Circulating HtrA2 as a novel biomarker for mitochondrial induced cardiomyocyte apoptosis and ischemia-reperfusion injury in ST-segment elevation myocardial infarction.

BACKGROUND: Ischemia-reperfusion (I/R) injury in ST-segment elevation myocardial infarction (STEMI) significantly contributes to overall myocardial damage. As a consequence of I/R injury in the heart, the high-temperature requirement protein A2 (HtrA2) is released from the mitochondrial intermembrane space of cardiomyocytes to the cytoplasm, whereupon it induces apoptosis. METHODS: Serum was obtained from STEMI (n=37), non-ST-segment elevation myocardial infarction (NSTEMI) (n=20), stable coronary artery disease (CAD) (n=17) and patients with CAD excluded (n=9). In STEMI, I/R injury was assessed via measurement of ST-segment resolution. RESULTS: HtrA2 was significantly increased in STEMI compared to NSTEMI, stable CAD and patients with CAD excluded (981.3 (IQR: 543.5-1526.2)pg/mL vs. 494.5 (IQR: 413.8-607)pg/mL vs. 291 (IQR: 239-458.5)pg/mL vs. 692.2 (IQR: 276.6-964.7)pg/mL; p≤0.0001). STEMI patients with HtrA2 level of at least the median or above had a higher peak creatine kinase (CK) (p=0.0002) and cardiac troponin T levels (cTnT) (p=0.0019). Significantly more STEMI patients with HtrA2 levels of at least the median or above were identified as I/R injury (87% vs. 42%; p<0.0001). Serum HtrA2 demonstrated a superior area under a curve in a receiver operating characteristic analysis for predicting I/R injury compared to CK, creatine kinase myocardial-band (CK-MB) and cTnT levels (AUC=0.7105 vs. AUC=0.5632 vs. AUC=0.5660 vs. AUC=0.5407 respectively). CONCLUSION: HtrA2 shows promise as a novel potential biomarker for mitochondrial-induced cardiomyocyte apoptosis and may help to identify I/R injury after STEMI.

Torsade de pointes as a complication of subarachnoid hemorrhage: a critical reappraisal.

Subarachnoid hemorrhage is widely accepted as a potential cause of torsade de pointes (TdP), yet this putative etiologic relationship has never been systematically evaluated. We therefore undertook a MEDLINE search from 1966 through 1993, with relevant back referencing, and identified 20 cases of TdP in the setting of subarachnoid hemorrhage. It was impossible in any of these cases (usually because of insufficient data) to completely exclude one or more alternative explanations for TdP, including congenital long QT syndrome, hypokalemia, hypomagnesemia, or drug-induced QT prolongation. Furthermore, of a total of 1,139 patients in 16 prospective series of subarachnoid hemorrhage with electrographic analyses, there were only five reported cases of TdP, all in patients with hypokalemia. Thus, extremely limited scientific data exist to support the notion that subarachnoid hemorrhage can be a distinct cause of TdP. Until more definitive evidence is available, the development of TdP in patients with subarachnoid hemorrhage is probably better characterized as a multifactorial phenomenon occurring in an acute, typically intensive care, setting.

Facilitating and assessing progress toward independence: SPARX.

As children with spina bifida are thriving physically, a need for encouraging independent behavior has arisen. The dynamics of dependency undermine youngster's potential for autonomous functioning. As programs are being developed, there is a need to measure the dimensions which contribute to independent behavior. As an outgrowth of the SPARX independence-training program at Shepherd Spinal Center, Atlanta, such a tool is being developed. The Independent Behavior Inventory focuses on those dimensions contributing to development of independence, including problem-solving, communication, self-help, family support, etc. Although the sample is small, reliability and validity statistics have been computed, and look promising. Use of the instrument in clinical settings in encouraged. Professionals are encouraged to intervene early with families so that the dynamics of dependency can be undermined and independence facilitated.

Increased propensity of women to develop torsades de pointes during complete heart block.

INTRODUCTION: To determine whether an increased female gender susceptibility to torsades de pointes (TdP) may exist in a clinical model of bradycardia-induced long QT syndrome, we investigated reported cases of TdP associated with acquired complete heart block. METHODS AND RESULTS: Seventy-two cases reported in the medical literature dating from 1941 through 1993 were identified, all describing TdP or "transient ventricular tachycardia/fibrillation" (to include those cases reported prior to the use of TdP terminology) in the setting of acquired complete heart block unassociated with QT prolonging drugs. Expected female prevalence in complete heart block was estimated at 52%, based on projections derived from 206,016 hospital discharges in the National Inpatient Profile (Commission on Professional and Hospital Activities, Ann Arbor, MI), over the years 1985 through 1992. During complete heart block, mean heart rate was 37 beats/min in both sexes (combined n = 43), and absolute QT interval ranged from 0.52 to 0.88 seconds, with a mean of 0.68 seconds (n = 25). Female prevalence among patients with TdP during complete heart block was greater than expected: 72% for all studied cases (P < 0.001); 70% (P < 0.04) and 74% (P < 0.02) among those reported prior to (n = 35) and during or after (n = 37) 1980, respectively; 73% (P < 0.03) among those with documented normokalemia (n = 26); and 68% (P = 0.2) among those with a prolonged QT interval and known polymorphic VT (i.e., unequivocal TdP; n = 25). CONCLUSION: Despite inherent limitations of this retrospective study, the data are consistent in suggesting a greater than expected female prevalence among patients with TdP related to complete heart block. This finding lends support to a broadening concept of increased susceptibility of women to the development of TdP in various settings of QT prolongation.

Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender.

From published articles and adverse reactions reports filed with the FDA (available through the Freedom of Information Act), we analyzed occurrences of tachyarrhythmias and the magnitude of QTc prolongation associated with probucol therapy. Of 16 cases of tachyarrhythmic events reported in association with probucol, 15 (94%) occurred in women (p < 0.01 vs expected value of 58%). Tachyarrhythmias were specifically described as TdP in 11 (63%) cases, all women; additional potential contributory QT-prolonging factors (besides probucol) were not identifiable in 2 of the 11 cases. We also analyzed QTc responses in 359 probucol-treated patients, all having baseline QTc < or = 0.44 sec1/2. At doses of 500 to 1000 mg/day, probucol-associated prolongation of QTc to values > or = 0.45 sec1/2 was observed in 22% of women versus 7% of men (p < 0.001) and to values > or = 0.47 sec1/2 in 8% of women versus 2% of men (p < 0.03). Multivariate analysis identified baseline QTc (p < 0.0001) and female gender (p < 0.03), but neither age nor dose, as significant independent predictors of QTc prolongation to > or = 0.45 sec1/2 with probucol. These findings have relevance to the clinical use of probucol, provide further evidence that women have a relatively greater predisposition to development of acquired long QT syndrome, and carry implications for the design of trials involving QT-prolonging drugs.