Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction.

Seven hundred fifteen participants from a multicenter natural history study of acute myocardial infarction were studied (1) to determine the correlations among time and frequency domain measures of heart period variability, (2) to determine the correlations between the measures of heart period variability and previously established post-infarction risk predictors, and (3) to determine the predictive value of time domain measures of heart period variability for death during follow-up after acute myocardial infarction. Twenty-four hour electrocardiographic recordings obtained 11 +/- 3 days after acute myocardial infarction were analyzed and 11 measures of heart period variability were computed. Each of 4 bands in the heart period power spectrum had 1 or 2 corresponding variables in the time domain that correlated with it so strongly (r greater than or equal to 0.90) that the variables were essentially equivalent: ultra low frequency power with SDNN* and SDANN index,* very low frequency power and low-frequency power with SDNN index,* and high-frequency power with r-MSSD* and pNN50.* As expected from theoretical considerations, SDNN and the square root of total power were almost perfectly correlated. Correlations between the time and frequency domain measures of heart period variability and previously identified postinfarction risk predictors, e.g., left ventricular ejection fraction and ventricular arrhythmias, are remarkably weak. Time domain measures of heart period variability, especially those that measure ultra low or low-frequency power, are strongly and independently associated with death during follow-up. * Defined in Table II.     

Heart rate reactivity and heart period variability throughout the first year after heart transplantation

Heart rate reactivity to mental stress is substantially blunted early after heart transplantation, suggesting that the loss of neural modulation limits the cardiovascular response to mental stress. We tested whether reactivity to mental stress recovers during the first year after heart transplantation. Hemodynamic and respiratory responses to mental arithmetic challenge were studied in 20 heart transplant recipients 3, 6, and 12 months after surgery. A normal comparison group was studied at equivalent intervals. Heart rate reactivity to mental arithmetic was significantly reduced in the cardiac transplant group compared to the normal subjects. This effect persisted up to 1 year after transplantation. Heart period variability in the heart transplant recipients was minimal in all three-test sessions. The findings suggest that no functional reinnervation or other compensatory adaptation occurs up to 1 year after heart transplantation.     

Variation in route of microsomal activation of 7,12-dimethylbenz [a]anthracene with substrate concentration +

The nature of the metabolites of 7,12-dimethylbenz[a]anthracene(DMBA) binding to DNA in the presence of Aroclor-induced ratliver microsomes is not affected by the presence or absenceof magnesium ions, but is dependent on the concentration ofthe hydrocarbon. At high concentrations of DMBA, the primaryroute of metabolic activation is through the K-region oxidewhile, at low concentrations of DMBA, activation is throughother routes. A small proportion of these latter products elutefrom Sephadex LH-20 columns with mouse embryo cell [¹⁴C]DMBA-DNAadducts which are known to arise through reaction of the bayregion diol-epoxide of DMBA with cellular DNA. In contrast tothe dose-dependence of activation of DMBA by microsomes, thebinding of this carcinogen to DNA in intact cultured mouse embryocells is not qualitatively influenced by concentration overa forty-fold dose range. These findings suggest limitationsin the use of microsomal systems as models for target tissueactivation.     

The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders

In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual’s lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual’s immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.     

Efficacy,plasma concentrations and adverse effects of a new sustained release procainamide preparation

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamlde, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100 percent [mean ± standard deviation 91 ± 8.2]) in ventricular premature depolarization frequency at a dosage of 4.8 ± 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +- 6.02 and 12.0 ± 7.40 μg/ml, respectively. The respective mean minimal concentrations were 6.8 ± 4.50 and 8.7 ± 5.99 μg/ml In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.     

In vivo T‐cell depletion using alemtuzumab in family and unrelated donor transplantation for pediatric non‐malignant disease achieves engraftment with low incidence of graft vs. host disease

In vivo T‐cell depletion, using alemtuzumab therapy prior to SCT, can reduce the incidence of GVHD. This treatment has a potential to delay immune reconstitution resulting in increased morbidity due to viral illnesses. We retrospectively analyzed data on all pediatric patients with non‐malignant disorders who received alemtuzumab‐based conditioning regimens in our center over the last 10 yr (n = 91). Our data show an OS of 91.2%. The incidence of acute (grade 2–4) GVHD was 18.7% and that of chronic GVHD 5.5%. Viremia due to adenovirus, EBV and CMV was seen in 19.8%, 64.8% and 39.6% patients, respectively, with only two deaths attributed to viral infection (adenovirus). Chimerism level at three month was predictive of graft outcome. Nine patients, who had graft failure after first SCT, were salvaged with a second SCT using RIC and same donor (if available). Based on these results, we conclude that the use of in vivo T‐cell depletion is safe, achieves good chimerism and does not lead to increased morbidity and mortality due to viral infections. It is associated with a reduced incidence of chronic GVHD.     

Heart Rate Variability: Measurement and Clinical Utility

Electrocardiographic RR intervals fluctuate cyclically, modulated by ventilation, baroreflexes, and other genetic and environmental factors that are mediated through the autonomic nervous system. Short term electrocardiographic recordings (5 to 15 minutes), made under controlled conditions, e.g., lying supine or standing or tilted upright can elucidate physiologic, pharmacologic, or pathologic changes in autonomic nervous system function. Long‐term, usually 24‐hour recordings, can be used to assess autonomic nervous responses during normal daily activities in health, disease, and in response to therapeutic interventions, e.g., exercise or drugs. RR interval variability is useful for assessing risk of cardiovascular death or arrhythmic events, especially when combined with other tests, e.g., left ventricular ejection fraction or ventricular arrhythmias.     

Diabetes Control Among Hispanics in the Action to Control Cardiovascular Risk in Diabetes Trial

BACKGROUND

Hispanics in the United States represent diverse racial, ethnic, and socioeconomic groups, and manifest heterogeneous cardiovascular risks including diabetes. It is not known if there are residual differences in the control of diabetes among Hispanic groups given uniform access to diabetes care.

OBJECTIVE

To evaluate glucose control differences among Mexicans, Puerto Ricans, and Dominicans receiving substantial diabetes care and support in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

DESIGN

Secondary analysis of data from a randomized trial comparing two treatment strategies: intensive, targeting glycated hemoglobin below 6.0?%, and standard, targeting glycated hemoglobin between 7.0?% and 7.9?%.

PARTICIPANTS

Seven hundred and sixteen Hispanic and 6066 non-Hispanic white participants were recruited from 77 clinical sites across the United States and Canada. There were 243 Mexicans, 199 Puerto Ricans, and 150 Dominicans; and 135 of these Hispanic groups were born in the United States.

MAIN MEASURE

Glycated hemoglobin

RESULTS

Compared to Puerto Ricans, Mexicans were more likely (HR?=?1.38, CI:0.90?C2.10) and Dominicans as likely (HR?=?1.01, CI:0.66?C1.54) to achieve glycated hemoglobin goal in the intensive arm. Participants born in the United States achieved glycated hemoglobin goal at a higher rate than those born elsewhere (HR?=?1.57, CI:0.99?C2.51 in the intensive arm, HR?=?1.51, CI:0.95?C2.43 in the standard arm). These differences were not statistically significant. In the intensive arm, Puerto Ricans (OR?=?0.47, CI:0.31?C0.71), and Dominicans (OR?=?0.41, CI:0.26?C0.66) were less likely than non-Hispanic whites to achieve glycated hemoglobin goal, whereas the difference between non-Hispanic whites and Mexicans was not statistically significant, (OR?=?0.66, CI:0.43?C1.02).

CONCLUSIONS

Hispanic groups, given access to comprehensive diabetes care, differed from each other non-significantly and had a variable divergence from non-Hispanic whites in achieving intensive glycated hemoglobin goal. These differences, if confirmed, could be due to such factors as variable acculturation and functional health literacy levels that were not measured in the ACCORD trial, but should be further explored in future studies.     

Cost-effectiveness of a microvolt T-wave alternans screening strategy for implantable cardioverter-defibrillator placement in the MADIT-II-eligible population.

OBJECTIVES: This study was designed to compare the cost-effectiveness of implantable cardioverter-defibrillator (ICD) placement with and without risk stratification with microvolt T-wave alternans (MTWA) testing in the MADIT-II (Second Multicenter Automatic Defibrillator Implantation Trial) eligible population. BACKGROUND: Implantable cardioverter-defibrillators have been shown to prevent mortality in the MADIT-II population. Microvolt T-wave alternans testing has been shown to be effective in risk stratifying MADIT-II-eligible patients. METHODS: On the basis of published data, cost-effectiveness of three therapeutic strategies in MADIT-II-eligible patients was assessed using a Markov model: 1) ICD placement in all; 2) ICD placement in patients testing MTWA non-negative;, and 3) medical management. Outcomes of expected cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness were determined for patient lifetime. RESULTS: Under base-case assumptions, providing ICDs only to those who test MTWA non-negative produced a gain of 1.14 QALYs at an incremental cost of 55,700 dollars when compared to medical therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 48,700 dollars/QALY. When compared with a MTWA risk-stratification strategy, placing ICDs in all patients resulted in an ICER of 88,700 dollars/QALY. Most (83%) of the potential benefit was achieved by implanting ICDs in the 67% of patients who tested MTWA non-negative. Results were most sensitive to the effectiveness of MTWA as a risk-stratification tool, MTWA negative screen rate, cost and efficacy of ICD therapy, and patient risk for arrhythmic death. CONCLUSIONS: Risk stratification with MTWA testing in MADIT-II-eligible patients improves the cost-effectiveness of ICDs. Implanting defibrillators in all MADIT-II-eligible patients, however, is not cost-effective, with one-third of patients deriving little additional benefit at great expense.