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BMJ open 11(6), e046160 (2021). doi:10.1136/bmjopen-2020-046160, Published by BMJ Publishing Group, London

Objective: To assess the association between exercise capacity and the risk of developing chronic kidney disease (CKD). Patients and Methods: Exercise capacity was assessed in 5812 male veterans (mean age, 58.4� 11.5 years) from the Veterans Affairs Medical Center, Washington, DC. Study participants had an estimated glomerular filtration rate of 60 mL/min per 1.73 m 2 or more 6 months before exercise testing and no evidence of CKD. Those who developed CKD during follow-up were initially identified by the International Classification of Diseases, Ninth Revision and further verified by at least 2 consecutive estimated glomerular filtration rate values of less than 60 mL/min per 1.73 m 2 3 months or more apart. Normal kidney function for CKD-free individuals was confirmed by sequential normal eGFR levels. We established 4 fitness categories on the basis of age-stratified quartiles of peak metabolic equivalents (METs) achieved: least-fit (� 25%; 4.8� 0.90 METs; n¼1258); low-fit (25.1%-50%; 6.5� 0.96 METs; n¼1614); moderate-fit (50.1%-75%; 7.7� 0.91 METs; n¼1958), and high-fi t( >75%; 9.5� 1.0 METs; n¼1436). Multivariable Cox proportional hazard models were used to assess the association between exercise capacity and CKD. Results: During a median follow-up period of 7.9 years, 1010 developed CKD (20.4/1000 person-years). Exercise capacity was inversely related to CKD incidence. The risk was 22% lower (hazard ratio, 0.78; 95% CI, 0.75-0.82; P

Background and objectives AKI is associated with major adverse kidney events (MAKE): death, new dialysis, and worsened renal function. CKD (arising from worsened renal function) is associated with a higher risk of major adverse cardiac events (MACE): myocardial infarction (MI), stroke, and heart failure. Therefore, the study hypothesis was that veterans who develop AKI during hospitalization for an MI would be at higher risk of subsequent MACE and MAKE. Design, setting, participants, & measurements Patients in the Veterans Affairs (VA) database who had a discharge diagnosis with International Classification of Diseases, Ninth Revision, code of 584.xx (AKI) or 410.xx (MI) and were admitted to a VA facility from October 1999 through December 2005 were selected for analysis. Three groups of patients were created on the basis of the index admission diagnosis and serum creatinine values: AKI, MI, or MI with AKI. Patients with mean baseline estimated GFR 2 were excluded. The primary outcomes assessed were mortality, MAKE, and MACE during the study period (maximum of 6 years). The combination of MAKE and MACE—major adverse renocardiovascular events (MARCE)—was also assessed. Results A total of 36,980 patients were available for analysis. Mean age±SD was 66.8±11.4 years. The most deaths occurred in the MI+AKI group (57.5%), and the fewest (32.3%) occurred in patients with an uncomplicated MI admission. In both the unadjusted and adjusted time-to-event analyses, patients with AKI and AKI+MI had worse MARCE outcomes than those who had MI alone (adjusted hazard ratios, 1.37 [95% confidence interval, 1.32 to 1.42] and 1.92 [1.86 to 1.99], respectively). Conclusions Veterans who develop AKI in the setting of MI have worse long-term outcomes than those with AKI or MI alone. Veterans with AKI alone have worse outcomes than those diagnosed with an MI in the absence of AKI.

Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘ c ' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘ c ' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD.

ObjectiveSocial support is considered an important resource in coping with chronic conditions. By conducting a series of interviews with people who suffer from inflammatory bowel disease (IBD), we received the impression that social support in face-to-face or online communication could also be a source of stress and strain. The aim of our study was to better understand and describe possible negative effects of social support.DesignThis is a secondary analysis of narrative interviews. The interviewees were selected using a maximum-variation sampling approach. Grounded theory and the ‘OSOP’ (one sheet of paper) method were applied to categorise those parts of the interviews that touched on the negative effects of social support.SettingThe open-end interview collection took place throughout Germany from September 2011 to June 2012. Most of the participants were interviewed in their homes, some in the Department of General Practice in Göttingen.Participants42 patients with IBD.ResultsTwo interrelated categories emerged: (1) unwanted confrontation and (2) undesirable reactions. The interviewees perceived social support as negative, especially if they felt overwhelmed and/or if they had not asked for it. Consequently, some of our interview partners developed strategies to prevent coming into social contact with others or stopped talking entirely about their disease.ConclusionWhile social support is usually conceptualised and perceived as a positive resource in chronic disease, it sometimes turns into a negative experience and may end in social isolation and deteriorate health. This process also happens in online support groups and increases anxiety when exchanging with other people on the internet. Before motivating ill people to seek contact with others, they should know about the negative effects of social support.

A higher proportion of patients initiate hemodialysis (HD) with an arteriovenous fistula (AVF) in countries with universal health care systems compared with the United States. Because federally sponsored national health care organizations in the United States, such as the Department of Veterans Affairs (DVA) and the Department of Defense (DoD), are similar to a universal health care model, we studied AVF use within these organizations. We used the US Renal Data System database to perform a cross-sectional analysis of patients who initiated HD between 2005 and 2006. Patients who received predialysis nephrology care had 10-fold greater odds of initiating dialysis with an AVF (adjusted odds ratio [aOR] 10.3; 95% confidence interval [CI] 9.6 to 11.1). DVA/DoD insurance also independently associated with initiating HD with an AVF (aOR 1.4; 95% CI 1.2 to 1.5). Fewer patients initiated HD at a DoD facility, but these patients were also approximately twice as likely to use an AVF (aOR 2.3; 95% CI 1.2 to 4.6). In conclusion, patients in DVA/DoD systems are significantly more likely to use an AVF at initiation of HD than patients with other insurance types, including Medicare. Further study of these federal systems may identify practices that could improve processes of care across health care systems to increase the number of patients who initiate HD with an AVF.

When patients develop acute kidney injury, a small fraction of them will develop end-stage renal disease later. The severity of renal impairment in the remaining patients is uncertain because studies have not carefully examined renal function over time or the precise timing of entry into a late stage of chronic kidney disease. To determine these factors, we used a United States Department of Veterans Affairs database to ascertain long-term renal function in 113,272 patients. Of these, 44,377 had established chronic kidney disease and were analyzed separately. A cohort of 63,491 patients was hospitalized for acute myocardial infarction or pneumonia and designated as controls. The remaining 5,404 patients had diagnostic codes indicating acute renal failure or acute tubular necrosis. Serum creatinine, estimated glomerular filtration rates, and dates of death over a 75-month period were followed. Renal function deteriorated over time in all groups, but with significantly greater severity in those who had acute renal failure and acute tubular necrosis compared to controls. Patients with acute kidney injury, especially those with acute tubular necrosis, were more likely than controls to enter stage 4 chronic kidney disease, but this entry time was similar to that of patients who initially had chronic kidney disease. The risk of death was elevated in those with acute kidney injury and chronic kidney disease compared to controls after accounting for covariates. We found that patients who had an episode of acute tubular necrosis were at high risk for the development of stage 4 disease and had a reduced survival time when compared to control patients.

Background Many patients with inflammatory bowel disease strongly believe that food or certain food products heavily influence the symptoms or even trigger acute flare-ups. Unfortunately, there is no generalizable information for these patients, and therefore no effective diet has been identified to date. Methods The narrative interviews we used for this study provide the basis for the German website www.krankheitserfahrungen.de. Maximum-variation sampling was used to include a broad range of experiences and a variety of different factors that might influence people’s experiences. The sample included men and women of different age groups and social and ethnic backgrounds from across Germany. The interviews were analyzed using grounded theory. Results Four interrelated categories emerged: managing uncertainty, eating: between craving and aversion, being different and professional help as a further source of uncertainty. The most important issue for our responders was the handling of uncertainty and to find a way between desire for, and aversion against, eating. Many participants described difficulties during formal social occasions such as weddings, birthdays, or when going out to a restaurant. Conclusions Many of the experiences the participants reported in their daily struggle with food and their illness, such as cravings for and abstaining from certain foods, were rather unusual and often stressful. Because they decided not to go out in public any longer, some of the interviewees experienced even more social isolation than they did before. Health professionals need to become more involved and not only advice about food and eating, but also help their patients find strategies for avoiding social isolation.

BACKGROUND: Many patients with inflammatory bowel disease strongly believe that food or certain food products heavily influence the symptoms or even trigger acute flare-ups. Unfortunately, there is no generalizable information for these patients, and therefore no effective diet has been identified to date. METHODS: The narrative interviews we used for this study provide the basis for the German website www.krankheitserfahrungen.de . Maximum-variation sampling was used to include a broad range of experiences and a variety of different factors that might influence people's experiences. The sample included men and women of different age groups and social and ethnic backgrounds from across Germany. The interviews were analyzed using grounded theory. RESULTS: Four interrelated categories emerged: managing uncertainty, eating: between craving and aversion, being different and professional help as a further source of uncertainty. The most important issue for our responders was the handling of uncertainty and to find a way between desire for, and aversion against, eating. Many participants described difficulties during formal social occasions such as weddings, birthdays, or when going out to a restaurant. CONCLUSIONS: Many of the experiences the participants reported in their daily struggle with food and their illness, such as cravings for and abstaining from certain foods, were rather unusual and often stressful. Because they decided not to go out in public any longer, some of the interviewees experienced even more social isolation than they did before. Health professionals need to become more involved and not only advice about food and eating, but also help their patients find strategies for avoiding social isolation. Open-Access-Publikationsfonds 2015 peerReviewed

Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha1-adrenoceptors (rho-TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi-MrIA and chi-MrIB from the mollusk-hunting C. marmoreus). rho-TIA and chi-MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.

In this paper, the authors developed and tested strategies for estimating myocardial blood flow (MBF) and generating MBF parametric images using positron emission tomography (PET), N-13 ammonia, and the generalized linear least square (GLLS) method. GLLS was generalized to the general linear compartment model, modified for the correction of spillover, validated using simulated N-13 ammonia data, and examined using PET data from several patient studies. In comparison to the standard model-fitting procedure, the GLLS method provided similar accuracy and superior computational speed.

Elevated levels of plasma lipoprotein(a) [Lp(a)] have frequently been associated with coronary artery disease (CAD). Recently Lp(a) was fractionated into two species with different affinities for Lysine-Sepharose. The influence of lysine-binding heterogeneity of Lp(a) on its cardiovascular pathogenicity has not previously been studied. The authors have determined plasma levels of total Lp(a), its lysine-binding [lys+] and unretained [lys-] species in 67 male CAD patients undergoing cardiac catheterization. Forty-three patients have severe CAD (two- or three-vessel disease) and 24 patients have less pronounced CAD (one-vessel disease or less than 50% narrowing of coronary vessels). All patients were ranked in order of their Lp(a) levels and then grouped into quartiles. The prevalence of severe CAD was significantly higher in the upper Lp(a) quartile as compared with the other three quartiles (odds ratio 10-5; chi-square 11.2; P = 0.0008). Similar results were obtained when the same analysis was carried out for [lys+] and [lys-] species of Lp(a) (odds ratio 11.52 and 3.3, respectively; chi-square 12.3 and 4.34, respectively; P = 0.0004 and 0.037, respectively). Thus, measurement of either species of Lp(a) does not provide any additional improvement in the prediction of CAD as compared to the estimation of total Lp(a) levels.

We examined the role of chronic (greater than 1 month) angina pectoris (AP) before acute myocardial infarction (AMI) in predicting hospital and long-term mortality rates among 4166 patients with first AMIs. The prevalence of AP in these patients was 43%. Chronic AP was more common in women (49%), patients with hypertension (49%), and diabetic patients (49%) than in men and counterparts free of the former conditions (p less than 0.005). In patients with AP the hospital course was more complicated and non-Q-wave AMI was more common than in counterparts without AP. In-hospital (16%), as well as 1 (8%)- and 5-year postdischarge (26%), mortality rates in hospital survivors were higher among patients with previous AP than in patients without previous AP (12%, 6%, and 19%, respectively) (p less than 0.01). After adjustment for age and all other predictors of increased hospital mortality rates in this cohort of patients, AP preceding AMI emerged as an independent predictor of increased hospital mortality rates (odds ratio 1.30; 90% confidence interval 1.10 to 1.53). For postdischarge mortality rates (mean follow-up 5 1/2 years), the covariate-adjusted relative risk of death in patients with AP was similar at 1.29 (p less than 0.0001; 90% confidence interval 1.16 to 1.44), according to estimation by Cox proportional hazards model. These data support the notion that preexisting AP identifies a group of patients at increased risk of death.

1. Prairie dog gallbladders mounted in a Ussing-type chamber and bathed with symmetrical Ringer's solutions exhibited a transepithelial resistance (Rt) of 51 +/- 5 omega cm2, a lumen negative potential difference (Vms) of 11.5 +/- 0.7 mV and a short-circuit current (Isc) of 6.9 +/- 0.3 microEq/hr/cm2. 2. Radioisotopic ion flux experiments revealed that the basal Isc of 6.9 +/- 0.3 microEq/hr/cm2 was mostly accounted for by net Na+ absorption of 3.2 +/- 0.5 microEq/hr/cm2 and net Cl- secretion of 2.9 +/- 0.3 microEq/hr/cm2. 3. In HCO3- free Ringer's, net Na+ flux was virtually abolished, net Cl- flux decreased by 50% and Isc was reduced by 77%. 4. 10(-3) M mucosal amiloride and DIDS reduced Isc by 28 and 24%, respectively. 5. Mucosal NaCl diffusion potentials indicated that the paracellular pathway was cation selective. 6. Thin section electron micrographs showed a single cell population in this epithelium suggesting that net Na+ absorption and Cl- secretion may emerge from the same cells. 7. We conclude that prairie dog gallbladder epithelium is an electrogenic tissue and, in contrast to gallbladders of most other species, simultaneously but independently absorbs Na+ and secretes Cl-.

The efficiency of bopindolol (B) in the treatment of moderate stable angina pectoris was compared with that of diltiazem (D) by clinical evaluation and exercise tolerance. Following washout of previous treatment, patients were randomly assigned to either medication: 16 to D and 15 to B. The initial dose of B was 1 mg once daily, increased after 4 weeks to 2 mg once daily; the respective doses of D were 120 and 240 mg, given in 4 divided doses. Therapy resulted in an average decrease of 22 pain episodes and 256 min of pain time per month in the B group, whereas the respective reductions in the D group were 1.65 episodes and 129 min. Improvement in the exercise test indices following 8 weeks of treatment was more marked in the B group than in the D group. The average double product at peak exercise decreased markedly in the B group and more moderately in the D group. Thus, 2 mg B given once daily effectively blocked B receptors and relieved angina more efficiently than 240 mg D given in 4 divided doses.

Glomerular mesangial cells require Cl ions for the development of a variety of metabolic and functional properties. In the present study the electrochemical distribution for Cl- was examined in cultured rat mesangial cells with Cl--sensitive intracellular microelectrodes. It was determined that the intracellular Cl activity exceeded the levels predicted for a passively distributed ion. This was further substantiated by exposing mesangial cells to 10-5M bumetanide which drove intracellular Cl to a value close to electrochemical equilibrium. We conclude that Cl accumulates in mesangial cells, against its electrochemical gradient, through a transport pathway that is highly sensitive to bumetanide.

Xen2174 is a structural analogue of Mr1A, a chi-conopeptide recently isolated from the venom of the marine cone snail, Conus marmoreus. Although both chi-conopeptides are highly selective inhibitors of the norepinephrine transporter (NET), Xen2174 has superior chemical stability relative to Mr1A. It is well-known that tricyclic antidepressants (TCAs) are also potent NET inhibitors, but their poor selectivity relative to other monoamine transporters and various G-protein-coupled receptors, results in dose-limiting side-effects in vivo. As TCAs and the alpha(2)-adrenoceptor agonist, clonidine, have established efficacy for the relief of neuropathic pain, this study examined whether intrathecal (i.t.) Xen2174 alleviated mechanical allodynia in rats with either a chronic constriction injury of the sciatic nerve (CCI-rats) or an L5/L6 spinal-nerve injury. The anti-allodynic responses of i.t. Mr1A and i.t. morphine were also investigated in CCI-rats. Paw withdrawal thresholds were assessed using calibrated von Frey filaments. Bolus doses of i.t. Xen2174 produced dose-dependent relief of mechanical allodynia in CCI-rats and in spinal nerve-ligated rats. Dose-dependent anti-allodynic effects were also produced by i.t. bolus doses of Mr1A and morphine in CCI-rats, but a pronounced 'ceiling' effect was observed for i.t. morphine. The side-effect profiles were mild for both chi-conopeptides with an absence of sedation. Confirming the noradrenergic mechanism of action, i.t. co-administration of yohimbine (100 nmol) with Xen2174 (10 nmol) abolished Xen2174s anti-allodynic actions. Xen2174 appears to be a promising candidate for development as a novel therapeutic for i.t. administration to patients with persistent neuropathic pain.

A peptide contained in the venom of the predatory marine snail Conus tulipa, rho-TIA, has previously been shown to possess alpha1-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, rho-TIA inhibited alpha1-adrenoreceptor-mediated increases in cytosolic Ca2+ concentration that were triggered by norepinephrine, but did not affect presynaptic alpha2-adrenoreceptor-mediated responses. In radioligand binding assays using [125I]HEAT, rho-TIA displayed slightly greater potency at the alpha 1B than at the alpha 1A or alpha 1D subtypes. Moreover, although it did not affect the rate of association for [3H]prazosin binding to the alpha 1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by rho-TIA. N-terminally truncated analogs of rho-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of rho-TIA (Arg4). An alanine walk of rho-TIA confirmed the importance of Arg4 for activity and revealed a number of other residues clustered around Arg4 that contribute to the potency of rho-TIA. The unique allosteric antagonism of rho-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive alpha1-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective.

Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides stable plasma concentrations over the entire 24 h dosing interval. Two-hundred and one patients with Canadian Cardiovascular Society class II to III angina who were on 50 mg of atenolol yet still experiencing angina symptoms were randomized to receive either placebo or nifedipine GITS 30, 60 or 90 mg/day. After four weeks of treatment, the changes in time from baseline to onset of 1 mm ST segment depression in the 183 eligible patients were 26.7+/-10.2 s, 40.9+/-11.3 s, 63.2+/-12.9 s and 70.3+/-12.6 for the placebo, and 30, 60 and 90 mg/day groups, respectively. These differences were significant (P0.05) for the 60 and 90 mg/day groups compared with placebo and for the 60 mg/day group compared with the 30 mg/day group. The times to onset of pain and termination of exercise showed similar prolongation but did not achieve statistical significance. During the one-year open label phase of the study, patients exhibited statistically significant improvements in the time to onset of ST segment depression, time to anginal pain and time to termination of exercise at a mean dose of 52.3 mg/day of nifedipine GITS. Adverse events were primarily vasodilatory in nature. This study supports the use of nifedipine GITS in patients with chronic stable angina inadequately controlled on beta-blocker alone.

The response of cells to mechanical forces depends on the rheological properties of their membranes and cytoplasm. To characterize those properties, mechanical and electrical responses to swelling were measured in rat mesangial cells (MC) using electrophysiologic and video microscopic techniques. Ion transport rates during hyposmotic exposures were measured with whole-cell recording electrodes. Results showed that cell swelling varied nonlinearly with positive internal pressure, consistent with a viscoelastic cytoplasm. The extrapolated area expansivity modulus for small deformations was estimated to be 450 dyne/cm. Cell swelling, caused either by positive pipet pressure or hyposmotic exposure (40–60 mOsm Kg−1), rapidly induced an outwardly rectifying membrane conductance with an outward magnitude 4–5 times the baseline conductance of 0.9±0.5 nS (p

Several functions of mesangial cells, such as contraction and release of nitric oxide, are dependent on the ambient Cl- concentration. Herein we describe a direct effect of Cl- on mesangial cell membrane conductance. Rat mesangial cells were isolated, cultured, and were patch-clamped in the whole-cell configuration. The external concentration - ([Cl-]o) - of standard Ringer's solutions was changed isotonically from standard of 160 mM to 35 mM while cell membrane conductance was continuously recorded. Results indicated that control I-V curves of the steady state current had a linear slope conductance of 0.95 nS (n = 10, r = 0.9). In low [Cl-]o, conductance outwardly rectified and increased to 4.1 nS between -120 and 0 mV and to 16.8 nS between 0 and 40 mV (n = 10, r = 0.9; p0.01). The increase in conductance occurred within a few seconds and was reversible. Our results show that a large mesangial cell membrane conductance for cations is activated upon exposure to low [Cl-]o.

Objectives: Oxidative modifications of low-density lipoproteins (LDL) are considered to be important in the pathogenesis of atherosclerosis. However, the data on the association between LDL oxidation and severity of clinical manifestations of coronary artery disease (CAD) are contradictory. Previous reports were concerned mostly with unstable angina patients. The present study was undertaken to evaluate plasma lipid oxidation status in patients with stable CAD. Design and Methods: 37 male patients with angiographically confirmed CAD (asymptomatic or suffering from stable angina pectoris) and 32 control subjects were used in the study. Plasma levels of vitamin E and products of lipid peroxidation, as well as parameters of the test for oxidizability of LDL in vitro were measured. Results: We did not find differences between 2 groups of individuals regarding the levels of products of lipid peroxidation, vitamin E levels, lag time, maximal rate of oxidation, and total amount of conjugated dienes in the test for oxidizability of LDL. Conclusion: The results of our study challenge, but do not disprove, the oxidative hypothesis of atherosclerosis. Real atherosclerotic modifications of plasma LDL occur apparently in the vascular wall after trapping of LDL by the interstitial matrix. The rise in oxidative parameters in unstable angina reported in the literature may not be the cause of the disease but, rather, the consequence of the multiple brief episodes of ischemia-reperfusion.

Objective, design and patients Between August 1981 and July 1983, 5839 consecutive myocardial infarction patients were hospitalized in 13 coronary care units in Israel. The present study examines 10 year survival among 4037 consecutive patients with a first myocardial infarction with either Q or non-Q waves. Demographic and medical data were collected from hospital records, and 1 year clinical follow-up was complete for 99% of hospital survivors. Mortality follow-up was extended to June 1992 (mean 10 years of follow-up). Results Five hundred and eighty patients (14%) had first myocardial infarctions of the non-Q wave type and 3457 of the Q wave type. Hospital mortality was significantly higher in patients with a Q wave (l0%) than those with a non-Q wave myocardial infarction (7%) ( P

Objectives. This study sought to establish the risk ratio for mortality associated with calcium antagonists in a large population of patients with chronic coronary artery disease. Background. Recent reports have suggested that the use of short-acting nifedipine may cause an increase in overall mortality in patients with coronary artery disease and that a similar effect may be produced by other calcium antagonists, in particular those of the dihydropyridine type. Methods. Mortality data were obtained for 11,575 patients screened for the Bezafibrate Infarction Prevention study (5,843 with and 5,732 without calcium antagonists) after a mean follow-up period of 3.2 years. Results. There were 495 deaths (8.5%) in the calcium antagonist group compared with 410 in the control group (7.2%). The age-adjusted risk ratio for mortality was 1.08 (95% confidence interval [CI] 0.95 to 1.24). After adjustment for the differences between the groups in age and gender and the prevalence of previous myocardial infarction, angina pectoris, hypertension, New York Heart Association functional class, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes and current smoking, the adjusted risk ratio declined to 0.97 (95% CI 0.84 to 1.11). After further adjustment for concomintant medication, the risk ratio was estimated at 0.94 (95% CI 0.82 to 1.08). Conclusions. The current analysis does not support the claim that calcium antagonist therapy in patients with chronic coronary artery disease, whether myocardial infarction survivors or others, harbors an increased risk of mortality.

Mechanical stimulation of mesangial cells enhances expression of early response protooncogenes is an extracellular Ca2+-dependent manner. This has lead investigators to postulate that a mechanosensitive Ca2+ channel may exist in these cells. At the present time, however, very little is known about single channel Ca2+ currents in mesangial cells. To examine this question, cell-attached patches of rat mesangial cells in early passages were studied with 100 mM BaCl 2 patch-clamp pipets. Our studies identified a 21 pS, Co2+-sensitive channel that responded with an increase in open probability to mechanical stretch, applied through the patch pipet. The channel was also activated by a reduction in extracellular osmolarity. In both instances, channel responses underwent spontaneous adaptation despite continuous stimulation. This Ca2+ channel exhibited electrophysiological and kinetic properties that distinguished it from other cation-selective channels previously reported by us and other investigators on rat mesangial cell membranes.

Earlier studies have suggested that patients exhibiting late (> 24 h) ventricular fibrillation during acute myocardial infarction had a poorer outcome in comparison to myocardial infarction patients with early (< 24 h) ventricular fibrillation. Between August 1981 and July 1983, 5839 consecutive patients with acute myocardial infarction were hospitalized in 13 out of 21 operating coronary care units in Israel. Demographic and medical data were collected from hospitalization charts and during 1 year of follow-up. Mortality assessment was done for 99% of hospital survivors up to mid-1988 (mean, 5.5 years). The incidence of ventricular fibrillation in the SPRINT Registry was 6% (371/5839). Patients with ventricular fibrillation in the setting of cardiogenic shock (n = 107) were excluded from analysis. Patients with late ventricular fibrillation (n = 109; 41%) were older and had a more complicated hospital course than patients with early ventricular fibrillation (n = 155; 59%). In-hospital and 1-year post-discharge mortality were significantly higher in patients with late ventricular fibrillation (63% and 17%) as compared to patients with early ventricular fibrillation (26% and 4%, respectively; P < 0.05 for each). This difference vanished 5 years after hospital discharge. After multiple logistic regression analysis late occurrence of ventricular fibrillation emerged as an independent predictor of increased in-hospital mortality (Odds ratio, 4.29; 95% confidence interval, 2.11-8.74) but not for subsequent death. Patients with late ventricular fibrillation during the hospital course of acute myocardial infarction had a poorer immediate and subsequent outcome in comparison to patients with early ventricular fibrillation.

Of 3,981 patients with a first Q-wave acute myocardial infarction (AMI), 1,929 (48%) had an anterior and 1,724 (43%) an inferior wall AMI. These 2 groups were well-matched with respect to age, gender and relevant history. The in-hospital mortality rate was 18%, and the 1- and 5-year post-discharge mortality rates were 9 and 25%, respectively, in patients with anterior wall AMI compared with the corresponding rates of 11, 6 and 19% in those with inferior wall AMI (p0.0001 for each category). The frequency of recurrent nonfatal AMI in the year after the index AMI was 8% in the patients with anterior wall AMI compared with 4% in those with inferior wall AMI (p0.0001). By multiple logistic regression analysis of events, anterior wall AMI was an independent predictor of in-hospital mortality only. The findings indicate that the anatomic location of a Q-wave AMI influences immediate and short-term survival of patients with a first Q-wave AMI.

Controlled clinical trials have demonstrated the efficacy of reducing the blood levels of low-density lipoprotein cholesterol in reducing the incidence of coronary artery disease in hypercholesterolemic middle-aged men. However, a similar reversibility of the risk of coronary artery disease has not been demonstrated for high-density lipoprotein cholesterol elevation and triglyceride reduction. Therefore, the effect of administering 400 mg of bezafibrate retard daily versus placebo (double blind) to patients with myocardial infarction preceding randomization by 6 months to 5 years, or a clinically manifest anginal syndrome documented by objective evidence of dynamic myocardial ischemia, or both, is being investigated. Three thousand subjects (aged 45 to 74 years) are being enrolled from 19 cardiac departments in Israel, with total serum cholesterol between 180 and 250 mg/dl, high-density lipoprotein cholesterolor = 45 mg/dl and triglyceridesor = 300 mg/dl. In addition, low-density lipoprotein cholesterol concentrations are required to beor = 180 mg/dl (or = 160 mg/dl for patients aged50 years). Patients needing lipid-modifying therapy, exhibitingor = 1 prespecified exclusion criterion or not giving informed consent, or a combination, are not randomized. The primary end points for evaluating efficacy are the incidence of fatal and nonfatal myocardial infarction, and sudden death. The hypothesized effect of bezafibrate administration under the aforementioned protocol is to reduce an estimated cumulative end point event incidence ofor = 15% by 20 to 25% over an average follow-up period of 6.25 years, through early 1998, when the last patient recruited will have completed 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Among 4,720 consecutive hospital survivors from acute myocardial infarction (AMI) treated in 13 coronary care units between July 1981 and August 1983, the estimated prevalence of electrocardiographic left ventricular (LV) hypertrophy was 6.1%. The prevalence of electrocardiographic LV hypertrophy increased with age and was higher in patients with previous myocardial infarction, angina and systemic hypertension. Mean age of patients with electrocardiographic LV hypertrophy was 67.2 vs 61.4 years in counterparts free of electrocardiographic LV hypertrophy. Patients with electrocardiographic LV hypertrophy had a higher rate of congestive heart failure on admission, or developing during their stay in coronary care units. The 1- and 5-year mortality rates were 19.7 and 46.6% among patients with electrocardiographic LV hypertrophy versus 8.7 and 26.2%, respectively (p less than 0.001) in patients without this finding. The covariate-adjusted odds ratio of 1-year mortality was 1.88 for the presence of electrocardiographic LV hypertrophy when age alone was adjusted for, and 1.51 (90% confidence interval, 1.09 to 2.10) when multiple covariate adjustment was undertaken. After multiple covariate adjustment for 5-year mortality after discharge, the relative risk associated with electrocardiographic LV hypertrophy was 1.51 (90% confidence interval, 1.26 to 1.80). The results of the present study showed that the presence of electrocardiographic LV hypertrophy on the discharge electrocardiogram of survivors from AMI is associated with a 1.5-fold increase of short- and long-term mortality. Patients with electrocardiographic LV hypertrophy, potentially at an increased post-discharge risk, may be candidates for early noninvasive testing and more intensive follow-up after recovering from AMI.

Thrombolysis is now generally accepted as the initial treatment for patients with acute myocardial infarction (AMI). The extent to which this therapy is implemented in daily practice and the reasons for exclusion from thrombolytic therapy among 413 consecutive patients with AMI hospitalized in 18 coronary care units in Israel during a 1-month survey were prospectively investigated. Thrombolytic therapy administered to 145 patients (35%) was given to 38% of men versus 29% of women (p = not significant), to 38% of patients less than 75 years old compared with 18% of the very elderly (p less than 0.005), and more often to patients with a first or anterior AMI (40 and 48%) than to counterparts with recurrent or inferior AMI (23 and 31%, respectively, p less than 0.005 for both). The 2 most frequent reasons for excluding patients from thrombolysis were late arrivals to coronary care units (33%) and lack of ST elevation on the admission electrocardiogram (28%). Hospital mortality was 6% in the thrombolytic group versus 20% in patients found ineligible for thrombolysis. The significance of this difference is not clear as treatment was not randomized.

The purpose of this study was to report the incidence, the antecedents, and the clinical significance of clinically recognized cerebrovascular accidents or transient ischemic attacks (CVA-TIA) complicating acute myocardial infarction.During 1981 to 1983, a secondary prevention study with nifedipine (SPRINT) was conducted in 14 hospitals in Israel among 2,276 survivors of acute myocardial infarction. During the study, demographic, historical, and medical data were collected on special forms for all patients with diagnosed acute myocardial infarction in 13 of these 14 hospitals (the SPRINT registry, n = 5,839). Mortality follow-up was completed for 99% of hospital survivors for a mean follow-up of 5.5 years (range: 4.5 to 7 years).The incidence of CVA-TIA was 0.9% (54 of 5,839). The latter rate increased significantly only with age, from 0.4% among patients up to 59 years old to 1.6% among those aged greater than or equal to 70 years. Multivariate analysis identified age, congestive heart failure, and history of stroke as predictors of CVA-TIA during the acute phase of myocardial infarction. Patients with CVA-TIA exhibited a complicated hospital course, with a 15-day mortality rate of 41%. Subsequent mortality rates in survivors at 1 and 5 years were 34% and 59%, respectively. Rates at the same time points in patients without CVA-TIA were 16%, 11%, and 29% (p less than 0.01). In a multivariate analysis that included age, gender, congestive heart failure, history of previous myocardial infarction, and hypertension, CVA-TIA was independently associated with increased 15-day mortality (covariate-adjusted odds ratio [OR] = 2.62; 90% confidence interval [CI], 1.59 to 4.32), as well as subsequent 1-year (OR = 3.29; 90% CI, 1.70 to 6.36) and long-term (mean follow-up = 5.5 years) mortality (OR = 2.46; 90% CI, 1.30 to 4.69).In this large cohort of consecutive patients with myocardial infarction, CVA-TIA was a relatively infrequent complication of acute myocardial infarction. Factors independently favoring the occurrence of CVA-TIA were old age, previous CVA, and congestive heart failure. CVA-TIA occurring during acute myocardial infarction independently increased the risk of early death threefold as well as the risk of long-term mortality in early-phase survivors. (2.5-fold).

Polymorphous ventricular tachycardia (VT) is thought to be uncommon in acute coronary heart disease, but its prevalence has not been determined. Seven hundred seventy-one consecutive patients admitted with acute myocardial infarction (MI) were reviewed for the occurrence of this arrhythmia. Nine patients (1.2%) had polymorphous VT. No patient had any of the predisposing factors previously associated with polymorphous VT. The arrhythmia was resistant to multiple drugs, and repeated cardioversion was effective in only 3 patients. Overdrive pacing was ineffective in the 3 patients in whom it was attempted. Verapamil was effective in 3 of 4 patients in whom it was tried. Six patients with polymorphous VT died during hospitalization; the remaining 3 died within 6 months of discharge. It is concluded that, when compared with regular VT, polymorphous VT in MI carries a poor prognosis. When the arrhythmia occurs in the context of acute ischemia, it appears to be more difficult to treat compared with its occurrence due to other predisposing factors. Verapamil, not usually indicated for ventricular arrhythmias, should be tested in a therapeutic trial.

A family with sinus node disease is presented. The mother was severely affected by sinus bradycardia and required a permanent atrial pacing system. The father is asymptomatic and has no evidence of conduction disturbances. All their offspring (one son and two daughters) are affected with variable degrees of severity. The occurrence of the disease in this family is suggestive of autosomal dominant inheritance with variable penetrance.

Multiple anomalies of persistent left superior vena cava and left hepatic vein emptying into the left atrium associated with atrial septal defect, right aortic arch and multiple skeletal malformations are presented. The anatomy and the embryology of these anomalous venous connections are briefly reviewed. Clinical, hemodynamic and surgical implications of these anomalies are discussed.

A 56-year-old man with the Wolf-Parkinson-White (WPW) syndrome (type A) is described. His presenting signs were paroxysmal atrial tachycardia and fibrillation induced by swallowing. This supraventricular tachyarrhythmia (SVT) could be abolished by performing the valsalva maneuver or carotid stimulation, and prevented only by treatment with amiodarone.

Two patients suffered respiratory arrest and cardiac standstill immediately following the administration of an intravenous bolus of lidocaine. In one case, lidocaine was administered directly into the superior vena cava and in the other directly into a pulmonary artery. Cardiorespiratory arrest was assumed to have occurred secondary to toxic levels of lidocaine achieved in brain tissue using these routes of administration. We emphasize the hazards of injecting lidocaine directly into the central blood pool.

We describe a patient with hypertrophic cardiomyopathy who experienced several episodes of syncopal attacks, in whom the mechanism was transient electromechanical dissociation.

Recent studies indicate that biliary lipids influence in vivo gallbladder absorption and solute-coupled water flow. To clarify the electrophysiologic effects that underlie this phenomenon, prairie dog gallbladders were mounted in an Ussing-type chamber, and the influence of bile acids and varying ratios of bile acids and biliary phospholipids on transepithelial potential difference (Vms), resistance (Rt), and short-circuit current (Isc) was examined. Exposure to 5 mmol/L taurodeoxycholate (TDC) resulted in inhibition of Vms (p less than 0.01) and Isc (p less than 0.01) and an increase (p less than 0.05) in Rt. Subsequent perfusion with bile acids and phospholipids (5 mmol/L TDC + 0.3 mmol/L phosphatidylcholine [PC]) led to continued inhibition of ion transport. In contrast, exposure to 5 mmol/L TDC + 1.7 mmol/L PC resulted in a significant increase in transport, as manifested by an increase in Vms (p less than 0.02) and Isc (p less than 0.01) and a decrease in Rt (p less than 0.05) compared with bile acids. These results indicate that the ratio of phospholipids to bile salts modulates ion transport across prairie dog gallbladder and that this ratio may be an important determinant of gallbladder absorption in health and disease.

We describe eight patients treated for angina with prenylamine who developed life-threatening ventricular arrhythmias after QT interval prolongation. When prenylamine administration was stopped QT interval shortened to within normal values, while the ventricular arrhythmias were controlled by a temporary ventricular pacemaker and disappeared after several days. We stress the importance of surveillance of the QT interval and ventricular arrhythmias in patients receiving long-term treatment with prenylamine.

R wave amplitude changes during stress testing were validated in 12 ischemic patients with normal coronary angiograms. The data were compared with findings obtained from 10 patients with clinical and angiographic evidence of coronary arterial disease and 10 normal controls. An abnormal R wave amplitude response occurred in 83.3% of the group with normal coronary angiography, in 80% of the group of patients with clinical and angiographic evidence of coronary arterial disease, and in only 10% of the control group. The similarity of R wave amplitude changes in the first two group suggests that these changes are related to ischemia. If so, then R wave amplitude response to exercise could be of value in the electrocardiographic diagnosis of ischemia in patients with angiographically normal coronary arteries.

SUMMARY Thyroid hormones and cortisol levels were serially measured over seven mornings and evenings in 23 consecutive patients with acute myocardial infarction (AMI) or acute coronary insufficiency (ACI). The patients were divided into two groups, high level cortisol (HLC) and low level cortisol (LLC) groups, according to mean morning and evening cortisol levels. The transient increase in plasma rT3, decrease in T3 and TSH was significantly greater in the HLC group. A diurnal variation in cortisol levels was observed in the LLC group 48 h and in the HLC group 72 h after admission. Taking the 23 patients together, no significant correlation was observed between infarct size (peak CPK levels) and the altered rT3, T4 or TSH levels. However, a significant correlation was obtained between the maximal change in T3, rT3 or TSH and the mean cortisol levels preceding these alterations, as well as between cortisol levels and infarct size. It is suggested that cortisol rather than infarct size may be the dominant factor involved in the alteration of thyroidal levels in AMI patients.