Kristopher L. Arheart

Low Circulating Folate and Vitamin B6 Concentrations Risk Factors for Stroke, Peripheral Vascular Disease, and Coronary Artery Disease

BACKGROUND A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis. METHODS In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. RESULTS In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 micromol/L) or after a methionine load (38.0 micromol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B6 below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B6 and atherosclerosis was independent of homocysteine levels both before and after methionine loading. CONCLUSIONS Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.

Prospective Study of Hyperhomocysteinemia as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease

BACKGROUND Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes. METHODS AND RESULTS In all, 167 patients (93 men, 74 women; mean age, 56.3+/-14.7 years) were followed for a mean duration of 17.4+/-6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0+/-48.6 versus 26.9+/-14.9 micromol/L, P=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per micromol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01). CONCLUSIONS These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per micromol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.

Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations

BACKGROUND A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease. METHODS AND RESULTS Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage

Bedside microcomputer-derived, minute-to-minute mean arterial pressure (MAP) values during the first 48 hours of life were studied in 100 preterm babies with birth weight less than or equal to 1500 gm. In those babies (n = 72) with no periventricular-intraventricular hemorrhage (PV-IVH) or with grade 1 PV-IVH, the MAP values increased during the study period, with minute-to-minute variation and interval undulation. The MAP values in those with birth weight greater than 1000 gm were higher than in those of lower birth weight. Infants in whom grades 2 to 4 PV-IVH developed (n = 28) had consistently lower MAP values during the study period. Minute-to-minute variability, expressed as the average of the coefficients of variation at 15-minute intervals, did not differ between birth weight groups, nor did they differ between the PV-IVH group and their matched control subjects. However, those with PV-IVH spent a greater percentage of time, with a coefficient of variation greater than or equal to 13% or less than 3%, than their matched control subjects spent (p less than 0.005). This study provides reference data for MAP changes in premature babies. The observed MAP changes in those with PV-IVH lend support to a significant role for MAP alterations in the pathogenesis of PV-IVH.

Cardioversion guided by transesophageal echocardiography: The ACUTE Pilot Study : A Randomized, controlled trial

A trial fibrillation is characterized by a lack of organized electrical and mechanical atrial activity that results in an irregular heartbeat and increased risks for congestive heart failure, thromboembolism, and death [1-3]. Since 1962, direct-current cardioversion has been used to restore sinus rhythm in patients with atrial fibrillation [4]. However, successful cardioversion, with the sudden resumption of sinus rhythm, is itself associated with an increased risk for embolic stroke, which can result when thrombi in the left atrial appendage are dislodged [5-12]. Transesophageal echocardiography (TEE) is an excellent method with which to detect thrombi in the left atrial appendage [13-19]. Its use has therefore been proposed as a way to allow cardioversion to be done earlier and more safely than would be possible with conventional therapy, which consists of a total of 7 weeks of treatment with warfarin [14-23]. Recent studies [15-19] indicate that TEE-guided cardioversion with short-term anticoagulation therapy may have several advantages over the conventional approach. These advantages include a decreased risk for embolism, which results from the avoidance of cardioversion in patients who have thrombi in the left atrial appendage [15]; a decreased risk for bleeding, which occurs because anticoagulation therapy can be briefer [19]; greater initial conversion to and long-term maintenance of sinus rhythm, which result from doing cardioversion earlier [18, 19]; and greater cost-effectiveness, which results from the decreased incidence of embolic stroke [17]. The ACUTE (Assessment of Cardioversion Using Transesophageal Echocardiography) Pilot Study was a multicenter, randomized clinical trial designed to compare TEE-guided cardioversion with conventional management of cardioversion in patients with atrial fibrillation who have cardioversion [19]. The study had two objectives: to assess the general feasibility of a TEE-guided approach to cardioversion and to determine the general safety of the TEE-guided approach by comparing its clinical outcome with those of conventional management. Methods Patient Selection Patients who were candidates for electrical cardioversion were eligible for inclusion if they had atrial fibrillation, or atrial flutter with a history of atrial fibrillation, lasting longer than 2 days. Patients were excluded if they had received anticoagulant therapy for more than 7 days, had required urgent cardioversion as a result of hemodynamic instability, had had a cardioembolic event within the previous month, had contraindications to TEE or warfarin, were women with childbearing potential in whom pregnancy could not be excluded, were unable to give informed consent, or were unable to return for a follow-up visit. Our study protocol was approved by the institutional review boards at all clinical sites, and all patients provided written informed consent in advance. Study Protocol Patients who met the inclusion criteria were randomly assigned to receive either a conventional or a TEE-guided approach to cardioversion. Randomization was done using presealed, opaque envelopes that were computer generated and distributed to each clinical site (Figure 1). Random assignments were stratified by site and were generated in blocks of six. Figure 1. The ACUTE (Assessment of Cardioversion Using Transesophageal Echocardiography) study protocol. The conventional approach to cardioversion was that recommended by the American College of Chest Physicians: 3 weeks of therapeutic warfarin therapy, then cardioversion, then 4 weeks of warfarin therapy, and then a follow-up examination at the end of the 4 weeks [23]. Prothrombin times were monitored regularly, and the target international normalized ratio (INR) was 2 to 3. If assigned to the TEE group, patients began receiving anticoagulation therapy at their initial visit. The goal was to have patients therapeutically anticoagulated (therapeutic anticoagulation was defined as a partial thromboplastin time 1.5 to 2.5 times control values or an INR of 2.0 to 3.0) at the time of and after the planned cardioversion, for a total of 4 weeks of therapy. The initial choice of antithrombotic agent was determined by whether the patient was an inpatient or an outpatient at the time of randomization: Heparin was used for inpatients; warfarin was administered to outpatients. Transesophageal echocardiography, with subsequent cardioversion within 24 hours, was then scheduled as soon as stable therapeutic anticoagulation was assured. For example, if a patient was hospitalized and intravenous heparin therapy was administered, TEE was done as soon as a stable therapeutic partial thromboplastin time could be documented (for 24 to 36 hours); subsequent cardioversion was done if the presence of a thrombus was excluded. A 4- to 5-day overlap of warfarin therapy and intravenous heparin therapy was often necessary to maintain adequate anticoagulation after cardioversion. If the patient was to be managed as an outpatient, warfarin therapy was initiated on the day of study enrollment, and TEE and subsequent possible cardioversion were scheduled for at least 5 to 7 days later. Again, cardioversion was done when the patient was therapeutically anticoagulated, and all patients received maintenance therapy with warfarin for 4 weeks after cardioversion [15]. In the TEE group, cardioversion was done immediately after or within 24 hours of TEE because of the potential for thrombus formation in the period between TEE and cardioversion. If thrombi were detected in the left or right atrial appendages or atrial cavities, cardioversion was postponed and the patient received warfarin therapy for 4 weeks. After 4 weeks, TEE was repeated and, if no thrombus was detected, cardioversion was done. If a thrombus was still present, another 4-week course of warfarin therapy was administered and cardioversion was not done [15]. Clinical Outcomes Our feasibility outcomes were frequency of cardioversion, frequency of cardioversion occurring as scheduled, time to cardioversion, and time to sinus rhythm. Our clinical safety outcomes were clinically apparent ischemic stroke, transient ischemic attack, systemic embolization, deaths related to cardioversion or episodes of bleeding, and detected episodes of clinical hemodynamic instability (worsening congestive heart failure or hypotension) that rendered the patient unable to complete the protocol. Other outcome variables were the prevalence of thrombi, the number of patients without thrombi who had early cardioversion, and the immediate and follow-up rhythms after cardioversion. These outcomes were assessed for as long as 4 weeks after cardioversion but for no longer than 8 weeks after randomization. In the patients who did not have cardioversion and who spontaneously reverted to sinus rhythm, the variables were assessed at 4 weeks after spontaneous reversion. Study Organization and Procedures The administrative organization of the pilot study is described in the Appendix. Echocardiographic Examination Conventional transthoracic echocardiography was done in both study groups using commercially available equipment. In the TEE group, TEE was done according to standard techniques using phased-array biplane or multiplane transducers [24-26]. Complete transesophageal echocardiographic examination was done, and special attention was paid to imaging the left and right atria and left and right atrial appendages to assess the presence or absence of thrombi and spontaneous echo contrast. Echocardiographic Data Analysis Two-dimensional directed M-mode transthoracic echocardiography was used to derive the left ventricular septal and posterior wall thicknesses and the end-diastolic, end-systolic, and left atrial dimensions. Ejection fraction was calculated using standard techniques [27, 28]. The maximal left atrial and right atrial areas were planimetered on-line, and the severity of mitral regurgitation was qualitatively graded from 0 to 4+ by using color-flow mapping [29]. A thrombus was considered to be present if a mass detected in the appendage or body of the atrium appeared to be distinct from the underlying endocardium, was not caused by pectinate muscles, and was detected in more than one imaging plane. The presence or absence of spontaneous echo contrast was analyzed and defined as dynamic intracavitary echoes with a characteristic swirling pattern distinct from artifact. The degree of spontaneous echo contrast was categorized independently as absent, mild, or severe [30, 31]. Quality Control Measures Standard definitions of echocardiographic measurements were available to all of the clinical centers as part of a pilot operations manual. Echocardiograms at each clinical center were interpreted locally by a single physician who was highly experienced in echocardiography. Videotapes that showed the results of the first five echocardiographic examinations and all videotapes that showed thrombi were forwarded from the clinical centers to a central laboratory and overread by three experienced reviewers for consensus [19]. Electrical Cardioversion Cardioversion was done by using the standard method of Lown and associates [4] with an initial energy of at least 40 J for atrial flutter and 200 J for atrial fibrillation. Statistical Analysis Summaries of clinical, echocardiographic, and outcome data are expressed as means or frequencies with 95% CIs. Data that were not normally distributed were log-transformed and presented as geometric means. Outcomes were compared for the TEE and conventional therapy groups, for patients with and without thrombus (in the TEE group only), and for patients in the TEE and conventional therapy groups who had cardioversion. These analyses were done using the t-test for independent groups for continuous variables and the Fisher exact test for categorical variables. StatXact (Cytel Software, Cambridge, Massachusetts) was used to compute binary CIs; SAS softwar

Antimicrobial therapy in expectant management of preterm premature rupture of the membranes

We review the impact of antimicrobial treatment on maternal and fetal outcome during expectant management of preterm premature rupture of the membranes. Relevant studies were retrieved from Medline (1966 to August, 1994) with the search term fetal-membrane-premature-rupture and antibiotics or antimicrobial, Excerpta Medica (1972 to August, 1994) with the search term premature fetus, membrane rupture, and antibiotic or antimicrobial therapy, and the Cochrane database of systemic reviews with the criterion antibiotics and prelabour rupture of membranes. We also obtained unpublished data from a randomised clinical trial of ceftizoxime versus placebo. The selected studies were randomised controlled trials of systemic antimicrobial therapy for prolongation of gestation in non-labouring women after preterm premature rupture of the membranes. Data extraction was done by a single reviewer. Studies were evaluated for post-randomisation exclusion and other confounding variables that might introduce analytical bias. Analysis was done with SAS statistical software by a blinded investigator. Antimicrobial therapy after preterm premature rupture of the membranes is associated with a reduced number of women delivering within 1 week (62 vs 76%; OR 0.51, 95% CI 0.41-0.68), and reduced diagnosis of maternal morbidity including chorioamnionitis (12 vs 23%; 0.45, 0.33-0.60) and postpartum infection (8 vs 12%; 0.63, 0.41-0.97). Fetal morbidity, including confirmed sepsis (5 vs 9%; 0.57, 0.36-0.88), pneumonia (1 vs 3%; 0.32, 0.11-0.96), and intraventricular haemorrhage (9 vs 14%; 0.65, 0.45-0.92) were less often diagnosed after antimicrobial therapy. Separate analysis of the six placebo-controlled trials revealed similar or improved odds of pregnancy prolongation, chorioamnionitis, neonatal sepsis, postpartum infection, positive infant blood cultures, and pneumonia. Antimicrobial therapy, when used in the expectant management of preterm premature rupture of the membranes is associated with prolongation of pregnancy and a reduction in the diagnosis of maternal and infant morbidity. Further study should be directed towards determination of optimal antimicrobial therapy, increasing pregnancy prolongation, and enhancement of corticosteroid therapy for induction of pulmonary maturity after preterm premature rupture of the membranes.

Mapping of brain metabolite distributions by volumetric proton MR spectroscopic imaging (MRSI).

Distributions of proton MR‐detected metabolites have been mapped throughout the brain in a group of normal subjects using a volumetric MR spectroscopic imaging (MRSI) acquisition with an interleaved water reference. Data were processed with intensity and spatial normalization to enable voxel‐based analysis methods to be applied across a group of subjects. Results demonstrate significant regional, tissue, and gender‐dependent variations of brain metabolite concentrations, and variations of these distributions with normal aging. The greatest alteration of metabolites with age was observed for white‐matter choline and creatine. An example of the utility of the normative metabolic reference information is then demonstrated for analysis of data acquired from a subject who suffered a traumatic brain injury. This study demonstrates the ability to obtain proton spectra from a wide region of the brain and to apply fully automated processing methods. The resultant data provide a normative reference for subsequent utilization for studies of brain injury and disease. Magn Reson Med, 2009.

Use of Exercise Echocardiography for Prognostic Evaluation of Patients With Known or Suspected Coronary Artery Disease

OBJECTIVES This study prospectively compared the incremental prognostic benefit of exercise echocardiography with that of exercise testing in a large cohort. BACKGROUND Exercise echocardiography is widely accepted as a diagnostic tool, but the prognostic information provided by this test, incremental to clinical and stress testing evaluation, is ill-defined. METHODS Clinical, exercise and echocardiographic variables were studied in a consecutive group of 500 patients undergoing exercise echocardiography. After exclusion of patients who underwent revascularization within 3 months of the stress test (n = 16, 3%) and those lost to follow-up (n = 21, 4%), the remaining 463 patients (mean [+/-SD] age 57 +/- 12 years, 302 men) were followed-up for 44 +/- 11 months. Outcome was related to the exercise and echocardiographic findings, and the incremental prognostic benefit of exercise echocardiography was compared with that of standard exercise testing. RESULTS Cardiac events occurred in 81 patients (17%), including 33 (7%) with spontaneous events (cardiac death, myocardial infarction and unstable angina) and 48 with late revascularizations due to progressive symptoms. In a multivariate Cox proportional hazards model, the likelihood of any cardiac event was increased in the presence of ischemia (relative risk [RR] 5.06, 95% confidence interval [CI] 3.09 to 8.29, p < 0.001) and lessened by more maximal stress, measured as percent age-predicted maximal heart rate (RR per 5% increment 0.84, 95% CI 0.77 to 0.92, p < 0.001). Spontaneous events were more strongly predicted by ischemia (RR 8.20, 95% CI 3.41 to 19.71, p < 0.001) and percent age-predicted maximal heart rate (RR per 5% increment 0.78, 95% CI 0.67 to 0.91, p < 0.001). An interactive logistic regression model showed that the addition of echocardiographic to exercise and clinical data offered incremental predictive value. CONCLUSIONS The presence of ischemia on the exercise echocardiogram can predict whether patients will experience an event. This relation is independent of, and incremental to, clinical and exercise data.

Left atrial appendage 'stunning' after electrical cardioversion of atrial flutter: An attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events

OBJECTIVES This study sought to determine whether left atrial appendage stunning occurs in patients with atrial flutter and to compare left atrial appendage function in the pericardioversion period with that in patients with atrial fibrillation. BACKGROUND Left atrial appendage stunning has recently been proposed as a key mechanistic phenomenon in the etiology of postcardioversion thromboembolic events in atrial fibrillation. Atrial flutter is thought to be associated with a negligible risk of thromboembolic events; therefore, anticoagulation is commonly withheld before and after cardioversion in these patients. METHODS Sixty-three patients with atrial flutter (n = 19) or atrial fibrillation (n = 44) underwent transesophageal echocardiography immediately before and after electrical cardioversion. In addition to assessing the presence of thrombus and spontaneous echo contrast, we measured left atrial appendage emptying velocity and calculated shear rates by pulsed wave Doppler and two-dimensional echocardiography. RESULTS Patients with atrial flutter exhibited greater left atrial appendage flow velocities before cardioversion than those with atrial fibrillation (42 +/- 19 vs. 28 +/- 15 cm/s [mean +/- SD], p < 0.001). Left atrial appendage shear rates were also higher in patients with atrial flutter (103 +/- 82 vs. 59 +/- 37 s-1, p < 0.001). After cardioversion, left atrial appendage flow velocities decreased compared with precardioversion values in patients with atrial fibrillation (28 +/- 15 before to 15 +/- 14 cm/s after cardioversion, p < 0.001) and atrial flutter (42 +/- 19 to 27 +/- 18 cm/s, respectively, p < 0.001). Shear rates decreased from 59 +/- 37 before cardioversion to 30 +/- 31 s-1 after cardioversion in atrial fibrillation (p < 0.001), and from 103 +/- 82 s to 65 +/- 52 s-1, respectively (p < 0.001), in atrial flutter. This decrease in flow velocity from before to after cardioversion occurred in 36 (82%) of 44 patients with atrial fibrillation and 14 (74%) of 19 with atrial flutter. The impaired left atrial appendage function after cardioversion was less pronounced in the group with atrial flutter (27 +/- 18 cm/s for atrial flutter vs. 15 +/- 14 cm/s for atrial fibrillation, p < 0.001). New or increased spontaneous echo contrast occurred in 22 (50%) of 44 patients with atrial fibrillation versus 4 (21%) of 19 with atrial flutter (p < 0.05). CONCLUSIONS Left atrial appendage stunning also occurs in patients with atrial flutter, although to a lesser degree than in those with atrial fibrillation. These data suggest that patients with atrial flutter are at risk for thromboembolic events after cardioversion, although this risk is most likely lower than that in patients with atrial fibrillation because of better preserved left atrial appendage function.

Conservation of residual acoustic hearing after cochlear implantation.

Objective: This study was designed to test the hypothesis that partial hearing conservation is attainable after cochlear implantation with a long perimodiolar electrode. Surgical strategies for hearing conservation during cochlear implantation are described. Study design: Prospective, single-subject, repeated-measures design. Setting: Academic tertiary care center. Patients: Twenty-eight severely to profoundly hearing-impaired adult cochlear implant recipients who had some measurable hearing preoperatively. Intervention: Cochlear implantation using Nucleus Freedom Contour Advance electrode. Main Outcome Measures: Preimplant and postimplant pure-tone thresholds and speech recognition scores were obtained to determine the incidence and degree of conserved hearing at a mean interval of 9 (±3.9) months. Results: Thirty-two percent of subjects experienced complete conservation of hearing (0- to 10-dB loss), and 57% experienced partial conservation of hearing (>11 dB) after implantation. However, open-set speech recognition was partially conserved in only one subject. Cochlear implant performance was not better in patients with conservation of residual hearing. Conclusion: Conservation of pure-tone hearing was possible in 89% of implanted patients; however, residual speech perception was not conserved with this long perimodiolar electrode. A ceiling effect tends to inflate the prevalence of hearing conservation in implantation studies of severely to profoundly hearing-impaired patients.