frequently measured to guide patient care. By a change and utilization of an Aquasil C18 column and the addition of an acetonitrile clean-up gradient to the potassium phosphate, with sodium perchlorate and bisulfite buffer between samples we report the modification of a previously described method for analysis of PLP. The result is a more practical, efficient, reliable and robust method for daily clinical use. We also determined and report that it is critical to protect freshly prepared standard PLP samples from light exposure during assay preparation.

Proximal tubule cell response to radiographic contrast media.

Renal dysfunction associated with contrast media (CM) administration is generally attributed to reduced renal blood flow. Studies, however, also suggest direct tubular effects of CM, whose mechanisms remain unclear. This study was conducted to assess the chemotoxic effects of iopamidol, a prototypic CM, on a porcine proximal tubule (PT) cell line, LLC-PK(1) cells. Results indicate that iopamidol did not affect cell viability (determined by trypan blue exclusion and fluorescein staining), but did reduce cell proliferation. Moreover, iopamidol altered mitochondrial function, as determined by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and mitochondrial membrane potential. Decreased MTT reduction was evident with all CM tested, and its rapid recovery after CM removal suggests that inhibition of mitochondrial function is reversible. Injury to PT cells by iopamidol is supported by the fact that CM increase extracellular adenosine, an indicator of cellular stress. This study provides greater insight into the mechanism underlying the nephrotoxicity induced by contrast in patients and explains the reversibility of this toxicity.

If LDL-C is the answer...what was the question? What do the data really show?

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are frequently utilized in the treatment of hypercholesterolemia. With recently completed statin clinical cardiovascular outcomes data available, the purpose of this review is to analyze the relative benefits of each molecule and to determine whether "lower is better" is a correct hypothesis for secondary prevention. Twenty-one clinical studies, each with a duration of statin therapy of 6 months or longer, were reviewed, and the pharmacologic effects of these agents on cardiovascular outcomes was examined. As evaluated by study drug, statistical event reduction was achieved in seven of nine pravastatin studies, one of three simvastatin studies, one of six lovastatin studies, zero of two fluvastatin studies, and zero of one atorvastatin study. Pravastatin was the only statin proven statistically to reduce events in both primary and secondary prevention. Thus, all of the statins do not appear to be the same in terms of their ability to reduce cardiovascular events. Until head-to-head trials have been completed, these clinical outcomes data suggest that in patients with severe hypercholesterolemia who require high-dose statin therapy, simvastatin 80 mg each evening would appear to be the agent of choice. However, pravastatin 40 mg daily at bedtime appears to be a unique molecule, with the strongest evidence for event reduction in the majority of patients with moderate hypercholesterolemia with, or who are at risk for, coronary heart disease.

Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency.

The safety of gadolinium (Gd-benzyloxypropionictetra-acetate [BOPTA] dimeglumine) infusion was evaluated in 32 patients with severe or moderate chronic renal failure in a prospective, randomized, double-blind, placebo-controlled study. Renal failure was defined as severe if creatinine clearance was between 10 and 29 mL/min, and as moderate if creatinine clearance was between 30 and 60 mL/min. Serum creatinine level and 24-hour urine samples for creatinine clearance were followed up serially for 7 days after the administration of either gadolinium (Gd-BOPTA dimeglumine), 0.2 mmol/kg, or a saline infusion. No patient experienced a significant change in renal function, defined as an increase in serum creatinine level greater than 0.5 mg/dL more than baseline, and no patient required hospitalization or dialysis during the study period. Gadolinium (Gd-BOPTA dimeglumine) appears to be well tolerated in patients with moderate to severe renal failure.

Clinical predictors of improved long-term blood pressure control after successful stenting of hypertensive patients with obstructive renal artery atherosclerosis.

Despite a high procedural success rate, long-term blood pressure control after successful renal artery stenting of hypertensive patients has been inconsistent. This most likely reflects the absence of clinical guidelines for the selection of patients likely to benefit from renal revascularization. A cohort of 150 consecutive hypertensive patients (mean age, 66.7 years; 86 women) with 180 renal artery lesions (> or =75%) underwent primary Palmaz stent deployment. Mean arterial blood pressure (MAP), serum creatinine, and antihypertensive medication requirements were monitored prospectively. Specific definitions of blood pressure cure, improvement, or treatment failure were followed. Renal artery duplex Doppler or angiography was performed to assess stent patency at a mean 13 months (range, 7-15 months). Multivariate logistic regression analysis was used to select clinical variables that best related to a beneficial blood pressure control at follow-up. The procedural success rate was 97.3% (146 patients) and major in-laboratory complications were infrequent (1.3%). Late MAP values in 127 patients (91%) fell from 110 +/- 13.7 to 97.6 +/- 10.6 mm Hg (P < 0.001); antihypertensive medication requirements decreased from 2.9 +/- 1.2 to 1.9 +/- 1.1 (P < 0.01). The 13-month stent restenosis rate defined by duplex Doppler or angiography was 12%. Multivariate logistic regression analysis identified a preprocedure MAP of >110 mm Hg (odds ratio, 2.9; P = 0.003) and bilateral renal stenoses (odds ratio, 4.6; P = 0.009) as predictors of a beneficial blood pressure response at follow-up. This study provides general preprocedure guidelines for the selection of hypertensive patients with atherosclerotic renal lesions likely to benefit from primary Palmaz stenting and confirms a high procedural success and low stent restenosis rate.

Oxygen free radicals and contrast nephropathy.

Ionic, high-osmolality contrast medium causes nephrotoxicity associated with increased intrarenal adenosine production. To test the hypothesis that oxygen free radicals (produced during intrarenal adenosine catabolism to xanthine) should be implicated in the pathogenesis of ionic, high-osmolality contrast medium nephrotoxicity in humans and to determine whether magnesium protects the kidney from oxygen free radical injury following contrast, 39 patients with mild renal dysfunction were divided into low (LoMg++) and normal (NlMg++) magnesium states and randomized to precoronary angiography oral allopurinol (a xanthine oxidase inhibitor) or placebo. Creatinine clearance and urinary xanthine excretion were measured before and after angiography. Forty-eight hours after contrast medium exposure, placebo-treated LoMg++ and NlMg++ patients had 61%+/-5% and 67%+/-6% increases in urinary xanthine excretion, respectively; however, placebo-treated LoMg++ patients had a greater (79%+/-9% v 35%+/-6%; P < 0.01) decrease in creatinine clearance than placebo-treated NlMg++ patients. Allopurinol-treated LoMg++ and NlMg++ patients had no significant change in urinary xanthine excretion, but did have 40%+/-7% and 33%+/-5% decreases, respectively, in creatinine clearance 48 hours after contrast medium exposure. There was no difference in renal dysfunctional response among placebo-treated NlMg++ patients or allopurinol-treated LoMg++ or NlMg++ patients. These data suggest (1) that oxygen free radicals contribute to ionic, high-osmolality contrast medium nephrotoxicity in hypomagnesemic patients with mild renal disease and (2) that magnesium attenuates the nephrotoxicity mediated by oxygen free radicals.

Hypertensive heart disease syndrome in women in a cardiology practice.

The authors hypothesized that a population of female patients exist whose historical and clinical findings are typical regarding hypertensive heart disease syndrome, so they can be readily identified in a clinical practice and benefit from specific therapy.

Nephrotoxicity from contrast media: attenuation with theophylline.

PURPOSE: To determine if depression of creatinine clearance after administration of contrast medium may be prevented with theophylline. MATERIALS AND METHODS: A nonionic, low-osmolality contrast medium (iopamidol) or an ionic, high-osmolality contrast medium (sodium diatrizoate) was administered to 93 patients. Before the examination, these patients were given theophylline or a placebo orally. There were also 30 patients who received an adenosine-uptake inhibitor (dipyridamole). Creatinine clearance and urinary adenosine levels were measured before and after angiography. RESULTS: Creatinine clearance decreased 18% +/- 4 in the placebo-iopamidol group but did not decrease in the theophylline group; urinary adenosine increased 67% +/- 7. Creatinine clearance decreased 42% +/- 5 in the placebo-sodium diatrizoate group and decreased 24% +/- 3 in the theophylline group; urinary adenosine increased 119% +/- 8. In the dipyridamole group in which iopamidol was given, urinary adenosine increased 96% +/- 7 and creatinine clearance decreased 37% +/- 5. CONCLUSION: Intrarenal adenosine can be implicated in the pathogenesis of hypertonic contrast medium nephrotoxicity.

A difference between front-loaded streptokinase and standard-dose recombinant tissue-type plasminogen activator in preserving left ventricular function after acute myocardial infarction (the Central Illinois Thrombolytic Therapy Study).

A blinded, randomized trial compared the effects of front-loaded streptokinase with those of the conventional dose of intravenous recombinant tissue-type plasminogen activator (rt-PA) on left ventricular (LV) function after acute myocardial infarction (AMI). Thrombolytic therapy was administered in the emergency departments of 30 community hospitals in central Illinois, and subsequent studies were performed at 1 tertiary referral center. Patients aged < or = 75 years with a first AMI who could be treated within 4 hours of the onset of chest pain were randomly assigned to receive either streptokinase (375,000 IU bolus, followed by 1,125,000 IU over 1 hour) or rt-PA (10 mg bolus, followed by 50 mg in the first hour, and 20 mg/hour for the next 2 hours). All patients were treated with aspirin (325 mg) and intravenous heparin. Patients were transferred for angiography within 24 hours. During the 30-month study, 253 patients were treated with intravenous thrombolytic therapy 2.4 +/- 1.0 hour after the onset of AMI. In patients with anterior wall AMI (n = 90), global LV ejection fraction measured by angiography within 24 hours was 45 +/- 12% with rt-PA, and 39 +/- 13% with streptokinase (p < 0.03). Convalescent radionuclide angiography documented a persistent beneficial effect of rt-PA on LV regional wall contractility, but not global ejection fraction. There were no differences between rt-PA and streptokinase in preserving global or regional LV function in patients with inferior wall AMI.

Nephrotoxicity of nonionic low-osmolality versus ionic high-osmolality contrast media: a prospective double-blind randomized comparison in human beings.

To test whether a nonionic, low-osmolality contrast medium (iopamidol) administered for coronary angiography was less harmful to renal function than ionic, high-osmolality medium (sodium diatrizoate), a prospective, double-blind randomized study of 70 patients with normal or mildly depressed renal function (serum creatinine < or = 2.0 mg/dL (175 mumol/L) was performed. Creatinine clearance was determined before coronary angiography and 24 and 48 hours after. There were no significant differences between the low- and high-osmolality groups with regard to age, baseline creatinine clearance, or dose of contrast medium given. In patients receiving low-osmolality medium (n = 35), creatinine clearance decreased by 19% +/- 13 (1 standard deviation) at 24 hours and recovered by 48 hours. In patients receiving high-osmolality medium (n = 35), creatinine clearance decreased by 40% +/- 16 at 24 hours and remained depressed by 47% +/- 14 at 48 hours. In patients with normal or mildly depressed renal function, use of a non-ionic, low-osmolality contrast medium minimized nephrotoxicity as measured by reductions in creatinine clearance after coronary angiography.

Increased incidence of silent ischemia after acute myocardial infarction.

OBJECTIVE: To determine the incidence of angina pectoris during induced myocardial ischemia in patients who have had thrombolytic therapy for acute myocardial infarction in comparison with patients with angina pectoris. DESIGN: During percutaneous transluminal coronary angioplasty, both study groups had coronary artery occlusion by the balloon dilatation catheter for 5 minutes. SETTING: A tertiary, cardiology referral center. PATIENTS: Twenty-five patients with angina pectoris who were undergoing angioplasty were compared with 30 patients having angioplasty 2 days after thrombolytic therapy for acute myocardial infarction. OUTCOMES: Development of angina pectoris during balloon occlusion of the coronary artery was the primary end point; the ischemic response and muscle viability were assessed using both surface and intracoronary electrocardiograms and pulmonary artery wedge pressure. RESULTS: During balloon occlusion 16 (64%) of 25 patients in the angina pectoris group developed angina. In contrast, nine (30%) of 30 patients in the thrombolysis group had angina pectoris during balloon occlusion of the infarct artery (P less than .01). The electrocardiographic response to ischemia and changes in pulmonary wedge pressure were similar in the two study groups. CONCLUSION: After thrombolytic therapy for myocardial infarction, silent ischemia may be the rule rather than the exception.

Six-year survival after coronary thrombolysis and early revascularization for acute myocardial infarction.

Six-year follow-up was conducted in a consecutive series of 192 patients receiving thrombolytic therapy for acute myocardial infarction (AMI) with ST-segment elevation. Cardiac catheterization was performed within a day, and patients with an open infarct artery routinely had early revascularization: 99 (67%) underwent coronary bypass surgery and 18 (12%) coronary angioplasty. With this treatment strategy, 6-year cardiac mortality was 14.5%, 6% (12 patients) in hospital and 9% (16 patients) for survivors of hospitalization. Multivariate analysis showed that predictors of cardiac death among survivors of hospitalization were a closed infarct artery at catheterization (p less than 0.01), diabetes (p less than 0.01) and anterior myocardial infarction (p = 0.01). A subset of 146 patients underwent radionuclide angiography before hospital discharge; for them, predictors of mortality were a closed infarct artery at catheterization (p less than 0.01), anterior wall AMI (p = 0.02), and Killip class III to IV on admission (p less than 0.06). Left ventricular ejection fraction was not a significant predictor of mortality for this subset of patients.

Axial heterogeneity of adenosine transport and metabolism in the rabbit proximal tubule.

Transport and metabolism of adenosine were studied in the S1, S2, and S3 segments of the rabbit proximal renal tubule. Isolated segments were perfused in vitro with uniformly labelled 14C-adenosine to measure the lumen-to-bath flux of adenosine. This flux rate was measured by the disappearance of 14C from the luminal fluid (JD) and simultaneously by the appearance of 14C in the bathing solution (JA), expressed as femtomoles per minute per millimeter of tubule length (fmol.min-1.mm-1). At a perfused concentration of 83.3 microM adenosine, when corrected for metabolism, the JDs for adenosine in the S1, S2, and S3 segments were 735, 212, and 273, respectively. JAs, corrected for metabolism, were 0, 0, and 4.8 fmol.min-1.mm-1 for the S1, S2, and S3 segments, indicating that very little or no 14C-adenosine moved across the basolateral membrane. To correct for metabolism of 14C-adenosine, the perfusion fluid, collected fluid, tubular extract, and bathing fluid, from three tubules of each segment type, were analyzed by high-performance liquid chromatography to identify 14C-adenosine and its 14C-metabolites. At 83.3 microM, all segments metabolized adenosine extensively. Consequently, adenosine-5'-monophosphate (AMP) and inosine were found in tubule cells of all segments. Inosine also appeared in the collected fluid, but AMP did not. In S1 and S2 segments, none of the 14C in the bathing solutions could be identified and no adenosine was found. Of the small amounts of 14C found in bathing solutions from S3 segments, about 27% appeared to be adenosine, the rest were inosine and hypoxanthine or unidentified metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of artifacts in plasma adenosine determinations.

The literature concerning the role of adenosine (ADO) in physiology reveals no agreement about plasma ADO concentrations and suggests two main sources of error in these determinations: rapid ADO uptake by red blood cells or rapid ADO production from ADO nucleotides, which may be released by any cell lysis or platelet aggregation during plasma preparation. We therefore studied ADO concentrations in plasma from normal human forearm venous blood. ADO was determined by a high-performance liquid chromatographic procedure with a sensitivity of 3 nM (original plasma). Observed ADO concentrations ranged from 894 nM to 8.2 nM depending on the conditions of plasma preparation. In plasma prepared in plastic tubes from 4.5 ml of blood drawn into a plastic syringe containing 1.5 ml of an isotonic stopping solution (pH 7.4) containing heparin (60 units ml), dilazep (40 microM), EGTA (40 mM, EDTA (40 mM), erythro-9-(2-hydroxy-3-nonyl) adenine (40 microM), and alpha, beta-methylene adenosine-5'-diphosphate (525 nM), the plasma ADO concentration was 13.3 +/- 1.88 nM (SE) after correction for a simultaneous ADO recovery determination. The mean ADO recovery was 78% +/- 3.39. The mean plasma ADO concentration found by this method of collection and preparation is lower then reported by others. Proper collection methods are required to avoid artifacts when determining plasma ADO concentrations.

Recurrent bacterial endocarditis in a man with tetralogy of Fallot: earliest recurrence on record.

Enterococcal endocarditis occurred in a young man with tetralogy of Fallot who had just completed therapy for staphylococcal endocarditis. The patient had a transient reversal of flow through the ventricular septal defect during staphylococcal endocarditis with lung abscesses and had persistently elevated teichoic acid antibody titers during the second episode caused by enterococcus. Our review of the literature on recurrent infective endocarditis indicates that our case represents one of the shortest intervals of recurrence with a second organism.

Determinants of hospital charges for coronary artery bypass surgery: the economic consequences of postoperative complications.

This is a prospective study of 500 consecutive patients having coronary artery bypass surgery; mean hospital charge from time of surgery to discharge was +11,900 +/- 12,700. Multiple regression analysis was performed using preoperative variables and postoperative complications. No preoperative clinical feature was a significant predictor of higher average charge. Sternal wound infection (p = 0.0001), respiratory failure (p = 0.0001) and left ventricular failure (p = 0.017) were associated with higher average hospital charge. The absence of any complication predicted a lower average charge, and postoperative death (4.4 +/- 4.5 days after surgery) was also associated with lower average charge. A cost equation was developed: hospital charge equalled $11,217 + $41,559 of sternal wound infection, + $28,756 for respiratory failure, + $5,186 for left ventricular failure, - $1,798 for no complication and - $6,019 for death. Recognition of the influence of complications on charges suggests that low average charges can only be achieved by surgical programs with a low complication rate.