Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

Background

After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.

Objectives

The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients.

Methods

LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated.

Results

Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation.

Conclusions

The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.     

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease

Background

Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).

Methods and results

We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.

Conclusions

In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.     

Positive remodeling at 3 year follow up is associated with plaque free coronary wall segment at baseline: A serial IVUS study

Aims

At present it is unknown what limits the arterial remodeling process during atherosclerotic plaque formation. In healthy arteries remodeling is regulated by the shear stress induced response by the endothelium. As endothelium at the plaque site is assumed to be dysfunctional, we tested the hypothesis that plaque free wall (PFW) determines vascular remodeling during atherosclerotic plaque build-up.

Methods & results

66 human coronary ROIs (38 patients) were studied at baseline and at 3 years follow up applying intravascular ultrasound (IVUS). From the IVUS images the lumen and external elastic membrane contours were delineated to assess wall thickness (WT), vessel area (VA), Plaque Area (PA) and plaque burden (PA/VA*100%). WT < 0.5 mm was defined as normal and determined the arc of the PFW (0–360°). Positive remodeling was defined as relative difference of VA over time >5%. At baseline, IVUS-PFW was inversely related to plaque burden (p < 0.05). Positive remodeling was most frequently observed in ROIs with IVUS-PFW > 180° (i.e. larger than half of the circumference) compared to PFW < 180° (55% vs. 12%, p < 0.05). Accordingly, plaques with IVUS-PFW > 180° at baseline had the largest change in VA (1.1 ± 2.1 vs. −0.4 ± 0.6 mm², p < 0.05) with an odds ratio of 9.2 to develop positive remodeling.

Conclusions

Our serial IVUS data show that IVUS-PFW is a determinant of vascular remodeling. ROIs with PFW > 180 at baseline had the highest probability to undergo positive remodeling.     

Competencies of specialised wound care nurses: a European Delphi study

Health care professionals responsible for patients with complex wounds need a particular level of expertise and education to ensure optimum wound care. However, uniform education for those working as wound care nurses is lacking. We aimed to reach consensus among experts from six European countries as to the competencies for specialised wound care nurses that meet international professional expectations and educational systems. Wound care experts including doctors, wound care nurses, lecturers, managers and head nurses were invited to contribute to an e‐Delphi study. They completed online questionnaires based on the Canadian Medical Education Directives for Specialists framework. Suggested competencies were rated on a 9‐point Likert scale. Consensus was defined as an agreement of at least 75% for each competence. Response rates ranged from 62% (round 1) to 86% (rounds 2 and 3). The experts reached consensus on 77 (80%) competences. Most competencies chosen belonged to the domain ‘scholar’ (n = 19), whereas few addressed those associated with being a ‘health advocate’ (n = 7). Competencies related to professional knowledge and expertise, ethical integrity and patient commitment were considered most important. This consensus on core competencies for specialised wound care nurses may help achieve a more uniform definition and education for specialised wound care nurses.     

Educational paper: Parenting a child with a disfiguring condition—how (well) do parents adapt?

Studies indicate serious levels of stress among parents of children with a medical condition. Moreover, adaptation seems to be a specific challenge for parents of children with a disfiguring condition because of the visible nature of the condition. In the present overview, we performed a literature search in PubMed, Embase, and PsycINFO to identify both qualitative and quantitative studies concerning psychological distress among parents of children with a disfiguring condition. Two of the authors critically appraised the retrieved citations. A total of 1,459 publications were identified, of which 21 qualitative and 22 quantitative studies met our inclusion criteria. Most qualitative studies infer that the birth of a child with a disfiguring condition starts an adaptation process in which parents experience a range of negative emotions and have concerns related to the visible nature of the condition. The results of quantitative studies are mixed and contradictory, and together suggest that some, but not all parents of a child with a disfiguring condition experience stress. Methodological limitations of the quantitative studies and potential stressors are discussed, and recommendations for future research are made. Conclusion The present overview neither shows that the existing literature is conclusive about the perceived strain among the parents of children with a disfiguring condition nor does it provide evidence for a relationship between visibility and parental strain.     

The efficacy of the back school: An analysis of the literature

One of the possible treatments for patients suffering from low back pain is the so-called back school, which is of Swedish origin. Back schools offer an education and skills program in a group setting, directed toward pain management and consisting of elements of education and/or training of skills. The contents and, briefly, the efficacy of all reported and evaluated back schools in a group setting are presented. Based on the different contents of back schools and the necessity of a multidimensional approach to treating low back pain, we designed the Maastricht Back School to be a combination of all those elements about which we consider a back school should give information and/or training.     

Glucosamine sulfate and cartilage type II collagen degradation in patients with knee osteoarthritis: randomized discontinuation trial results employing biomarkers

OBJECTIVE: To determine whether glucosamine sulfate has an effect on cartilage type II collagen degradation in patients with knee osteoarthritis (OA). METHODS: A randomized, double blind, placebo controlled glucosamine discontinuation trial was conducted in 137 subjects with knee OA, who had had at least moderate relief of knee pain after starting glucosamine. Subjects were randomized to glucosamine at prestudy dose or placebo at an equivalent dose. Treatment was continued to Week 24 or disease flare, whichever occurred first. Serum and urine samples were collected at Weeks 0, 4, 12, and 24 or flare visit. Samples were analyzed in triplicate for 2 type II collagen degradation biomarkers: C2C epitope (COL2-3/4C(long)) and C1,2C epitope (COL2-3/4C(short)). The primary outcome was the mean change in serum and urine C1,2C/C2C ratio in the glucosamine and placebo groups from baseline to final (flare or Week 24) visit. Linear regression analyses were conducted to adjust for potential confounders. Due to non-normal distributions, the data were log-transformed (lnC1,2C/C2C). Secondary outcomes included comparison of mean change scores at final visit compared to baseline for serum and urine C1,2C and C2C in the 2 treatment groups and in Flare versus No-Flare groups. RESULTS: Baseline and final visit samples were available in 130 subjects for serum analysis and 126 subjects for urinalysis. No significant difference was seen between placebo and glucosamine groups in the serum C1,2C/C2C ratio, with a mean (SD) change from baseline to final visit of 0.8 (27.8) and -0.1 (1.8), respectively (mean difference 0.9; 95% CI -6.0, 7.7, p = 0.80). Similarly, no differences between treatment groups were seen for mean change in urine C1,2C/C2C (p = 0.82), or for mean change in C2C or C1,2C. In linear regression analysis, after adjustment for sex, radiographic severity, baseline lnC1,2C/C2C ratio, WOMAC function, and flare status, treatment was not a significant predictor of final serum or urine lnC1,2C/C2C ratio. When those who experienced flare were contrasted with those without flare, there was a nonsignificant trend toward a difference in mean baseline to final visit change score for serum C1,2C/C2C ratio (p = 0.12). In addition, in the multivariable linear regression analysis, flare status showed a borderline association with final visit serum lnC1,2C/C2C ratio (p = 0.16). CONCLUSION: No statistically significant effect of glucosamine sulfate on type II collagen fragment levels in serum or urine was observed for knee OA over 6 months. Further research is necessary to elucidate which biopathologic systems, if any, are affected by glucosamine treatment. While collagen degradation products may be of value in predicting progression, at least as defined by clinical flare, a larger dataset would be needed to prove this.     

Hematopoietic plakophilin‐3 regulates acute tissue‐specific and systemic inflammation in mice

Plakophilin‐3 (PKP3) is a member of the armadillo protein family, which is important in cell?cell contacts and signaling during development and tumorigenesis. In conventional facilities, PKP3‐deficient mice (PKP3^?/?) develop spontaneous dermatitis, indicating a possible involvement of PKP3 in inflammatory responses. Here, we show that PKP3 deficiency sensitizes mice to irritant contact dermatitis induced by phorbol myristate acetate (PMA). This sensitization occurred in mice with PKP3 deficiency in the hematopoietic system (PKP3^?/?hem), but not if the deficiency was specific to skin keratinocytes (PKP3^?/?ker). In a model of dextran sulfate sodium induced colitis, ubiquitous PKP3 deletion, but not intestinal epithelial PKP3 deficiency (PKP3^?/?IEC), impaired survival from disease. Interestingly, PKP3^?/?hem mice also displayed increased sensitivity to dextran sulfate sodium induced colitis. Finally, PKP3^?/? mice were more sensitive to the lethality of lipopolysaccharide (LPS) injection than wild‐type (WT) mice, and this phenotype was associated with increased intestinal permeability. PKP3^?/?IEC mice did not reproduce the enhanced endotoxin reactivity of PKP3^?/? mice, in contrast to PKP3^?/?hem mice. Finally, in vitro stimulation of WT neutrophils with LPS or PMA increased Pkp3 expression. In conclusion, our data highlight a novel role for hematopoietic PKP3 in the regulation of both locally and systemically induced immune responses. Nonetheless, further research is needed to unravel the underlying mechanism.     

Protein kinase C α and ε phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium

Previous studies indicated that the increase in protein kinase C (PKC)-mediated myofilament protein phosphorylation observed in failing myocardium might be detrimental for contractile function. This study was designed to reveal and compare the effects of PKCα- and PKCε-mediated phosphorylation on myofilament function in human myocardium. Isometric force was measured at different [Ca²⁺] in single permeabilized cardiomyocytes from failing human left ventricular tissue. Activated PKCα and PKCε equally reduced Ca²⁺ sensitivity in failing cardiomyocytes (ΔpCa₅₀ = 0.08 ± 0.01). Both PKC isoforms increased phosphorylation of troponin I- (cTnI) and myosin binding protein C (cMyBP-C) in failing cardiomyocytes. Subsequent incubation of failing cardiomyocytes with the catalytic subunit of protein kinase A (PKA) resulted in a further reduction in Ca²⁺ sensitivity, indicating that the effects of both PKC isoforms were not caused by cross-phosphorylation of PKA sites. Both isozymes showed no effects on maximal force and only PKCα resulted in a modest significant reduction in passive force. Effects of PKCα were only minor in donor cardiomyocytes, presumably because of already saturated cTnI and cMyBP-C phosphorylation levels. Donor tissue could therefore be used as a tool to reveal the functional effects of troponin T (cTnT) phosphorylation by PKCα. Massive dephosphorylation of cTnT with alkaline phosphatase increased Ca²⁺ sensitivity. Subsequently, PKCα treatment of donor cardiomyocytes reduced Ca²⁺ sensitivity (ΔpCa₅₀ = 0.08 ± 0.02) and solely increased phosphorylation of cTnT, but did not affect maximal and passive force. PKCα- and PKCε-mediated phosphorylation of cMyBP-C and cTnI as well as cTnT decrease myofilament Ca²⁺ sensitivity and may thereby reduce contractility and enhance relaxation of human myocardium.     

Taxonomy and pathogenicity of Ceratocystis species on Eucalyptus trees in South China, including C. chinaeucensis sp. nov.

Commercial plantations of Eucalyptus species have been established in South China, especially during the past 20 years, to meet the needs of a rapidly growing national economy. As part of a survey of fungal diseases affecting Eucalyptus species in South China, Ceratocystis species were collected from Eucalyptus plantations in the GuangDong Province. The aims of this study were to identify these Ceratocystis isolates and to test their pathogenicity to Eucalyptus. The most aggressive isolates were also used to screen different species and clones of Eucalyptus for susceptibility to infection under field conditions. The fungi were identified based on morphology and through comparisons of DNA sequence data of the ITS, partial β-tubulin and TEF-1α gene regions. Morphological and DNA sequence comparisons showed that isolates collected from Chinese Eucalyptus plantations represent two species, C. acaciivora in the C. fimbriata s.l. species complex and a previously undescribed species belonging to the C. moniliformis s.l. species complex, for which the name C. chinaeucensis sp. nov. is provided. In pathogenicity trials, both C. acaciivora and C. chinaeucensis gave rise to lesions on wounded Eucalyptus trees, and the former fungus was most pathogenic. Differences were also observed in the responses of different Eucalyptus clones to inoculation and this could be useful in reducing disease, if C. acaciivora should emerge as a pathogen in the future.