Ernest V. Gervino

The human metabolic response to chronic ketosis without caloric restriction: Preservation of submaximal exercise capability with reduced carbohydrate oxidation

To study the effect of chronic ketosis on exercise performance in endurance-trained humans, five well-trained cyclists were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g protein/kg/d and the remainder of kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD), isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented to meet the recommended daily allowances for vitamins and minerals. Pedal ergometer testing of maximal oxygen uptake (VO2max) was unchanged between the control week (EBD-1) and week 3 of the ketogenic diet (EKD-3). The mean ergometer endurance time for continuous exercise to exhaustion (ENDUR) at 62%-64% of VO2max was 147 minutes at EBD-1 and 151 minutes at EKD-4. The ENDUR steady-state RQ dropped from 0.83 to 0.72 (P less than 0.01) from EBD-1 to EKD-4. In agreement with this were a three-fold drop in glucose oxidation (from 15.1 to 5.1 mg/kg/min, P less than 0.05) and a four-fold reduction in muscle glycogen use (0.61 to 0.13 mmol/kg/min, P less than 0.01). Neither clinical nor biochemical evidence of hypoglycemia was observed during ENDUR at EKD-4. These results indicate that aerobic endurance exercise by well-trained cyclists was not compromised by four weeks of ketosis. This was accomplished by a dramatic physiologic adaptation that conserved limited carbohydrate stores (both glucose and muscle glycogen) and made fat the predominant muscle substrate at this submaximal power level.

American College of Cardiology/American Heart Association Clinical Competence statement on stress testing: a report of the American College of Cardiology/American Heart Association/American College of Physicians--American Society of Internal Medicine Task Force on Clinical Competence.

The granting of clinical staff privileges is one of the primary mechanisms used by institutions to uphold the quality of care. The Joint Commission on Accreditation of Healthcare Organizations requires that the granting of initial or continuing medical staff privileges be based on assessment of applicants against professional criteria specified in medical staff bylaws. Physicians and other healthcare providers are thus charged with identifying the criteria that constitute professional competence and with evaluating their peers accordingly. The process of evaluating clinical knowledge and competence is often constrained by the evaluator’s own knowledge and ability to elicit the appropriate information, a problem that is compounded by the growing number of highly specialized procedures for which privileges are requested. The American College of Cardiology (ACC)/American Heart Association (AHA)/American College of Physicians–American Society of Internal Medicine (ACP-ASIM) Task Force on Clinical Competence was formed in 1998 to develop recommendations to attain and maintain the cognitive and technical skills necessary for the competent performance of a specific cardiovascular service, procedure, or technology. These documents are evidence based, and where evidence is not available, expert opinion is called upon to formulate recommendations. Indications and contraindications for specific services or procedures are not included in the scope of these documents. Recommendations are intended to assist those who must judge the competence of cardiovascular healthcare providers entering practice for the first time and/or those who are in practice and undergo periodic review of their practice expertise. Because the assessment of competence is complex and multidimensional, isolated recommendations contained herein may not necessarily be sufficient or appropriate for judging overall competence. Board specialty certification is not a required part of these recommendations but is another measure of expertise. This statement is a revision and extension of the previous ACP/ACC/AHA Task Force Statement on Clinical Competence in Exercise Testing. …

Catecholamine Modulation of Rapid Potassium Shifts during Exercise

Plasma potassium rises during muscular exercise and falls rapidly when exercise is stopped. Since the sympathoadrenal system is stimulated with exertion and both alpha- and beta-adrenergic agonists affect internal potassium homeostasis, we studied the influence of catecholamines on potassium shifts during and after exercise. Six healthy subjects were given maximal exercise stress tests under three conditions: with no medication (control), during beta-blockade with propranolol, and during alpha-blockade with phentolamine. Compared with a peak rise in plasma potassium of 1.23 +/- 0.27 mmol per liter (mean +/- S.E.M.) during the control study, propranolol caused a rise of 1.89 +/- 0.35 (P less than 0.01) and a sustained elevation during recovery. Phentolamine diminished the rise of potassium (0.70 +/- 0.21 mmol per liter; P less than 0.01) and lowered the potassium level throughout recovery. These effects of catecholamines were independent of the venous pH, the plasma bicarbonate and serum glucose levels, and urinary potassium excretion, and they did not appear to be due to insulin. High norepinephrine and epinephrine levels confirmed the release of catecholamines capable of stimulating alpha- and beta-receptors. Exercise work did not differ among the groups. beta-Adrenergic receptors appear to moderate the acute hyperkalemia of exercise, whereas alpha-adrenergic receptors act to enhance hyperkalemia and may protect against hypokalemia when exertion ceases.

Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

CONTEXT A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. OBJECTIVE To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. DESIGN, SETTING, AND PARTICIPANTS (1) Case-control study of 734 type 2 diabetes patients (322 with angiographically diagnosed CAD and 412 with no evidence of CAD) who were recruited between 2001 and 2006 at the Joslin Clinic, Beth Israel Deaconess Medical Center; and (2) independent cohort study of 475 type 2 diabetes patients from the Joslin Clinic whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004. Participants for both studies were genotyped for a representative single-nucleotide polymorphism at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A(1c) (HbA(1c)) measurements taken in the years before study entry. MAIN OUTCOME MEASURES For the case-control study, association between single-nucleotide polymorphism rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof was assessed and for the cohort study, cumulative 10-year mortality was documented. RESULTS Individuals who were homozygous for the risk allele were significantly more frequent among case than control participants (42.3% vs 28.9P = .0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted P for interaction = .048) in the presence of poor glycemic control (worst tertile of the distribution of HbA(1c) at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD odds for participants having 2 risk alleles but not poor glycemic control were increased 2-fold (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.17-3.41), whereas the odds for study participants with the same genotype and with poor glycemic control were increased 4-fold (OR, 4.27; 95% CI, 2.26-8.01). The interaction was stronger (adjusted P = .005) when a measure of long-term glycemic control (7-year average rather than most recent HbA(1c)) was used with ORs of 7.83 (95% CI, 3.49-17.6) for participants having 2 risk alleles and a history of poor glycemia and 1.54 (95% CI, 0.72-3.30) for participants with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with 2 risk alleles and poor glycemic control, 23.1% in individuals with only the 2 risk alleles, 30.0% in individuals with only poor glycemic control, and 31.6% in individuals with neither factor, P for interaction, = .036). CONCLUSION In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.

American College of Cardiology/American Heart Association Clinical Competence Statement on Stress Testing

The granting of clinical staff privileges is one of the primary mechanisms used by institutions to uphold the quality of care. The Joint Commission on Accreditation of Healthcare Organizations requires that the granting of initial or continuing medical staff privileges be based on assessment of applicants against professional criteria specified in medical staff bylaws. Physicians and other healthcare providers are thus charged with identifying the criteria that constitute professional competence and with evaluating their peers accordingly. The process of evaluating clinical knowledge and competence is often constrained by the evaluator’s own knowledge and ability to elicit the appropriate information, a problem that is compounded by the growing number of highly specialized procedures for which privileges are requested. The American College of Cardiology (ACC)/American Heart Association (AHA)/American College of Physicians–American Society of Internal Medicine (ACP-ASIM) Task Force on Clinical Competence was formed in 1998 to develop recommendations to attain and maintain the cognitive and technical skills necessary for the competent performance of a specific cardiovascular service, procedure, or technology. These documents are evidence based, and where evidence is not available, expert opinion is called upon to formulate recommendations. Indications and contraindications for specific services or procedures are not included in the scope of these documents. Recommendations are intended to assist those who must judge the competence of cardiovascular healthcare providers entering practice for the first time and/or those who are in practice and undergo periodic review of their practice expertise. Because the assessment of competence is complex and multidimensional, isolated recommendations contained herein may not necessarily be sufficient or appropriate for judging overall competence. Board specialty certification is not a required part of these recommendations but is another measure of expertise. This statement is a revision and extension of the previous ACP/ACC/AHA Task Force Statement on Clinical Competence in Exercise Testing. …

Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-κB (NF-κB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4–3.8, P = 0.001) and 2.0 (1.3–2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C ≤7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30–45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

Psychological predictors of subsequent medical care among patients hospitalized with cardiac disease.

BACKGROUND There have been numerous reports indicating a relation between psychological distress and coronary artery disease. The authors tried to determine whether psychological distress in patients hospitalized for coronary artery disease is associated with the amount of medical care required after discharge. METHODS Using a prospective clinical cohort, 210 patients who had been admitted for myocardial infarction (n = 67), percutaneous transluminal coronary angioplasty (n = 75), or coronary artery bypass grafting (n = 68) were followed for 6 months. Index psychological status was determined from questionnaires measuring depression and anxiety. Disease severity was assessed by the index hospitalization medical record of left ventricular ejection fraction, number of stenotic vessels, and number of noncardiac comorbidities. The amount of subsequent medical care delivered was based on the number of days of rehospitalization for cardiac-related illness and for any reason within 6 months after discharge. This was determined from a combination of computer medical record and patient self-report. RESULTS The authors first determined that both psychological depression and disease severity each predicted days of rehospitalization. (Anxiety was not predictive of rehospitalization.) Next, disease severity was controlled for using partial correlation, and depression was still predictive of rehospitalization. Finally, the authors combined the predictor variables using a regression model to predict rehospitalization. Depression was a significant main effect in all models predicting rehospitalization. CONCLUSIONS Psychological depression appears to be an important predictor of rehospitalization among persons who have been admitted with coronary artery disease.

Anxiety and Hypervigilance to Cardiopulmonary Sensations in Non-Cardiac Chest Pain Patients With and Without Psychiatric Disorders

We investigated body vigilance, cardiac anxiety, and the mediating role of interoceptive fear on pain in patients with non-cardiac chest pain (NCCP; a syndrome of chest pain in the absence of identifiable organic etiology). Patients were more attentive to cardiac-congruent sensations than cardiac-incongruent sensations (e.g., gastrointestinal, cognitive dyscontrol; ps < .001). Patients with a DSM-IV Axis I anxiety or mood disorder were more body vigilant compared to patients who did not have a disorder (ps < .05). Patients with anxiety disorders were particularly vigilant to and fearful of cardiac sensations relative to patients without anxiety disorders. Latent variable path models examined the extent that interoceptive fear mediated the association between body vigilance and cardiac anxiety on chest pain. Within each model, diagnostic status, body vigilance, and cardiac anxiety were exogenous and predicted interoceptive fear that in turn predicted pain. Separate models examined body vigilance and cardiac anxiety, and both models fit the data well. Findings showed partial mediation for the body vigilance factor, and full mediation for the cardiac anxiety factor. Interoceptive fear played a mediating role in both models. The syndrome of NCCP may persist partly due to conscious hypervigilance to and fear of cardiac-congruent body sensations, particularly among anxious patients.

Common haplotypes at the adiponectin receptor 1 (ADIPOR1) locus are associated with increased risk of coronary artery disease in type 2 diabetes

Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common polymorphisms in the adiponectin receptor 1 (ADIPOR1) gene mediating these effects influence the risk of coronary artery disease (CAD) in type 2 diabetes. Linkage disequilibrium analysis of 28 single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR1 locus revealed two haplotype blocks that could be tagged by six SNPs. These six markers were typed in two populations of CAD-positive and -negative subjects with type 2 diabetes, one from Boston (n = 411) and the other from Italy (n = 533). In the Boston population, the three tags of the more 3′ block were all significantly associated with CAD (P = 0.001–0.01). A similar trend, although not significant, was found in Italian subjects. Haplotype analysis of the combined populations revealed different haplotype distributions in case and control subjects (P = 0.0002), with one common haplotype being associated in homozygotes with a greater than threefold increase in cardiovascular risk (odds ratio 3.6 [95% CI 1.8–7.2]). Some of the genotypes associated with increased cardiovascular risk were associated with 30–40% lower ADIPOR1 mRNA levels in blood mononuclear cells (n = 60) and adipose tissue biopsies (n = 28) (P = 0.001–0.014). Our findings point to genetic variability at the ADIPOR1 locus as a strong determinant of CAD susceptibility in type 2 diabetes.

Reversal of changes in left ventricular diastolic filling associated with normal aging using diltiazem

Abstract Congestive heart failure is a common problem in clinical geriatrics and often the result of diastolic rather than systolic dysfunction. 1 Normal aging is associated with a reduction in the rate of calcium ion uptake by the sarcoplasmic reticulum. 2 Because intracellular handling of calcium may affect isovolumic relaxation and left ventricular (LV) compliance, a calcium antagonist may be beneficial. The pattern of LV diastolic filling may be accurately characterized by both pulsed Doppler transmitral flow velocities 3 and radionuclide scintigraphy. 4 The present study tests the hypothesis that a calcium antagonist, diltiazem, may be effective in reversing the impairment of early diastolic LV filling seen in elderly subjects.