Ca handling during excitation–contraction coupling in heart failure

In the heart, coupling between excitation of the surface membrane and activation of contractile apparatus is mediated by Ca released from the sarcoplasmic reticulum (SR). Several components of Ca machinery are perfectly arranged within the SR network and the T-tubular system to generate a regular Ca cycling and thereby rhythmic beating activity of the heart. Among these components, ryanodine receptor (RyR) and SR Ca ATPase (SERCA) complexes play a particularly important role and their dysfunction largely underlies abnormal Ca homeostasis in diseased hearts such as in heart failure. The abnormalities in Ca regulation occur at practically all main steps of Ca cycling in the failing heart, including activation and termination of SR Ca release, diastolic SR Ca leak, and SR Ca uptake. The contributions of these different mechanisms to depressed contractile function and enhanced arrhythmogenesis may vary in different HF models. This brief review will therefore focus on modifications in RyR and SERCA structure that occur in the failing heart and how these molecular modifications affect SR Ca regulation and excitation–contraction coupling.     

Rural and urban microbiota: To be or not to be?

A multitude of metagenomic studies has brought to light an enormous richness of human gut microbiota compositions. In this space of possible configurations, clinical specialists are trying to mine the markers of healthy microbiota via case-control and longitudinal studies. We have discovered potentially beneficial communities while examining the microbial diversity in rural Russians in comparison with the urban dwellers. In this addendum, we further examine the data by elaborating on some of the less common types and suggesting the possible co-metabolism of their drivers. In the light of the first validated clinically effective bacterial transplantation, we discuss the concept of a reference healthy microbiota, outline the problems encountered on the way to its restoration in the developed world, and speculate if rural communities can serve as a source for its prototype.     

Inhibition of macrophage fatty acid β-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses

Aims/hypothesis

Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA.

Methods

We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures.

Results

To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD.

Conclusions/interpretation

Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.     

Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases. Corallococcus coralloides synthesizes corallopyronin A, a noncompetitive inhibitor of RNA polymerase ineffective against Mycobacterium spp. Corallopyronin A depleted Wolbachia from infected insect cells (1.89 Thus the antibiotic is effective against intracellular bacteria despite the many intervening surfaces (blood vessels, pleura, worm cuticle) and membranes (worm cell, vesicle, Wolbachia inner and outer membranes). Corallopyronin A is an antibiotic to develop further for filariasis elimination without concern for cross-resistance development in tuberculosis.     

Comparison of squatting stress echocardiography and dobutamine stress echocardiography for the diagnosis of coronary artery disease

Background: Dobutamine stress echocardiography (DSE) is commonly used for the diagnosis for coronary artery disease (CAD). We previously demonstrated that squatting induces wall motion abnormalities (WMA) in areas subtended by stenotic coronary arteries. Objective: This study was designed to test the hypothesis that dobutamine and squatting stress echocardiography are equally useful for the diagnosis of CAD. Methods: We studied 39 patients who were scheduled to have coronary angiography for the evaluation of chest pain. Each patient had squatting stress echocardiography followed by DSE. For squatting stress echocardiography the echocardiogram in standard views was recorded in the standing position. The procedure was repeated during squatting for 2 minutes. Dobutamine echocardiography was performed using standard protocol. The squatting and dobutamine stress echocardiograms were interpreted by an observer blinded to the results of coronary angiography. Results: During squatting, new or worsening WMA developed in 20 patients. Six patients developed WMA in the left anterior descending artery territory, three in circumflex territory, three in the right coronary artery territory, and eight in multiple coronary territories. The sensitivity, specificity, and accuracy of squatting echocardiography for diagnosis of CAD were 95%, 94%, and 94%, respectively. For DSE, the sensitivity, specificity, and accuracy for the diagnosis of CAD were 85%, 94%, and 90%, respectively. There was no significant difference between squatting and dobutamine stress echocardiography for the diagnosis of CAD (P = 0.702). Conclusion: These data indicate that squatting and dobutamine echocardiography are equally useful in the diagnosis of CAD. In selected patients, squatting echocardiography may be used in place of dobutamine echocardiography for the diagnosis of CAD. (Echocardiography 2012;29:695–699)     

Stress‐induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC‐vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre‐ and post‐exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post‐exposure). We found that soldiers with decreased HC volume following military service (i.e., post‐exposure) displayed more PTSD‐related symptoms post‐exposure as well as reduced HC‐vmPFC functional and structural connectivity post‐exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre‐exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress‐induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential. Hum Brain Mapp 34:2808–2816, 2013. © 2012 Wiley Periodicals, Inc.     

Sleep Apnea: Is Routine Preoperative Screening Necessary?

Background

Because perioperative complications of unrecognized obstructive sleep apnea (OSA) can be severe, many bariatric surgery programs routinely screen all patients. However, many obese non-bariatric surgery patients do not get screened. We wanted to evaluate the need for routine preoperative OSA screening.

Methods

Morbidly obese patients with a body mass index (BMI)?>?40 kg/m² undergoing bariatric surgery—all screened for OSA—were compared to morbidly obese orthopedic lower extremity total joint replacements (TJR) patients—not screened for OSA. Cardio-pulmonary complications were recorded.

Results

Eight hundred eighty-two morbidly obese patients undergoing either bariatric (n?=?467) or orthopedic TJR surgery (n?=?415) were compared. As a result of screening, 119 bariatric surgery patients (25.5 %) were newly diagnosed with OSA, bringing the incidence to 42.8 % (200/467). Orthopedic surgery group had 72 of 415 (17.3 %) patients with pre-existing OSA. The unscreened orthopedic patients had a 6.7 % (23/343) cardiopulmonary complications rate compared to 2.6 % (7/267) for screened bariatric surgery patients. This difference was not statistically significant when adjusted for age and comorbidity (p?=?0.3383).

Conclusion

Sleep apnea screening prior to bariatric surgery identifies an additional 25 % of patients as having OSA. In this study, unscreened morbidly obese patients did not have an increased incidence of cardiopulmonary complications after surgery compared to screened patients. Prospective randomized studies should be conducted to definitively assess utility and cost effectiveness of routine OSA screening of all morbidly obese patients undergoing surgery. Preoperative OSA screening may be safely omitted when randomizing patients for such a trial.