Eugene E. Wolfel

Chronic changes in skeletal muscle histology and function in peripheral arterial disease.

BackgroundPeripheral arterial disease (PAD) is associated with an impairment in exercise performance and muscle function that is not fully explained by the reduced leg blood flow during exercise. This study characterized the effects of PAD on muscle function, histology, and metabolism. Methods and ResultsTwenty-six patients with PAD and six age-matched control subjects were studied. Ten of the PAD patients had unilateral disease, which permitted paired comparisons between their diseased and nonsymptomatic legs. All PAD patients had a lower peak treadmill walking time and peak oxygen consumption than controls. Vascular disease (diseased leg in unilateral patients and the most severely diseased leg in bilateral patients) was associated with decreased calf muscle strength compared with control values. In patients with unilateral disease, the diseased legs had a greater percentage of angular fibers (indicating chronic denervation) and a decreased type H fiber cross-sectional area (expressed as percent of total fiber area) compared with the nonsymptomatic, or control, legs. In diseased legs, gastrocnemius muscle strength was correlated with the total calf cross-sectional area (r=0.78, p<0.05) and type II fiber cross-sectional area (r=0.63, p<0.05). Activities of citrate synthase, phosphofructokinase, and lactate dehydrogenase in all 26 PAD patients (most diseased leg) did not differ from control values. Despite a wide range in citrate synthase activity in PAD patients, activity of this enzyme was not correlated with muscle strength or treadmill exercise performance. ConclusionIn patients with PAD, gastrocnemius muscle weakness is associated with muscle fiber denervation and a decreased type II fiber cross-sectional area. In contrast, the PAD patients displayed substantial heterogeneity in muscle enzyme activities that was not associated with exercise performance. Denervation and type H fiber atrophy may contribute to the muscle dysfunction in patients with PAD and further confirm that the pathophysiology of chronic PAD extends beyond arterial obstruction.

Drug Therapy in the Heart Transplant Recipient Part II: Immunosuppressive Drugs

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. nnPart I of this series describes the mechanisms and types of rejection and the intravenous immunosuppressive drugs commonly used for induction or antirejection therapy. In this article, we review the commonly used oral immunosuppressive drugs. Intravenous corticosteroid methylprednisolone is included in the discussion of corticosteroids. Table 1 gives trade names, pharmacology, necessary adjustments for renal or hepatic dysfunction, and dosing and general monitoring guidelines for drugs described in this section. Table 2 lists the major adverse effects of immunosuppressive drugs described in Parts I and II of this review and provides an estimate of their relative frequency. nnView this table:nnTABLE 1. Commonly Used Oral (and Intravenous) Immunosuppressive Drugs nnnnView this table:nnTABLE 2. Major Adverse Effects of Immunosuppressive Drugs nnnnSteroids, among the first immunosuppressive agents used in clinical transplantation, have remained an important component of induction, maintenance, and rejection regimens.nn### Mechanism of ActionnnGlucocorticoids are potent immunosuppressive and antiinflammatory agents (the Figure). They diffuse freely across cell membranes and bind to high-affinity cytoplasmic glucocorticoid receptors. The glucocorticoid receptor–steroid complex translocates to the nucleus, where it binds to a glucocorticoid response element within the DNA.1 The glucocorticoid receptor–steroid complex may also bind to other regulatory elements, inhibiting their binding to DNA. Both actions cause transcriptional regulation, thereby altering the expression of genes involved in immune and inflammatory response. Glucocorticoids affect the number, distribution, and function of all types of leukocytes (T and B lymphocytes, granulocytes, macrophages, and monocytes), as well as endothelial cells.2 The major effect on lymphocytes appears to be mediated by inhibition of 2 transcription factors, activator protein-1 and nuclear factor (NF) κ-B.3,4 This affects the expression of a number of genes, including those for growth factors, cytokines, CD40 ligand, GM-CSF, and adhesion and myosin heavy chain molecules.2 In nonlymphoid …

Drug therapy in the heart transplant recipient: part I: cardiac rejection and immunosuppressive drugs.

Survival after heart transplantation has improved considerably over the past 20 years. Half of all patients now live >9 years, and ≈25% live ≥17 years.1 Currently, ≈20 000 heart transplant recipients live in the United States.2 Improved longevity means prolonged immunosuppression and the concomitant use of drugs to prevent or treat the long-term complications of immunosuppressive agents, such as infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies. In 1989, heart transplant recipients surviving 1 year were reported to be taking 16±6 drug doses per day (prescription and nonprescription).3 In 2001, heart transplant recipients surviving an average of 76 months were taking 7 prescription drugs (range, 2 to 14), along with a number of nonprescription drugs.4 Thus, despite prolonged survival, heart transplant recipients continue to take multiple medications. With the large number of heart transplant recipients in the community and the increasing number of immunosuppressive and nonimmunosuppressive drugs used by these patients, it is important that the general cardiologist understand these drugs, their side effects, and the very real potential for drug–drug interactions. These interactions may result in adverse events caused by supratherapeutic and subtherapeutic drug concentrations. In this series, we review mechanisms and types of rejection, immunosuppressive drugs commonly used in the heart transplant recipient, common medical problems after transplantation, and clinically significant drug–drug interactions.nnA brief review of known immunologic mechanisms leading to graft rejection highlights the action of individual immunosuppressive drugs, as well as the rationale for combination therapy5–8 (Figure). The rejection of a transplanted organ is primarily a T-lymphocyte (T-cell)–mediated event, although humoral (B-cell) responses also contribute. The exception is hyperacute rejection, which occurs when preformed antibodies to human leukocyte antigens (HLA) result in an immediate and catastrophic rejection. Immune recognition of donor antigens that differ from those of …

Carnitine and acylcarnitine metabolism during exercise in humans. Dependence on skeletal muscle metabolic state.

Carnitine metabolism has been previously shown to change with exercise in normal subjects, and in patients with ischemic muscle diseases. To characterize carnitine metabolism further during exercise, six normal male subjects performed constant-load exercise on a bicycle ergometer on two separate occasions. Low-intensity exercise was performed for 60 min at a work load equal to 50% of the lactate threshold, and high-intensity exercise was performed for 30 min at a work load between the lactate threshold and maximal work capacity for the individual. Low-intensity exercise was not associated with a change in muscle (vastus lateralis) carnitine metabolism. In contrast, from rest to 10 min of high-intensity exercise, muscle short-chain acylcarnitine content increased 5.5-fold while free carnitine content decreased 66%, and muscle total carnitine content decreased by 19% (all P less than 0.01). These changes in skeletal muscle carnitine metabolism were present at the completion of 30 min of high-intensity exercise, and persisted through a 60-min recovery period. With 30 min of high-intensity exercise, plasma short-chain and long-chain acylcarnitine concentrations increased by 46% and 23%, respectively. Neither exercise state was associated with a change in the urine excretion rates of free carnitine or acylcarnitines. Thus, alterations in skeletal muscle carnitine metabolism, characterized by an increase in acylcarnitines and a decrease in free and total carnitine, are dependent on the work load and, therefore, the metabolic state associated with the exercise, and are poorly reflected in the plasma and urine carnitine pools.

Drug Therapy in the Heart Transplant Recipient Part III: Common Medical Problems

Continued improvement in the long-term survival of heart transplant recipients has resulted in a population of patients with prolonged exposure to immunosuppressive drugs.1 This exposure, coupled with the increasing age of recipients, has resulted in an impressive prevalence of comorbidities in these patients. Indeed, by 5 years after transplantation, 95% of recipients have hypertension, 81% have hyperlipidemia, and 32% have diabetes.1 In addition, 25% to 50% have coronary allograft vasculopathy (CAV), and up to 33% have chronic renal insufficiency.2–5 As more drugs are developed to both prevent and treat these problems and common infectious complications after transplantation, it is likely that the heart transplant recipient will be taking an increasing number of drugs. Because standard immunosuppressive drugs have a high potential for drug–drug interactions, the heart transplant recipient is subject to an enormous risk for drug–drug interactions. In this article, we briefly review common medical problems in heart transplant recipients that are routinely addressed with drug therapy. In Part IV of this series, we provide specific details of known important and common drug–drug interactions, along with recommendations for management.

Left ventricular assist device as bridge to transplantation does not adversely affect one-year heart transplantation survival.

OBJECTIVEnLeft ventricular assist devices are increasingly used as a bridge to transplantation. It remains unclear whether the use of pretransplant left ventricular assist devices adversely affects short-term survival after cardiac transplantation.nnnMETHODSnA retrospective review of 317 consecutive patients undergoing cardiac transplantation at an academic center between 1986 and 2006 was undertaken. Left ventricular assist devices were used pretransplant in 23 of these 317 patients, and 294 patients did not require left ventricular assist device support. Patients with a left ventricular assist device were supported with a Heartmate VE or Heartmate XVE (Thoratec Corp, Pleasanton, Calif). Kaplan-Meier survival estimates were compared between the left ventricular assist device group and the non-left ventricular assist device group using the log-rank test. In addition, occurrence of death was analyzed between the 2 groups with a chi-square analysis. The results are expressed as 1-year survival with 95% confidence intervals in parentheses.nnnRESULTSnThe 1-year survival for all 317 patients was 0.86 (0.82-0.90). The patient survival for the group without a left ventricular assist device before cardiac transplant was 0.87 (0.83-0.90), and the survival for the group with a left ventricular assist device as bridge to transplantation was 0.83 (0.67-0.98; P = .77). For the deaths that occurred in all 317 patients, 19% of the patients without left ventricular assist devices died within 30 days of transplant, whereas 80% of the patients with left ventricular assist devices died within 30 days of transplant (P < .01).nnnCONCLUSIONnWhen used as a bridge to transplantation, left ventricular assist devices do not compromise 1-year survival after cardiac transplantation. Of the patients who die after transplantation, patients bridged with left ventricular assist devices are at higher risk for death within 30 days of transplant. These data suggest that left ventricular assist devices as a bridge to transplantation should be considered for appropriately selected patients awaiting cardiac transplantation.

Effects of selective and nonselective beta-adrenergic blockade on mechanisms of exercise conditioning.

Exercise conditioning involves adaptations in the heart, peripheral circulation, and trained skeletal muscle that result in improved exercise capacity. Since the specific influence of beta-adrenergic stimulation on these various adaptations has not been clear, we studied the effect of beta 1-selective and nonselective beta-adrenergic blockade on the exercise conditioning response of 24 healthy, sedentary men after an intensive 6 week aerobic training program. Subjects randomly assigned to receive placebo, 50 mg bid atenolol, or 40 mg bid nadolol were tested before and after training both on and off drugs. Comparable reductions in maximal exercise heart rate occurred with atenolol and nadolol, indicating equivalent beta 1-adrenergic blockade. Vascular beta 2-adrenergic selectivity was maintained with atenolol as determined by calf plethysmography during intravenous infusion of epinephrine. All subjects trained at greater than 85% of maximal heart rate and 80% of VO2 max determined on drug. VO2 max increased after training 16 +/- 2% (p less than .05) in the placebo group and 6 +/- 2% (p less than .05) in the atenolol group, while there was no change in the nadolol group. At maximal exercise, subjects receiving placebo increased their exercise duration and oxygen pulse significantly greater than those receiving atenolol or nadolol. During submaximal exercise there were reductions in heart rate and heart rate-blood pressure product in all three groups, but these reductions were greater with placebo than with either drug. Leg blood flow during submaximal exercise decreased 24 +/- 2% (p less than .01) in the placebo group but was unchanged in the atenolol and nadolol groups. Lactates in arterialized blood during submaximal exercise were reduced equivalently in all three groups after training. Capillary/fiber ratio in vastus lateralis muscle biopsy specimens increased 31 +/- 6% in the placebo group and 21 +/- 6% in the atenolol group (both p less than .05) and tended to increase in the nadolol group. Succinic dehydrogenase and cytochrome oxidase activities in muscle biopsy specimens increased equivalently in all three groups, especially during submaximal exercise, these changes were less marked than that with placebo. While beta-adrenergic blockade attenuated the exercise conditioning response, skeletal muscle adaptations including increases in oxidative enzymes, capillary supply, and decreases in exercise blood lactates were unaffected. Cardiac and peripheral vascular adaptations do appear to be affected by beta-adrenergic blockade during training. Cardioselectivity does not seem to be important in modifying these effects.

Clinical problem-solving. Missing elements of the history.

A 59-year-old woman with a history of bilateral total hip replacements and a total knee replacement sees her physician for cough, exertional dyspnea, and foot swelling that had developed 2 weeks earlier while she was on vacation in Europe.

Myocardial glucose and lactate metabolism during rest and atrial pacing in humans.

There is minimal in vivo data in humans evaluating myocardial substrate utilization during increased heart work. This study was performed to determine the balance of myocardial glucose and lactate metabolism during rest and increased heart work induced by atrial pacing in seven healthy men and women (age, 49.7 ± 3.9 years; body mass index, 23.4 ± 1.1 kg m−2, maximum oxygen consumption, 35.5 ± 3.0 ml kg−1 min−1, ejection fraction, 68 ± 3%). After 3 days of dietary control, catheters were placed in coronary sinus, femoral arterial and venous, and peripheral venous blood vessels. Subjects received a primed continuous infusion of [3,3,3‐2H]lactate and [6,6‐2H]glucose throughout the study. Arterial and coronary sinus blood sampling and measurements of coronary sinus blood flow were made during rest and atrial pacing at approximately 111 beats min–1. Myocardial oxygen consumption increased (P= 0.04) from rest to atrial pacing. Net glucose uptake increased (P= 0.04) from rest to atrial pacing with unchanged fractional extraction (rest: 9.1 ± 2.7%, atrial pacing 9.8 ± 2.9%). The percentage of whole body glucose disposal from myocardial uptake also increased from rest to atrial pacing. Isotopically measured lactate uptake also increased significantly from rest to atrial pacing with no significant differences in fractional extraction. The myocardium released lactate throughout the experiment, which increased significantly from rest and atrial pacing (P < 0.05). The heart accounted for a significantly greater percentage of whole body lactate disposal during atrial pacing (15.0 ± 4.4%) compared to rest (4.9 ± 0.9%, P= 0.03). These data suggest: (1) in the absence of ischaemia the myocardium is constantly taking up and releasing lactate at rest which increases during atrial pacing, and (2) when arterial substrate delivery is unchanged, increased myocardial work is accomplished with similar proportions of glucose and lactate utilization in healthy humans in vivo.

Can We Predict and Prevent the Onset of Acute Decompensated Heart Failure

Watch the disease in time: For when, within the dropsy rages, and extends the skin, in vain for helebore the patient cries, and sees the doctor, but too late is wise: Too late for cure, he proffers half his wealth; ten thousand doctors cannot give him health. — —Benjamin Franklin, Poor Richard’s Almanack, 1749 nnThis rather pessimistic representation of heart failure (dropsy) in the 18th century has some relevance to the presentation of acute decompensation in patients with chronic heart failure in our current century, despite the availability of various therapies that prolong survival and decrease the morbidity of this disorder. In 2006, >1 million hospitalizations for acute decompensated heart failure (ADHF) occurred, and the number of heart failure hospitalizations have increased 175% since 1979.1 The vast majority of these patients, 75.6%, had a history of heart failure,2 and the in-hospital mortality was 3.2%. Patients with preserved left ventricular (LV) systolic function have a slightly lower in-hospital mortality (2.9%) compared with those with an LV ejection fraction ≤40% (3.9%); however, the 3-month mortalities were similar at 9.5% to 9.8%.3 Rehospitalization rates remain high at 29% to 30% for patients with both preserved and decreased LV systolic function, and rehospitalization is an independent predictor of 1-year mortality, especially in elderly patients.4 In addition, patients with ADHF are at greater risk for death and morbidity than those with stable chronic heart failure.5 Thus, the natural history of heart failure may be altered by repeated episodes of decompensation requiring hospitalization. Finally, a tremendous financial burden is involved in the treatment of ADHF. Of the