Jobst-Hendrik Schultz

Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin

1 The transient outward K+ current (Ito) is a major repolarizing ionic current in ventricular myocytes of several mammals. Recently it has been found that its magnitude depends on the origin of the myocyte and is regulated by a number of physiological and pathophysiological signals. 2 The relationship between the magnitude of Ito, action potential duration (APD) and Ca2+ influx (QCa) was studied in rat left ventricular myocytes of endo‐ and epicardial origin using whole‐cell recordings and the action potential voltage‐clamp method. 3 Under control conditions, in response to a depolarizing voltage step to +40 mV, Ito averaged 12.1 ± 2.6 pA pF−1 in endocardial (n= 11) and 24.0 ± 2.6 pA pF−1 in epicardial myocytes (n= 12; P < 0.01). APD90 (90 % repolarization) was twice as long in endocardial myocytes, whereas QCa inversely depended on the magnitude of Ito. L‐type Ca2+ current density was similar in myocytes from both regions. 4 To determine the effects of controlled reductions of Ito on QCa, recordings were repeated in the presence of increasing concentrations of the Ito inhibitor 4‐aminopyridine. 5 Inhibition of Ito by as little as 20 % more than doubled QCa in epicardial myocytes, whereas it had only a minor effect on QCa in myocytes of endocardial origin. Further inhibition of Ito led to a progressive increase in QCa in epicardial myocytes; at 90 % inhibition of Ito, QCa was four times larger than the control value. 6 We conclude that moderate changes in the magnitude of Ito strongly affect QCa primarily in epicardial regions. An alteration of Ito might therefore allow for a regional regulation of contractility during physiological and pathophysiological adaptations.

Effects of Peyton's Four-Step Approach on Objective Performance Measures in Technical Skills Training: A Controlled Trial

Background: Although skills-lab training is widely used for training undergraduates in technical procedures, the way in which clinical skills are to be used and instructed remains a matter of debate. Purpose: We conducted a randomized controlled trial to evaluate the learning outcome of two different instructional approaches in the context of acquiring procedural–technical skills. Methods: Volunteer 2nd- and 3rd-year medical students were randomly assigned to an intervention group receiving instruction according to Peytons Four-Step Approach (IG; n = 17) or to a control group receiving standard instruction (CG; n = 17). Both groups were taught gastric-tube insertion using a manikin. Following each of the two forms of instruction, participants’ first independent gastric-tube insertions were video recorded and scored by two independent video assessors using binary checklists and global rating forms. The time required for each instructional approach and for the first independent performance of the skill was measured. Results: A total of 34 students agreed to participate in the trial. There were no statistically significant group differences with regard to age, sex, completed education in a medical profession, or completed medical clerkships. The groups did not differ in terms of correct stepwise performance of the procedure as assessed by a binary checklist (p < .802). However, ratings based on global rating scales assessing professionalism and accompanying patient-doctor communication proved significantly better in IG (both ps < .001). The length of the different instructional approaches did not differ significantly between the two groups (IG: 605 ± 65 s; CG: 572 ± 79 s; p < .122), but the time needed for the first independent performance of gastric-tube placement on the manikin was significantly shorter in IG (IG: 168 ± 30 s; CG: 242 ± 53 s; p < .001). Conclusions: Peytons Four-Step Approach is superior to standard instruction with respect to professionalism and accompanying doctor–patient communication and leads to faster performance when trainees perform the learned skill for the first time.

Heterogeneity of Kv2.1 mRNA Expression and Delayed Rectifier Current in Single Isolated Myocytes From Rat Left Ventricle

Expression of the voltage-gated K+ channel Kv2.1, a possible molecular correlate for the cardiac delayed rectifier current (IK), has recently been shown to vary between individual ventricular myocytes. The functional consequences of this cell-to-cell heterogeneity in Kv2.1 expression are not known. Using multiplex single-cell reverse transcriptase–polymerase chain reaction (RT-PCR), we detected Kv2.1 mRNA in 47% of isolated midmyocardial myocytes from the rat left ventricular free wall that were positive for &agr;-myosin heavy chain mRNA (n= 74). Whole-cell patch-clamp recordings demonstrated marked differences in the magnitude of IK (200 to 1450 pA at VPip=40 mV) between individual myocytes of the same origin. Furthermore, the tetraethylammonium (TEA)–sensitive outward current (ITEA), known to be partly encoded by Kv2.1 in mice, revealed a wide range of current magnitudes between single cells (150 to 1130 pA at VPip=40 mV). Combined patch-clamp recordings and multiplex single-cell RT-PCR analysis of the same myocytes, however, showed no differences in IK or ITEA magnitude or inactivation kinetics between myocytes expressing Kv2.1 mRNA and those that did not express Kv2.1 mRNA. In contrast, in all midmyocardial myocytes expressing the transient outward potassium current (Ito1), Kv4 mRNA, which has been shown to underlie Ito1, was detected (n= 10). These results indicate that IK heterogeneity among individual left ventricular myocytes cannot be explained by the distribution pattern of Kv2.1 mRNA. Other mechanisms besides Kv2.1 mRNA expression appear to determine magnitude and kinetics of IK in rat ventricular myocytes.

Association of anxious and depressive symptoms with medication nonadherence in patients with stable coronary artery disease

OBJECTIVE Depression and anxiety lead to increased morbidity and mortality in patients with coronary artery disease (CAD). Medication nonadherence is one possible pathway contributing to adverse outcome, but it is unknown how either depression or anxiety itself influences adherence compared to combined depressive-anxious comorbidity. The aim of the study was to evaluate the influence of simultaneous depressive and anxious symptoms on medication adherence in patients with stable CAD. METHODS Between 02/2009 and 06/2010 we examined the association between current depressive and anxious symptoms with medication nonadherence in a cross-sectional study of 606 inpatients with stable CAD. Symptoms were assessed by using the Hospital Anxiety and Depression Scale. Morisky Medical Adherence Scale measured medication adherence. RESULTS Depressive and anxious symptoms were weakly and independently associated with medication nonadherence (r=0.28, p<0.01 and r=0.27, p<0.01 respectively). Compared to non-depressed, patients with depressive symptoms had an up to 3.6-fold odds, those with anxious symptoms an up to 3.2-fold odds of nonadherence. The presence of combined anxiety and depressive symptoms was also weakly correlated with adherence (r=0.30, p<0.01). The risk for nonadherence in patients suffering from both anxiety and depression was up to 4.4 times higher compared to patients without symptoms. CONCLUSION Apart from depressive symptoms, anxiety is a second important and independent marker for nonadherence in patients with coronary artery disease. The negative effect of anxiety on medication adherence increases in case of comorbid depressive symptoms. Future studies addressing medication adherence should focus more on anxious-depressive comorbidity than on singular depressive or anxious symptoms.

The A-allele of the common FTO gene variant rs9939609 complicates weight maintenance in severe obese patients

Objective:The A-allele of the fat mass and obesity-associated (FTO) gene variant rs9939609 has been associated with increased body weight, whereas no effect on weight loss during weight reduction programs has been observed. We questioned whether the AA-genotype interferes with weight stabilization after weight loss.Design:We conducted a monocentric, longitudinal study involving obese individuals. The FTO gene variant rs9939609 was genotyped in participants attending a weight reduction program that was divided into two phases: a weight reduction period with formula diet (12 weeks) and a weight maintenance phase (40 weeks). Body weight, body mass index (BMI), blood pressure and concentrations of blood glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides were determined in week 0 (T0), after 12 weeks (T1) and at the end in week 52 (T2).Subjects:A total of 193 obese subjects aged between 18 and 72 years (129 female, 64 male; initial body weight: 122.4±22.3 kg, initial BMI: 41.8±6.7 kg m−2) were included.Results:Genotyping revealed 32.1% TT-, 39.4% AT- and 28.5% AA-genotype carriers. At T 0, carriers of the AA-genotype had significantly higher body weight (P=0.04) and BMI (P=0.005) than carriers of the TT-genotype. Of the 193 participants, 68 discontinued and 125 completed the program. Dropout rate was not influenced by genotype (P=0.33). Completers with AA-genotype showed significantly lower additional weight loss during the weight maintenance phase than TT-genotype carriers (P=0.02). Furthermore, among participants facing weight regain during weight maintenance (n=52), more subjects were carrying the AA-genotype (P=0.006). No influence of genotype on weight reduction under formula diet was observed (P=0.32).Conclusion:In this program, the AA-genotype of rs9939609 was associated with a higher initial body weight and did influence success of weight stabilization. Thus, emphasizing the maintenance phase during a weight reduction program might result in better success for AA-genotype carriers.

TaqIA polymorphism in dopamine D2 receptor gene complicates weight maintenance in younger obese patients

OBJECTIVE The A1 allele of the TaqIA polymorphism in the dopamine D2 receptor gene (rs1800497) has been associated with obesity. However, the effect of the polymorphism on the success in weight loss and/or weight maintenance during weight-loss programs has not been evaluated thus far. METHODS The rs1800497 was genotyped in 202 (135 female, 67 male) severely obese individuals with an initial body mass index of 41.7 ± 0.5 kg/m² who participated in a weight-loss program consisting of a weight-loss phase with a formula diet (12 wk) and a weight-maintenance phase (40 wk). Measurements were collected at baseline, after the weight-loss phase, and at the end of the weight-maintenance phase at 1 y. RESULTS Genotyping revealed 4 A1A1, 67 A1A2, and 131 A2A2 genotype carriers. Of the 202 subjects in the program, 66.8% completed the program and 33.2% terminated prematurely. Neither the attrition rate (P = 0.44) nor the overall weight loss was influenced by the different genotypes (P = 0.96). However, younger A1⁺ participants (A1A1 and A1A2) had a higher body mass index at all time points (baseline, P = 0.04; after weight loss, P = 0.05; after weight maintenance, P = 0.02). They also showed less overall weight loss (P = 0.05), which derived mainly from a greater weight regain during the maintenance phase (P = 0.02). CONCLUSION In this program, younger A1⁺ participants exhibited problems in maintaining weight loss during a weight-loss program.

Molecular and functional characterization of Kv4.2 and KChIP2 expressed in the porcine left ventricle.

Recent studies showed that the Ca2+-independent transient outward current (Ito) is very small or even not detectable in the porcine left ventricle. We investigated whether an altered molecular expression or function of voltage-dependent potassium channels belonging to the Kv4 sub-family and their ancillary Ca2+-binding β sub-unit KChIP2, which contribute to the major fraction of Ito in other species, may underlie this lack of a significant Ito in the porcine left ventricle. RT-PCR analysis with degenerate primers showed that both Kv4 mRNA and KChIP2 mRNA are expressed in porcine left ventricular tissue and in isolated ventricular myocytes. PCR cloning and sequence analysis predicted proteins with >98% identity to rat and human Kv4.2 and >99% identity to rat and human KChIP2. Heterologous expression of porcine Kv4.2 in Xenopus laevis oocytes gave rise to currents with characteristic properties of rat and human Kv4.2, and co-expression with its KChIP2 sub-unit increased current density (tenfold), slowed inactivation (twofold) and accelerated recovery from inactivation (tenfold). Kv4.2 immunohistochemistry in porcine left ventricular tissue revealed a predominant membrane-bound signal. Relative quantification of gene expression indicated that Kv4.2 and KChIP2 mRNA and protein are expressed at comparable ratios in porcine and rat left ventricular tissues, which displays a large Ito. Collectively, these data demonstrate that the lack of a significant Ito in the porcine left ventricle does not result from dysfunctional or insufficiently expressed Kv4.2 and KChIP2 sub-units.

Introducing a curricular program culminating in a certificate for training peer tutors in medical education.

Aim: Student tutorials are now firmly anchored in medical education. However, to date there have only been isolated efforts to establish structured teacher training for peer tutors in medicine. To close this gap, a centralized tutor training program for students, culminating in an academic certificate, was implemented at Heidelberg University Medical School. The program also counts within the scope of the post-graduate Baden-Württemberg Certificate in Academic Teaching (Baden-Württemberg Zertifikat für Hochschuldidaktik). Method: Based on a needs assessment, a modular program comprised of four modules and a total of 200 curricular units was developed in cooperation with the Department for Key Competencies and Higher Education at Heidelberg University and implemented during the 2010 summer semester. This program covers not only topic-specific training sessions, but also independent teaching and an integrated evaluation of the learning process that is communicated to the graduates in the form of structured feedback. In addition, to evaluate the overall concept, semi-structured interviews (N=18) were conducted with the program graduates. Results: To date, 495 tutors have been trained in the basic module on teaching medicine, which is rated with a mean overall grade of 1.7 (SW: 0.6) and has served as Module I of the program since 2010. A total of 17% (N=83) of these tutors have gone on to enroll in the subsequent training modules of the program; 27 of them (m=12, f=15) have already successfully completed them. Based on qualitative analyses, it is evident that the training program certificate and its applicability toward the advanced teacher training for university instructors pose a major incentive for the graduates. For successful program realization, central coordination, extensive coordination within the medical school, and the evaluation of the attained skills have proven to be of particular importance. Conclusion: The training program contributes sustainably to both quality assurance and professionalism, as well as to solving the issue of resources in medical education. The introduction and continued development of similar programs is desirable.

Anxiety and self-care behaviour in patients with chronic systolic heart failure: A multivariate model:

Background: While comprehensive evidence exists regarding negative effects of depression on self-care behaviours in patients with chronic heart failure (CHF), the relation between anxiety and self-care behaviours in patients with CHF is not clear. The aim of this study was to analyse the interactions between anxiety, depression and self-care behaviours in patients with CHF. Methods: The self-care behaviour of CHF outpatients was measured using the European Heart Failure Self-care Behaviour Scale (EHFScBS). The Patient Health Questionnaire (PHQ) was used to assess anxiety, the PHQ-9 was used to measure depression severity. Differences between patients with and without anxiety were assessed with the respective tests. Associations between anxiety, self-care and other predictors were analysed using linear regressions. Results: Of the 308 participating patients, 35 (11.4%) fulfilled the PHQ criteria for an anxiety disorder. These patients took antidepressants more frequently (11.8% versus 2.3%, p = .02), had had more contacts with their general practitioner within the last year (11.8 ± 16.1 versus 6.7 ± 8.6, p = .02), and had a higher PHQ-9 depression score (12.9 ± 5.7 versus 6.5 ± 4.7, p < .01) than patients without anxiety disorder. Anxiety and self-care were negatively associated (ß = −0.144, r2 = 0.021, p = 0.015). The explanation of variance was augmented in a multivariate regression with the predictors age, sex, education, living with a partner, and New York Heart Association (NYHA) class (r2 = 0.098) when anxiety was added (r2 = 0.112). Depression further increased the explanation of variance (ß = −0.161, r2 = 0.131, p = 0.019). Conclusions: Anxiety is negatively associated with self-care behaviour in patients with CHF. However, this effect disappears behind the stronger influence of depression on self-care. The consideration of mental comorbidities in patients with CHF is important.

The Effects of Mitral Valve Repair on Memory Performance, Executive Function, and Psychological Measures in Patients With Heart Failure.

Objectives Heart failure (HF) is a prevalent disease that remains costly and associated with a high mortality rate. HF is also associated with poor neurocognitive functioning. For the treatment for HF patients with severe mitral regurgitation, the MitraClip device has emerged as a promising interventional tool that reduces the mitral valve leakage and thus increases cardiac output. Currently, there is only limited knowledge on changes in cognitive and psychosocial functioning before and after the MitraClip intervention. Methods Cognitive function (memory and executive function) and psychosocial measures (depression, anxiety, and quality of life) were assessed before and after the MitraClip intervention in 24 HF patients and 23 healthy participants (comparison group). Results MitraClip intervention in HF patients was followed by improvements in figural long-term memory (p = .003) and executive function (planning ability, p < .001) relative to the comparison group. In addition, the intervention resulted in a significant improvement in depression (p = .002), anxiety (p = .003) and quality of life scores (physical p = .017, mental p = .013) as well as improved 6-minute walk test results over time (p = .002). Conclusions The presented data provide evidence of a significant improvement in memory and executive function as well as in depression, anxiety, and quality of life scores in patients with chronic HF after MitraClip intervention. Further research is needed to shed light on the long-term development of cognitive function, psychosocial well-being, and clinical parameters after MitraClip intervention and how these factors depend on one another.