Selective downregulation of PDE3A may account in part for the ineffectiveness of milrinone in the treatment of severe CHF.

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The relation between functional properties of the contractile apparatus, such as shortening velocity and ATPase activity, and myosin isoenzyme composition was studied in ventricular myocardium of adult (60-90-day-old) rats and of newborn (3-day-old) and young (10- and 20-day-old) rats. In adult animals, variations of isomyosin pattern were produced by reducing food intake and by changing the thyroid state. Hyperthyroidism was induced with triiodothyronine daily injection for 15 days; hypothyroidism was induced with iodine-free diet and KClO4 in drinking water for 50-60 days. The following parameters were studied: 1) calcium-magnesium-activated and magnesium-activated ATPase activity of washed and purified myofibrils, 2) calcium-activated ATPase activity of purified myosin, 3) isomyosin composition and relative content of alpha-myosin heavy chains (alpha-MHCs), and 4) force-velocity curve of left and right ventricle papillary muscles. To take into account the difference in excitation-contraction coupling between newborn and adult myocardium, the determination of the force-velocity curve was repeated in Krebs' solution with normal [CaCl2] (2.5 mM) and in Krebs' solution with high [CaCl2] (10 mM). During postnatal growth, the relative content of alpha-MHC increased and reached a maximum at about 20 days. Pronounced increases of myofibrillar and myosin ATPase activity and in shortening velocity occurred during the same period. In adult hyperthyroid rats, alpha-MHC content as well as enzymatic activity and shortening velocity were higher than in control adult animals. Hypothyroidism and food deprivation caused a decrease of alpha-MHC content and a reduction of both enzymatic activities and shortening velocity. The study of the relations between alpha-MHC relative content and functional parameters showed that 1) in ventricular myocardium of adult rats a linear relation existed between alpha-MHC content and myosin and myofibrillar ATPase activity and shortening velocity, and 2) in newborn and young rat ventricular myocardium, both enzymatic activities and shortening velocity were lower than would have been expected on the basis of the linear relation described above. This latter observation could be accounted for by a variation in specific activity of myosin during postnatal development or by the presence of peculiar isomyosins that cannot be detected with usual electrophoretic techniques.

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Phosphodiesterase III (PDE-3) inhibitors are inotropes used to treat congestive heart failure (HF). Previous studies showed PDE-3A mRNA levels were reduced in the left ventricle (LV) in dogs subjected to pacing-induced HF. The present study evaluated a time-course for RV-specific changes in PDE-3A mRNAs and proteins after pacing for 3 wk (n = 4) or in HF (4-5 wk; n = 4-6). Total RNA from LV/RV tissues was isolated for Northern analyses; cytosolic and microsomal proteins were prepared for PDE-3A immunoblots. PDE-3A mRNAs (7-8 and 10 kb) were normalized against glyceraldehyde-3-phosphodehydrogenase (GAPDH) or ribosomal 18s with similar results. PDE-3A/GAPDH ratios in 3 wk were unchanged in LV, but significantly (p < 0.05) reduced by 48% in RV vs unpaced controls (n = 8). In contrast, PDE-3A (7-8 kb)/GAPDH ratios were significantly reduced in HF by 50-59% in both ventricles. Consistent with mRNA levels, significant reductions in microsomal 135 kDa (93-96%) and cytosolic 120 kDa PDE-3A (57-69%) were seen in both ventricles in HF or in the RV at 3 wk; an LV-specific reduction (50%) in cytosolic 80 kDa PDE-3A in HF was also detected. In summary, RV-specific downregulation of PDE-3A mRNA/protein(s) at 3 wk suggests that hemodynamic rather than humoral mechanisms are responsible, and provides a molecular basis for the limited efficacy of milrinone in the progression of HF.

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A 1-month prospective quality improvement audit was performed to determine the incidence of self-extubation in the intensive care units (ICUs) at the Westchester County Medical Center (WCMC), a 625-bed tertiary care hospital with 92 intensive care beds in 11 ICUs. During the 1-month study period, there were seven unplanned extubations in six of 121 intubated patients, or one unplanned extubation for every 136 patient-ventilator days. Based on the initial review, a corrective action plan was initiated that consisted of education of nurses and house staff about the problem of unplanned extubation, daily assessment on rounds of patient risk of unplanned extubation, and careful documentation of any episodes of unplanned extubation. A 5-month follow-up review identified 12 unplanned extubations in 11 patients, which resulted in a reduced rate of one unplanned extubation per 455 patient-ventilator days. Risk factors for unplanned extubation included documented anxiety, routine care intervention, and a history of previous unplanned extubation. Unplanned extubation can be a serious complication associated with mortality and therefore is a quality-of-care concern. However, the majority of patients with this complication did well and were discharged from the hospital. The incidence of unplanned extubation can be reduced but not eliminated by a program of education and attention to risk factors for unplanned extubation.