Early remodeling of repolarizing K+ currents in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC403/+ mouse line in which one αMHC allele harbors a common HCM mutation (in ßMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC403/+ mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K+ (Kv) current (IK,peak) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, Ito,f, Ito,s and IK,slow, were significantly lower in αMHC403/+, compared with WT, septum cells, whereas Iss amplitudes were similar. The amplitudes/densities of IK,peak and IK,slow were also lower in αMHC403/+, compared with WT, LV wall and LV apex myocytes, whereas Ito,f was attenuated in αMHC403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC403/+ mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K+ channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K+ current amplitudes.

Defining Familial Interactions and Networks: An Exploratory Qualitative Study on Family Networks and Surrogate Decision-Making.

To characterize patient preferences for medical surrogate decision-makers in the ICU to capture the complexity of decision-making preferences and highlight potential conflicts between patients' preferences and clinicians' surrogate decision-maker identification in usual clinical practice. DESIGN: Prospective qualitative cross-sectional study. SETTING: Two ICUs in a quaternary referral center in the eastern United States. PATIENTS: Convenience sample of patients admitted to the ICU and their family members. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Twenty-six patient-family-clinician units were interviewed. Men were three times more likely than women to have a legally appointed decision-maker that matched their preferred decision-maker as expressed in the interview. Patients who were married or in a long-term relationship were the most consistent group of respondents, with 94% of them selecting their spouse or partner as the preferred decision-maker. The most common reasons for selecting a surrogate decision-maker were intangible themes such as feeling "known" by that person rather than having prior discussions about specific wishes or advance directives. CONCLUSIONS: Asking about a patient's familial network and qualities they value in a surrogate decision-maker may aid ICU teams in honoring patients' wishes for surrogate decision-making. This may be an important supplement to accepted legal hierarchies for proxy decision-makers and advance directive documents. Further studies with larger sample sizes could be used to shed light on the nuances of familial and relationship networks of a more diverse population of respondents.