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Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed. [Display omitted] • ANOCA is a common clinical presentation that is variably recognized and managed. • Standardization is needed for the identification, diagnosis, and treatment of patients with ANOCA. • Comprehensive coronary function testing is important for identifying underlying causes of ANOCA in individual patients. [ABSTRACT FROM AUTHOR]

Endothelial cell damage related to coronavirus disease 2019 (COVID‐19) has been described in multiple vascular beds, and many survivors of COVID‐19 report chest pain. This case series describes two previously healthy middle‐aged individuals who survived COVID‐19 and were subsequently found to have symptomatic coronary endothelial dysfunction months after initial infection. [ABSTRACT FROM AUTHOR]

Purpose. New treatment options for acute edema attacks caused by hereditary angioedema (HAE) are reviewed. Summary. HAE is characterized by mutations in the C1 inhibitor gene leading to either a reduced expression of C1 inhibitor in the plasma or expression of a functionally impaired C1 inhibitor. HAE is classified into two major types based on the cause of the C1 inhibitor deficiency. Type I HAE is defined by a reduced expression of C1 inhibitor in the plasma, whereas type II HAE is characterized by the expression of a dysfunctional C1 inhibitor protein. Clinical data were reviewed for C1 inhibitor, ecallantide, and icatibant in the treatment of acute edema attacks caused by HAE. C1 inhibitor leads to a faster onset of edema relief and is effective in decreasing the duration of edema. Dosing strategies include fixed dosing and weight-based dosing. Optimal dosing strategies have not been established, but fixed dosing (500-1000 units) or 20 units/kg has been effective in clinical trials and reports. No comparative trials suggest that one strategy is superior to another; however, the approved labeling for acute treatment is based on weight. Ecallantide is also efficacious for treating acute episodes; however, the available evidence is limited to a single published trial. Icatibant has shown variable effects in two trials with placebo and active controls. Conclusion. In patients with HAE, most edema episodes only involve the skin and gastrointestinal tract, though airway obstruction caused by laryngeal angioedema is the most common cause of death. I.V. C1 inhibitor should be considered first-line treatment for acute edema attacks because of its fast onset of action and effectiveness, though it is not clear whether fixed or weight-based dosing is preferred. Ecallantide can be considered as a second-line treatment option. [ABSTRACT FROM AUTHOR]

Abstract: To investigate the effect of docosahexaenoic acid (DHA) without other highly unsaturated fatty acids (HUFA) on n-3 and n-6 essential fatty acid (EFA) metabolism and fatty acid composition in mammals, a stable isotope tracer technique was used in adult rats fed diets with or without 1.3% of algal DHA in a base diet containing 15% of linoleic acid and 3% of alpha-linolenic acid over 8 weeks. The rats were administered orally a mixed oil containing 48 mg/kg body weight of deuterated linoleic and alpha-linolenic acids and euthanized at 4, 8, 24, 96, 168, 240, 360 and 600 h after administration of the isotopes. Fatty acid compositions and the concentrations of deuterated precursors and their respective metabolites were determined in rat liver, plasma, heart and brain as a function of time. DHA, docosapentaenoic acid and eicosapentaenoic acid in the n-3 EFA family were significantly increased in all organs tested in the DHA-fed group, ranging from 5% to 200% greater in comparison with the control group. The accumulation of the metabolites, deuterated-DHA and deuterated-docosapentaenoic acid n-6 was greatly decreased by 1.5- to 2.5-fold in the dietary DHA group. In summary, feeding preformed DHA led to a marked increase in n-3 HUFA content of rat organs at the expense of n-6 HUFA and also prevented the accumulation of newly synthesized deuterated end products. This is the first study which has isolated the effects of DHA on the de novo metabolism on both the n-6 and n-3 EFA pathways. [Copyright &y& Elsevier]

The effects of ethanol on development of postmitotic neurons include altered neurite outgrowth and differentiation, which may contribute to neuropathology associated with fetal alcohol spectrum disorders. We previously reported that ethanol exposure alters axon growth dynamics in dissociated cultures of rat hippocampal pyramidal neurons. Given the important regulatory role of small Rho guanosine triphosphatases (GTPases) in cytoskeletal reorganization associated with axon growth, and reports that ethanol alters whole cell Rho GTPase activity in other cell types, this study explored the hypothesis that ethanol alters Rho GTPase activity specifically in axonal growth cones. Fetal rat hippocampal pyramidal neurons were maintained in dissociated cultures for 1 day in control medium or medium containing 11 to 43 mM ethanol. Some cultures were also treated with brain-derived neurotrophic factor (BDNF), an activator of Rac1 and Cdc42 GTPases that promotes axon extension. Levels of active Rho GTPases in growth cones were measured using in situ binding assays for GTP-bound Rac1, Cdc42, and RhoA. Axon length, growth cone area, and growth cone surface expression of tyrosine kinase B (TrkB), the receptor for BDNF, were assessed by digital morphometry and immunocytochemistry. Although ethanol increased the surface area of growth cones, the levels of active Rho GTPases in axonal growth cones were not affected in the absence of exogenous BDNF. In contrast, ethanol exposure inhibited BDNF-induced Rac1/Cdc42 activation in a dose-dependent manner and increased RhoA activation at the highest concentration tested. Similar TrkB expression was observed on the surface of axonal growth cones of control and ethanol-treated neurons. These results reveal an inhibitory effect of ethanol on growth cone signaling via small Rho GTPases during early stages of hippocampal development in vitro, and suggest a mechanism whereby ethanol may disrupt neurotrophic factor regulation of axon growth and guidance. [ABSTRACT FROM AUTHOR]

The spacing, timing, and amount of gene expression are crucial for a range of biological processes, including development. For this reason, there have been many attempts to bring gene expression under the control of light. We have previously shown that RNA interference (RNAi) can be controlled with light through the use of siRNA and dsRNA that have their terminal phosphates modified with the dimethoxy nitro phenyl ethyl (DMNPE) group. Upon irradiation, these groups photolyze and release native RNA. The main problem with light activated RNA interference (LARI) to date is that the groups used only partially block RNA interference prior to irradiation, thus limiting the utility of the approach. Here, we describe a new photocleavable group, cyclo-dodecyl DMNPE (CD-DMNPE), designed to completely block the interaction of duplexes with the cellular machinery responsible for RNA interference prior to irradiation. This allowed us to switch from normal to a near complete reduction in gene expression using light, and to construct well-defined patterns of gene expression in cell monolayers. Because this approach is built on the RNA interference pathway, it benefits from the ability to quickly identify duplexes that are effective at low or subnanomolar concentrations. In addition, it allows for the targeting of endogenous genes without additional genetic manipulation. Finally, because of the regiospecificity of CD-DMNPE, it allows a standard duplex to be quickly modified in a single step. The combination of its efficacy and ease of application will allow for the facile control of the spacing, timing, and degree of gene expression in a range of biological systems. [ABSTRACT FROM AUTHOR]

Several studies have been conducted to elucidate the role of free fatty acids (FFAs) in the pathogenesis of type 2 diabetes, but the exact molecular mechanism by which FFAs alter glucose metabolism in the liver is still not completely understood. In a recent publication, Ragheb and co-workers have examined the effect of free fatty acid (FFA) treatment on insulin signaling and insulin resistance by using immunoprecipitation and immunoblotting to study the effect of high concentrations of insulin and FFAs on insulin receptor-beta (IR-β) and downstream elements in the PI3K pathway using the fructose-fed hamster model. Their results clearly show that free fatty acids have an insignificant effect on IR-β and supports previous findings that FFAs lead to insulin resistance in the liver via the PKC-NFκB pathway. [ABSTRACT FROM AUTHOR]

Coronary angiography has been the principle modality for assessing the severity of atherosclerotic coronary artery disease for several decades. However, there is a complex relationship between angiographic coronary stenosis and the presence or absence of myocardial ischemia. Recent technological advances now allow for the assessment of coronary physiology in the catheterization laboratory at the time of diagnostic coronary angiography. Early studies focused on coronary flow reserve (CFR) but more recent work has demonstrated the physiologic accuracy and prognostic value of the fractional flow reserve (FFR) and instantaneous wave free ratio (iFR) for the assessment of coronary artery disease. These measurements have been validated in large multi-center clinical trials and have become indispensable tools for guiding revascularization in the cardiac catheterization laboratory. The physiological assessment of chest pain in the absence of epicardial coronary artery disease involves coronary thermodilution to obtain the index of microcirculatory resistance (IMR) or Doppler velocity measurement to determine the coronary flow velocity reserve (CFVR). Physiology-based coronary artery assessment brings "personalized medicine" to the catheterization laboratory and allows cardiologists and referring providers to make decisions based on objective findings and evidence-based treatment algorithms. The purpose of this review is to describe the theory, technical aspects, and relevant clinical trials related to coronary physiology assessment for an intended audience of general medical practitioners. [ABSTRACT FROM AUTHOR]

Purpose Driveline infection (DLI) is a significant source of morbidity and mortality during left ventricular assist device (LVAD) support yet limited studies are available to describe the center‐level prevalence, preventive practices, and their potential effectiveness. Methods: We surveyed LVAD centers in the United States to determine program burden and preventive practices for DLI during HeartMate (HM) 3 support. An online, anonymous, question‐based survey was sent to expert providers at implanting centers. Only a single respondent completed the survey for each center. As an exploratory analysis, we compared specific DLI preventive practices between centers with low (≤10%) and high (>10%) reported prevalence of DLI. Results: Seventy‐eight centers responded to the survey (response rate: 50%). Respondents were comprised of 37 (47%) heart failure cardiologists, 27 (35%) LVAD coordinators, and 14 (18%) cardiothoracic surgeons. The prevalence of DLI during HM3 was reported as ≤10% by 27 (35%), 11%–25% by 36 (46%), and >25% by 16 (19%) centers. Thirteen (17%) centers had a body mass index threshold for device placement, 29 (37%) utilized a counter incision, 66 (81%) placed an anchor stitch, and 69 (88%) used an external device to stabilize the DL. Proportionally, more centers with a low DLI prevalence used a wound vacuum 6 (22%) versus 3 (6%, p = 0.03) than those with high DLI. Conclusion: Variation exists in reported prevalence and practices of preventing and managing driveline infections across centers during HM3 support. Further studies are warranted to develop and assess the effectiveness of standardized preventive strategies. [ABSTRACT FROM AUTHOR]

Intrinsic excitability is a plastic property of cells that, along with synaptic changes, can be modulated by learning. Action potential (AP) height, width, and frequency are intrinsically controlled properties which rely on the activation of Na[sup+], Ca[sup2+], and K[sup+] channels in the dendritic, somatic, and axonal membranes. The fast afterhyperpolarization (fAHP) after an AP is partially responsible for determining the half-width and duration of the AP and thus Ca[sup2+] influx during the depolarization. In CAl hippocampal pyramidal cells, the fAHP is carried by the voltageand Ca[sup2+]-dependent BK channel. In addition to modulating the duration of the AP, the BK-mediated potassium current exerts control over the frequency of AP generation in response to a depolarizing input. These facts position BK-mediated effects to not only modulate immediate intraneuronal communication, but also to control longer-term Ca[sup2+]-dependent changes in the neuron, such as kinase activation, gene transcription, and synaptic plasticity. We examined how the BK-mediated fAHP was altered in hippocampal neurons after learning trace eyeblink conditioning. By using current clamp methods, it was found that the fAHP is reduced and the AP duration is increased in cells from conditioned animals. Additionally, in vitro and in vivo measures of firing frequency show that BK-channel blockade increases both evoked (in vitro) and spontaneous (in vivo) firing frequency of CAl neurons, implicating the BK channel in the control of intrinsic excitability. These data indicate that the reduction of the BK-mediated fAHP is an essential part of the total increase of neuronal excitability known to accompany hippocampus-dependent learning. [ABSTRACT FROM AUTHOR]

Hayes, Matthew R., Rachael L. Moore, Samit M. Shah, and Mihai Covasa. 5-HT3 receptors participate in CCK-induced suppression of food intake by delaying gastric emptying. Am J Physiol Regul Integr Comp Physiol 287:R817-R823, 2004. First published June 10, 2004; 10.1152/ajpregu.00295.2004.—Serotonin type 3 (5-HT3) receptors have been shown to participate in the negative-feedback control of food intake. We previously reported that cholecystokinin (CCK)- induced suppression of food intake is partly mediated through 5-HT3 receptors when rats were tested on a preferred liquid diet, but whether such an effect occurs when they are tested on a solid maintenance diet is unknown. In the present study, we examined the effects of ondansetron, a selective 5-HT3 antagonist, on CCK-induced suppression of solid chow intake. Intraperitoneal administration of ondansetron significantly attenuated 30- and 60-min CCK-induced reduction of food intake, with suppression being completely reversed by 120 min. It is not known whether 5-HT3 receptors directly mediate CCK-induced satiation or whether their participation depends on CCK acting as part of a feedback cascade to inhibit ongoing intake. Because CCK- induced inhibition of sham feeding does not depend on additive gastric/postgastric-feedback signals, we examined the ability of ondansetron to reverse CCK-induced satiation in sham-feeding rats. Ondansetron did not attenuate reduction of sham feeding by CCK, suggesting that ondansetron does not directly antagonize CCK-satiation signals. CCK suppresses real feeding through a delay in gastric emptying. Ondansetron could attenuate CCK-induced reduction of food intake by reversing CCK-induced inhibition of gastric emptying. We found that blockade of 5-HT3 receptors attenuates CCK-induced inhibition of gastric emptying of a solid meal, as well as saline and glucose loads. We conclude that 5-HT3 receptors mediate CCK- induced satiation through indirect mechanisms as part of a feedback cascade involving inhibition of gastric emptying. [ABSTRACT FROM AUTHOR]

Background: The impact of COVID‐19 on heart transplant (HTx) recipients remains unclear, particularly in the early post‐transplant period. Methods: We share novel insights from our experience in five HTx patients with COVID‐19 (three within 2 months post‐transplant) from our institution at the epicenter of the pandemic. Results: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID‐19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C‐reactive protein, procalcitonin, and ferritin. All had bilateral ground‐glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. Conclusions: COVID‐19 appears to negatively impact outcomes early after heart transplantation. [ABSTRACT FROM AUTHOR]

Patient-reported difficulties in affording health care and their association with health status outcomes in peripheral artery disease (PAD) have never been studied. We sought to determine whether financial barriers affected PAD symptoms at presentation, treatment patterns, and patient-reported health status in the year following presentation. A total of 797 United States (US) patients with PAD were identified from the Patient-centered Outcomes Related to TReatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study, a prospective, multicenter registry of patients presenting to vascular specialty clinics with PAD. Financial barriers were defined as a composite of no insurance and underinsurance. Disease-specific health status was measured by Peripheral Artery Questionnaire (PAQ) and general health-related quality of life was measured by EuroQol 5 (EQ5D) dimensions at presentation and at 3, 6, and 12 months of follow-up. Among 797 US patients, 21% (n = 165) of patients reported financial barriers. Patients with financial barriers presented at an earlier age (64 ± 9.5 vs 70 ± 9.4 years), with longer duration of symptoms (59% vs 49%) (all p ⩽ 0.05), were more depressed and had higher levels of perceived stress and anxiety. After multivariable adjustment, health status was worse at presentation in patients with financial barriers (PAQ: –7.0 [–10.7, –3.4]; p < 0.001 and EQ5D: –9.2 [–12.74, –5.8]; p < 0.001) as well as through 12 months of follow-up (PAQ: –8.4 [–13.0, –3.8]; p < 0.001 and EQ5D: –9.7 [–13.2, –6.2]; p < 0.001). In conclusion, financial barriers are associated with later presentation as well as poorer health status at presentation and at 12 months. ClinicalTrials.gov Identifier: NCT01419080 [ABSTRACT FROM AUTHOR]

Risk of Mortality for Ventricular Arrhythmia. Background: There are limited data regarding the incidence and prognostic significance of ventricular arrhythmias (VA) in ambulatory continuous flow left ventricular assist device (LVAD) patients. Methods: Sixty-one consecutive patients from November 1, 2006 through December 31, 2010 with an LVAD and implantable cardioverter defibrillator that survived to discharge from the LVAD implantation admission were studied. Follow-up began from date of discharge with both devices in situ and ended with death, transplant, on June 1, 2011. Pre-LVAD VA history was related to the primary endpoints of post-LVAD VA, mortality, and the combined endpoint of post-LVAD VA/mortality. Results: During a mean follow-up of 622 days 19 patients (31%) experienced VA (14 episodes of VT, 5 episodes of VF). Pre-LVAD VA was predictive of post-LVAD VA (hazard ratio [HR] 2.91, P = 0.026) and the combined post-LVAD VA/mortality endpoint (HR 2.70, P = 0.021) but only displayed a nonsignificant association with mortality (HR 2.30, P = 0.11). In multivariate analysis, pre-LVAD VA remained a significant predictor of post-LVAD VA (HR 2.84, P = 0.03) and the combined post-LVAD VA/mortality endpoint (HR 2.65, P = 0.025). Post-LVAD VA was the strongest univariate predictor of mortality (HR 13.92, P < 0.001) and remained so after multivariate adjustment (HR 9.69, P = 0.001). Post-LVAD VA occurred at a mean of 1 year from mortality events with 45% within 1 month. Conclusions: Pre-LVAD VA is a significant predictor of post-LVAD VA but not of mortality. VA in the continuous flow LVAD population carries a significant risk of mortality often within the first month. (J Cardiovasc Electrophysiol, Vol. 23, pp. 515-520, May 2012) [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS). Background: Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology. Methods: Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events. Results: For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1–S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location–type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in α-helical domains than in subjects with mutations in β-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent β-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001). Conclusions: The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk. [Copyright &y& Elsevier]