Critical Care of Patients With Cardiopulmonary Complications of Sarcoidosis.

Sarcoidosis is a systemic inflammatory disease defined by the presence of aberrant granulomas affecting various organs. Due to its multisystem involvement, care of patients with established sarcoidosis becomes challenging, especially in the intensive care setting. While the lungs are typically involved, extrapulmonary manifestations also occur either concurrently or exclusively within a significant proportion of patients, complicating diagnostic and management decisions. The scope of this review is to focus on what considerations are necessary in the evaluation and management of patients with known sarcoidosis and their associated complications within a cardiopulmonary and critical care perspective.

Conduction abnormalities and role of cardiac pacing in cardiac amyloidosis: A systematic review.

Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure, characterized by extracellular deposition of insoluble protein fibrils leading to progressive myocardial dysfunction. The most common types of cardiac amyloidosis are immunoglobin light-chain (AL) and transthyretin (ATTR). Conduction abnormalities are commonly encountered among patients with cardiac amyloidosis and are an important cause of morbidity and mortality. Abnormalities range from infra-Hisian intraventricular conduction delay and bundle branch block to complete atrioventricular block. Pacemaker placement in CA patients follows established guidelines, similar to those for patients without CA, with generally good efficacy. The role and appropriate timing of pacemakers for primary prevention of brady-arrhythmias in CA remains uncertain. While biventricular (BiV) pacing has been shown to improve clinical outcomes in patients with systolic heart failure without CA, there are few data examining the utility of BiV pacing in patients with CA. With the advent of effective treatments for AL and ATTR, appropriate application of pacing is important to support patients with CA and conduction disease through therapeutic trials. This systematic review summarizes the current literature examining the utility of pacing in CA.

Transcriptional control of macrophage polarization.

Macrophages are key regulators of many organ systems, including innate and adaptive immunity, systemic metabolism, hematopoiesis, vasculogenesis, malignancy, and reproduction. The pleiotropic roles of macrophages are mirrored by similarly diverse cellular phenotypes. A simplified schema classifies macrophages as M1, classically activated macrophages, or M2, alternatively activated macrophages. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Transcriptional regulation is central to the differential speciation of macrophages, and several major pathways have been described as essential for subset differentiation. In this review, we discuss the transcriptional regulation of macrophages.

Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.

RATIONALE: The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. OBJECTIVE: Ca2+ promotes cell growth raising the possibility that changes in intracellular Ca2+ initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. METHODS AND RESULTS: Ca2+ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca2+. These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca2+ oscillations in hCPCs were regulated by the release of Ca2+ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca2+ by the sarco-/endoplasmic reticulum Ca2+ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na+-Ca2+ exchanger, store-operated Ca2+ channels and plasma membrane Ca2+ pump were present and functional in hCPCs, they had no direct effects on Ca2+ oscillations. Conversely, Ca2+ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca2+ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca2+ oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. CONCLUSION: IP3R-mediated Ca2+ mobilization control hCPC growth and their regenerative potential.

Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation.

Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.

The young mouse heart is composed of myocytes heterogeneous in age and function.

The recognition that the adult heart continuously renews its myocyte compartment raises the possibility that the age and lifespan of myocytes does not coincide with the age and lifespan of the organ and organism. If this were the case, myocyte turnover would result at any age in a myocardium composed by a heterogeneous population of parenchymal cells which are structurally integrated but may contribute differently to myocardial performance. To test this hypothesis, left ventricular myocytes were isolated from mice at 3 months of age and the contractile, electrical, and calcium cycling characteristics of these cells were determined together with the expression of the senescence-associated protein p16(INK4a) and telomere length. The heart was characterized by the coexistence of young, aged, and senescent myocytes. Old nonreplicating, p16(INK4a)-positive, hypertrophied myocytes with severe telomeric shortening were present together with young, dividing, p16(INK4a)-negative, small myocytes with long telomeres. A class of myocytes with intermediate properties was also found. Physiologically, evidence was obtained in favor of the critical role that action potential (AP) duration and I(CaL) play in potentiating Ca(2+) cycling and the mechanical behavior of young myocytes or in decreasing Ca(2+) transients and the performance of senescent hypertrophied cells. The characteristics of the AP appeared to be modulated by the transient outward K(+) current I(to) which was influenced by the different expression of the K(+) channels subunits. Collectively, these observations at the physiological and structural cellular level document that by necessity the heart has to constantly repopulate its myocyte compartment to replace senescent poorly contracting myocytes with younger more efficient cells. Thus, cardiac homeostasis and myocyte turnover regulate cardiac function.

Modulating the Baseline Impedance: An Adjunctive Technique for Maximizing Radiofrequency Lesion Dimensions in Deep and Intramural Ventricular Substrate: An Adjunctive Technique for Maximizing Radiofrequency Lesion Dimensions in Deep and Intramural Ventricular Substrate.

Background Radiofrequency ablation of intramural ventricular substrate is often limited by insufficient tissue penetration despite high energy settings. As lesion dimensions have a direct and negative relationship to impedance, reducing the baseline impedance may increase the ablation effect on deep ventricular tissue. Methods This study included 16 patients with ventricular tachycardia or frequent ventricular premature complexes refractory to ablation with irrigated catheters. After a failed response to radiofrequency ablation, impedance was modulated by adding or repositioning return patches in an attempt to decrease the circuit impedance. Ablation was repeated at a similar location and power settings, and the effect on arrhythmia suppression and adverse effects were evaluated. Results Six patients with idiopathic ventricular premature complexes originating from the left ventricular summit (n=4) or papillary muscles (n=2), 6 patients with noninfarct related ventricular tachycardia and 4 patients with infarct-related ventricular tachycardia had unsuccessful response to radiofrequency ablation at critical sites (number of applications: 10.4±3.1, power: 42.3±2.9 W, duration: 55.3±25.5 seconds, impedance reduction: 14.6±3.5 Ω, low-ionic solution was used in 81.25%). Modulating the return patches resulted in reduced baseline impedance (111.7±8.2 versus 134.7±6.6 Ω, P<0.0001), increased current output (0.6±0.02 versus 0.56±0.02 Amp; P<0.0001) and greater impedance drop (16.8±3.0 Ω, P<0.001). Repeat ablation at similar locations had a successful effect in 12 out of 16 (75.0%) patients. During a follow-up duration of 13±5 months, 10 out of 12 (83.3%) patients remained free of arrhythmia recurrence. The frequency of steam pops was similar between the higher and lower baseline impedance settings (7.1 versus 8.2%; P=0.74). Conclusions In patients with deep ventricular substrate, reducing the baseline impedance is a simple, safe, and effective technique for increasing the effect of radiofrequency ablation. However, its combination with low-ionic solutions may increase the risk for steam pops and neurological events.

Incremental Value of Left Atrial Geometric Remodeling in Predicting Late Atrial Fibrillation Recurrence After Pulmonary Vein Isolation: A Cardiovascular Magnetic Resonance Study.

Background Left atrial ( LA ) enlargement is a marker for increased risk of atrial fibrillation ( AF ). However, LA remodeling is a complex process that is poorly understood, and LA geometric remodeling may also be associated with the development of AF . We sought to determine whether LA spherical remodeling or its temporal change predict late AF recurrence after pulmonary vein isolation ( PVI ). Methods and Results Two hundred twenty-seven consecutive patients scheduled for their first PVI for paroxysmal or persistent AF who underwent cardiovascular magnetic resonance before and within 6 months after PVI were retrospectively identified. The LA sphericity index was computed as the ratio of the measured LA maximum volume to the volume of a sphere with maximum LA length diameter. During mean follow-up of 25 months, 88 patients (39%) experienced late recurrence of AF . Multivariable Cox regression analyses identified an increased pre- PVI LA sphericity index as an independent predictor of late AF recurrence (hazard ratio, 1.32; 95% confidence interval, 1.07-1.62, P=0.009). Patients in the highest LA sphericity index tertile were at highest risk of late recurrence (highest versus lowest: 59% versus 28%; P<0.001). The integration of the LA sphericity index to the LA minimum volume index and passive emptying fraction provided important incremental prognostic information for predicting late AF recurrence post PVI (categorical net reclassification improvement, 0.43; 95% confidence interval, 0.16-0.69, P=0.001). Conclusions The assessment of pre- PVI LA geometric remodeling provides incremental prognostic information regarding late AF recurrence and may be useful to identify those for whom PVI has reduced success or for whom more aggressive ablation or medications may be useful.

The role of the proteasome-ubiquitin pathway in regulation of the IFN-gamma mediated anti-VSV response in neurons.

Pharmacologic inhibition of the proteasome resulted in increased NOS-1 protein levels and increased NO production by neuronal cells. This correlated with an increased antiviral effect of IFN-gamma against the replication of vesicular stomatitis virus (VSV) replication in vitro. We also observed that a regulatory protein, Protein Inhibitor of NOS-1 (PIN) was down-regulated by IFN-gamma treatment, and more ubiquitinated PIN accumulated in IFN-gamma treated neurons. In cells of the reticuloendothelial system, IFN-gamma treatment induces the expression of a set of low molecular weight MHC-encoded proteins (LMPs), which replace the beta-subunit of the proteasome complex during the proteasome neosynthesis, resulting in a complex termed the immunoproteasome. LMP2, -7, and -10 were induced and the immunoproteasome was generated by IFN-gamma treatment in neuronal cells. Importantly, we observed that IFN-gamma induced inhibition of VSV protein synthesis was not dependent on ubiquitination.

Multi-drug-resistant Klebsiella pneumoniae pancreatitis: a new challenge in a serious surgical infection.

BACKGROUND: Klebsiella pneumoniae is an important cause of nosocomial infections, but its role in severe acute pancreatitis (SAP) is not well defined. Few cases of K. pneumoniae associated SAP have been reported. Due to the emergence of extended-spectrum beta-lactamases (ESBLs) and carbapenemases, treatment of multidrug-resistant (MDR) K. pneumoniae presents a challenge. Tigecycline and colistin have gained recent attention for their broad-spectrum antimicrobial activity. METHODS: We describe a case of SAP due to K. pneumoniae bearing K. pneumoniae carbapenemase (KPC) treated successfully with colistin plus tigecycline and offer a review of similar experiences published in the literature. RESULTS: The case reported herein required surgical drainage of multiple pancreatic abscesses and treatment with tigecycline and colistin. Our comparative analysis revealed a number of unique features associated with SAP due to K. pneumoniae: 1) underlying pancreatic injury, 2) multiple drug resistance determinants and virulence factors that complicate treatment, and 3) surgical debridement as a requirement for cure. CONCLUSION: As the prevalence of K. pneumoniae bearing KPC continues to increase in the healthcare setting, SAP caused by this MDR pathogen will become more common. Tigecycline plus colistin was a successful antibiotic regimen for the treatment of SAP due to K. pneumoniae bearing KPC.

Circadian control of bile acid synthesis by a KLF15-Fgf15 axis.

Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. Production of bile acids (BAs), which facilitate digestion and absorption of nutrients, is a major regulator of this process. Here we identify a KLF15-Fgf15 signalling axis that regulates circadian BA production. Systemic Klf15 deficiency disrupted circadian expression of key BA synthetic enzymes, tissue BA levels and triglyceride/cholesterol absorption. Studies in liver-specific Klf15-knockout mice suggested a non-hepatic basis for regulation of BA production. Ileal Fgf15 is a potent inhibitor of BA synthesis. Using a combination of biochemical, molecular and functional assays (including ileectomy and bile duct catheterization), we identify KLF15 as the first endogenous negative regulator of circadian Fgf15 expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis.