Adenosine A2A receptors in the rostral ventrolateral medulla participate in blood pressure decrease with electroacupuncture in hypertensive rats.

Acupuncture is increasingly used to manage high blood pressure (BP) as a complementary therapy. However, the mechanisms underlying its hypotensive effects remain unclear. Our previous studies have shown that electroacupuncture (EA) at the ST36-37 acupoints, overlying the deep peroneal nerve, attenuates pressor responses through adenosine A2A receptors (A2AR) in the rostral ventrolateral medulla (rVLM). However, it is uncertain whether rVLM A2AR contributes to EA's BP-lowering effect in sustained hypertension. We hypothesized that a course of EA treatment lowers BP, in part, through the activation of adenosine A2AR in the rVLM in hypertensive rats. To mimic essential hypertension in the clinic, we performed EA in conscious Dahl salt-sensitive hypertensive rats (DSHRs). EA (0.1-0.4 mA, 2 Hz) was applied at ST36-37 for 30 min twice weekly for four weeks, while sham-EA was conducted in a similar manner but without electrical input. In hypertensive rats, BP was reduced by EA (n = 14) but neither by sham-EA (n = 14) nor in the absence of needling (n = 8). Following four weeks of eight treatments and then under anesthesia, EA's modulatory effect on elevated BP was reversed by unilateral rVLM microinjection of SCH 58261 (1 mM in 50 nl; an A2AR antagonist; n = 7; P < 0.05) but not the vehicle (n = 5) in EA-treated DSHRs. Activation of rVLM A2AR in DSHRs treated with sham-EA by an A2AR agonist, CGS-21680 (0.4 mM in 50 nl; n = 8), decreased BP. Unilateral administration of SCH 58261 or CGS-21680 into the rVLM did not alter basal BP in Dahl salt-sensitive rats fed a regular diet with normal BP. The A2AR level in the rVLM after EA was increased compared to the sham-EA and untreated DSHRs (n = 5 in each group; all P < 0.05). These data suggest that a 4-week twice weekly EA treatment reduced BP in salt-sensitive hypertensive rats likely through adenosine-mediated A2AR in the rVLM.

Efficacy and Adherence Rates of a Novel Community-Informed Virtual World-Based Cardiac Rehabilitation Program: Protocol for the Destination Cardiac Rehab Randomized Controlled Trial.

BACKGROUND: Innovative restructuring of cardiac rehabilitation (CR) delivery remains critical to reduce barriers and improve access to diverse populations. Destination Cardiac Rehab is a novel virtual world technology-based CR program delivered through the virtual world platform, Second Life, which previously demonstrated high acceptability as an extension of traditional center-based CR. This study aims to evaluate efficacy and adherence of the virtual world-based CR program compared with center-based CR within a community-informed, implementation science framework. METHODS: Using a noninferiority, hybrid type 1 effectiveness-implementation, randomized controlled trial, 150 patients with an eligible cardiovascular event will be recruited from 6 geographically diverse CR centers across the United States. Participants will be randomized 1:1 to either the 12-week Destination Cardiac Rehab or the center-based CR control groups. The primary efficacy outcome is a composite cardiovascular health score based on the American Heart Association Life's Essential 8 at 3 and 6 months. Adherence outcomes include CR session attendance and participation in exercise sessions. A diverse patient/caregiver/stakeholder advisory board was assembled to guide recruitment, implementation, and dissemination plans and to contextualize study findings. The institutional review board-approved randomized controlled trial will enroll and randomize patients to the intervention (or control group) in 3 consecutive waves/year over 3 years. The results will be published at data collection and analyses completion. CONCLUSIONS: The Destination Cardiac Rehab randomized controlled trial tests an innovative and potentially scalable model to enhance CR participation and advance health equity. Our findings will inform the use of effective virtual CR programs to expand equitable access to diverse patient populations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05897710.

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Lipid-Lowering Nutraceuticals for an Integrative Approach to Dyslipidemia.

Dyslipidemia is a treatable risk factor for atherosclerotic cardiovascular disease that can be addressed through lifestyle changes and/or lipid-lowering therapies. Adherence to statins can be a clinical challenge in some patients due to statin-associated muscle symptoms and other side effects. There is a growing interest in integrative cardiology and nutraceuticals in the management of dyslipidemia, as some patients desire or are actively seeking a more natural approach. These agents have been used in patients with and without established atherosclerotic cardiovascular disease. We provide an updated review of the evidence on many new and emerging nutraceuticals. We describe the mechanism of action, lipid-lowering effects, and side effects of many nutraceuticals, including red yeast rice, bergamot and others.

Electroacupuncture for the management of symptom clusters in cancer patients and survivors (EAST).

BACKGROUND: Neuropsychiatric symptoms, comprising cognitive impairment, fatigue, insomnia, depression, and anxiety, are prevalent and may co-occur during and after chemotherapy treatment for cancer. Electroacupuncture (EA), which involves mild electrical stimulation with acupuncture, holds great potential in addressing the management of individual symptoms. However, there is a lack of studies evaluating if EA can manage concurrent neuropsychiatric symptoms in cancer (i.e., symptom cluster). Hence, we designed a trial to evaluate the efficacy, safety, and feasibility of administering EA as an intervention to mitigate neuropsychiatric symptom clusters amongst cancer patients and survivors. METHODS: The EAST study is a randomized, sham-controlled, patient- and assessor-blinded clinical trial. Sixty-four cancer patients and survivors with complaints of one or more neuropsychiatric symptom(s) in the seven days prior to enrollment are recruited from the University of California Irvine (UCI) and Children's Hospital of Orange County (CHOC). Individuals with needle phobia, metastases, bleeding disorders, electronic implants, epilepsy, exposure to acupuncture in the three months prior to enrollment, and who are breastfeeding, pregnant, or planning to get pregnant during the duration of the study will be excluded. Screening for metal fragments and claustrophobia are performed prior to the optional neuroimaging procedures. Recruited patients will be randomized (1:1) in random blocks of four or six to receive either ten weekly verum EA (treatment arm, vEA) or weekly sham EA (control arm, sEA) treatment visits with a follow-up appointment four to twelve weeks after their last treatment visit. The treatment arm will receive EA at 13 acupuncture points (acupoints) chosen for their therapeutic effects, while the control arm receives minimal EA at 7 non-disease-related acupoints. Questionnaires and cognitive assessments are administered, and blood drawn to assess changes in symptom clusters and biomarkers, respectively. CONCLUSION: The EAST study can provide insight into the efficacy of EA, an integrative medicine modality, in the management of cancer symptom clusters in routine clinical practice. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov NCT05283577.

Coronary calcium density in relation to coronary heart disease and cardiovascular disease in adults with diabetes or metabolic syndrome: the Multi-ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Coronary artery calcium (CAC) density is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD) risk. We examined this relation in those with diabetes mellitus (DM) or metabolic syndrome (MetS). METHODS: We studied 3,818 participants with non-zero CAC scores from the Multiethnic Study of Atherosclerosis and classified them as DM, MetS (without DM) or neither DM/MetS. Risk factor-adjusted CAC density was calculated and examined in relation to incident CHD and CVD events over a median follow-up of 15 years among these three disease groups. RESULTS: Adjusted CAC density was 2.54, 2.61 and 2.69 among those with DM, MetS or neither DM/MetS. Hazard ratios (HRs) for CHD per 1 SD increase of CAC density was 0.91 (95% CI: 0.72-1.16), 0.70 (95% CI: 0.56-0.87) and 0.79 (95% CI: 0.66-0.95) for those with DM, MetS or neither DM/MetS groups and were 0.77 (95% CI: 0.64-0.94), 0.83 (95% CI: 0.70-0.99) and 0.82 (95% CI: 0.71-0.95) for CVD, respectively. Adjustment for CAC density increased the HRs of CAC volume for CHD/CVD events. Compared to prediction models with or without single CAC measures, c-statistics of models with CAC volume and density were the highest ranging 0.67-0.72. CONCLUSION: CAC density is lower among patients with DM or MetS than those with neither DM/MetS and is inversely associated with future CHD/CVD risk among them. Including CAC density in risk assessment among those with MetS may improve prediction of CHD and CVD.

Neurogenic Hypotension and Bradycardia Modulated by Electroacupuncture in Hypothalamic Paraventricular Nucleus.

Electroacupuncture (EA) stimulates somatic median afferents underlying P5-6 acupoints and modulates parasympathoexcitatory reflex responses through central processing in the brainstem. Although decreases in blood pressure and heart rate by the neural-mediated Bezold-Jarisch reflex responses are modulated by EA through opioid actions in the nucleus tractus solitarius and nucleus ambiguus, the role of the hypothalamus is unclear. The hypothalamic paraventricular nucleus (PVN) is activated by sympathetic afferents and regulates sympathetic outflow and sympathoexcitatory cardiovascular responses. In addition, the PVN is activated by vagal afferents, but little is known about its regulation of cardiopulmonary inhibitory hemodynamic responses. We hypothesized that the PVN participates in the Bezold-Jarisch reflex responses and EA inhibits these cardiopulmonary responses through the PVN opioid system. Rats were anesthetized and ventilated, and their heart rate and blood pressures were monitored. Application of phenylbiguanide every 10 min close to the right atrium induced consistent depressor and bradycardia reflex responses. Unilateral microinjection of the depolarization blockade agent kainic acid or glutamate receptor antagonist kynurenic acid in the PVN reduced these reflex responses. In at least 70% of the rats, 30 min of bilateral EA at P5-6 acupoints reduced the depressor and bradycardia responses for at least 60 min. Blockade of the CCK-1 receptors converted the non-responders into EA-responders. Unilateral PVN-microinjection with naloxone reversed the EA inhibition. Vagal-evoked activity of the PVN cardiovascular neurons was reduced by 30 min EA (P5-6) through opioid receptor activation. These data indicate that PVN processes inhibitory cardiopulmonary reflexes and participates in EA-modulation of the neural-mediated vasodepression and bradycardia.

Association of polygenic risk scores with incident atherosclerotic cardiovascular disease events among individuals with coronary artery calcium score of zero: The multi-ethnic study of atherosclerosis.

BACKGROUND: Polygenic risk scores (PRS) are associated with atherosclerotic cardiovascular disease (ASCVD) events. We studied incident ASCVD among individuals with absent coronary artery calcium (CAC = 0), to investigate the association of PRS with incident ASCVD among such individuals. METHODS: Data was used from Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of participants free of clinical CVD at baseline. PRS were developed based on a literature-derived list of single-nucleotide polymorphisms (SNPs) weighted by effect size. The coronary heart disease (CHD) PRS contained 180 SNPs, and the stroke PRS had 32 SNPs. These SNPs were combined to compute an ASCVD PRS. The PRS were calculated among 3132 participants with CAC = 0. Multivariable-adjusted Cox proportional hazards models evaluated the association between each PRS (top 20% vs bottom 50%) and ASCVD. RESULTS: The study population included 3132 individuals with CAC = 0 [mean (SD) age 58 (9) years; 63% female, 33% White, 31% Black, 12% Chinese-American, 24% Hispanic]. Over a median follow-up of 16 years, there were 108 incident CHD events and 93 stroke events. ASCVD event rates were generally <7.5 per 1000-person years for all ASCVD events regardless of PRS risk stratum. The ASCVD PRS was significantly associated with incident ASCVD: (HR; 95% CI) (1.63; 1.11, 2.39). The CHD PRS was not associated with any ASCVD outcome, whereas the stroke PRS was significantly associated with ASCVD (1.84; 1.27, 2.68), CHD (1.79; 1.05, 3.06), and stroke (1.96; 1.19, 3.23). The stroke PRS results were significant among women and non-Whites. CONCLUSIONS: Among individuals with CAC = 0, the ASCVD PRS was associated with incident ASCVD events. This appears to be driven by genetic variants related to stroke but not CHD, and particularly among women and non-Whites. ASCVD event rates remained below the threshold recommended for consideration for initiation of statin therapy even in the high PRS groups.

Dietary potassium intake, kidney function, and survival in a nationally representative cohort.

BACKGROUND: In healthy adults, higher dietary potassium intake is recommended given that potassium-rich foods are major sources of micronutrients, antioxidants, and fiber. Yet among patients with advanced kidney dysfunction, guidelines recommend dietary potassium restriction given concerns about hyperkalemia leading to malignant arrhythmias and mortality. OBJECTIVES: Given sparse data informing these recommendations, we examined associations of dietary potassium intake with mortality in a nationally representative cohort of adults from the NHANES. METHODS: We examined associations between daily dietary potassium intake scaled to energy intake (mg/1000 kcal), ascertained by 24-h dietary recall, and all-cause mortality among 37,893 continuous NHANES (1999-2014) participants stratified according to impaired and normal kidney function (estimated glomerular filtration rates <60 and ≥60 mL · min-1 · 1.73 m-2, respectively) using multivariable Cox models. We also examined the impact of the interplay between dietary potassium, source of potassium intake (animal- compared with plant-based sources), and coexisting macronutrient and mineral consumption upon mortality. RESULTS: Among participants with impaired and normal kidney function, the lowest tertile of dietary potassium scaled to energy intake was associated with higher mortality (ref: highest tertile) [adjusted HR (aHR): 1.18; 95% CI: 1.02, 1.38 and aHR: 1.17; 95% CI: 1.06, 1.28, respectively]. Compared with high potassium intake from plant-dominant sources, participants with low potassium intake from animal-dominant sources had higher mortality irrespective of kidney function. Among participants with impaired kidney function, pairings of low potassium intake with high protein, low fiber, or high phosphorus consumption were each associated with higher death risk. CONCLUSIONS: Lower dietary potassium scaled to energy intake was associated with higher mortality, irrespective of kidney function. There was also a synergistic relation of higher potassium intake, plant-based sources, and macronutrient/mineral consumption with survival. Further studies are needed to elucidate pathways linking potassium intake and coexisting dietary factors with survival in populations with and without chronic kidney disease.

Cardiodiagnostic sex-specific differences of the female athlete in sports cardiology.

The cardiovascular care of highly active individuals and competitive athletes has developed into an important focus within the field of sports medicine. An evolving understanding of exercise-induced cardiovascular remodeling in athletes has led to a more robust characterization of physiologic adaptation versus pathological dysfunction, but this distinction is often challenging due to diagnostic commonalities. Current data reflects sporting-focused analyses of mainly male athletes, which may not be easily applicable to the female athletic heart. Increasingly female-specific cardiac dimensional and physiologic data are starting to emerge from comparative studies that may be utilized to address this growing need, and further guide individualized care. Here, we review current literature evaluating female-specific cardiovascular adaptations of the athletic heart, and formulate a discussion on cardiac remodeling, cardiodiagnostic findings, etiologic mechanisms, limitations of currently available data, and direction for future research in the cardiovascular care of female athletes.

Identification and Predictors for Cardiovascular Disease Risk Equivalents among Adults With Diabetes Mellitus.

OBJECTIVE: We examined diabetes mellitus (DM) as a cardiovascular disease (CVD) risk equivalent based on diabetes severity and other CVD risk factors. RESEARCH DESIGN AND METHODS: We pooled 4 US cohorts (ARIC, JHS, MESA, FHS-Offspring) and classified subjects by baseline DM/CVD. CVD risks between DM+/CVD- vs. DM-/CVD+ were examined by diabetes severity and in subgroups of other CVD risk factors. We developed an algorithm to identify subjects with CVD risk equivalent diabetes by comparing the relative CVD risk of being DM+/CVD- vs. DM-/CVD+. RESULTS: The pooled cohort included 27,730 subjects (mean age of 58.5 years, 44.6% male). CVD rates per 1000 person-years were 16.5, 33.4, 43.2 and 71.4 among those with DM-/CVD-, DM+/CVD-, DM-/CVD+ and DM+/CVD+, respectively. Compared with those with DM-/CVD+, CVD risks were similar or higher for those with HbA1c ≥ 7%, diabetes duration ≥10 years, or diabetes medication use while those with less severe diabetes had lower risks. Hazard ratios (95%CI) for DM+/CVD- vs. DM-/CVD+ were 0.96(0.86-1.07), 0.97(0.88-1.07), 0.96(0.82-1.13), 1.18(0.98-1.41), 0.93(0.85-1.02) and 1.00(0.89-1.13) among women, white race, age <55 years, triglycerides ≥2.26 mmol/L, hs-CRP ≥ 2 mg/L and eGFR<60 mL/min/1.73m2, respectively. In DM+/CVD- group, 19.1% had CVD risk equivalent diabetes with a lower risk score but a higher observed CVD risk. CONCLUSION: Diabetes is a CVD risk equivalent in one-fifth of CVD-free adults living with diabetes. High HbA1c, long diabetes duration, and diabetes medication use were predictors of CVD risk equivalence. Diabetes is a CVD risk equivalent for women, white people, those of younger age, with higher triglycerides or CRP, or reduced kidney function.

The costs outweigh the benefits: seeing side-effects online may decrease adherence to statins.

BACKGROUND: The prevalence of medical misinformation on the Internet has received much attention among researchers concerned that exposure to such information may inhibit patient adherence to prescriptions. Yet, little is known about information people see when they search for medical information and the extent to which exposure is directly related to their decisions to follow physician recommendations. These issues were examined using statin prescriptions as a case study. METHODS: We developed and used a tool to rank the quality of statin-related web pages based on the presence of information about side effects, clinical benefits, management of side effects, and misinformation. We then conducted an experiment in which students were presented with a hypothetical scenario in which an older relative was prescribed a statin but was unsure whether to take the medication. Participants were asked to search the web for information about statins and make a recommendation to this relative. Their search activity was logged using a web-browser add-on. Websites each participant visited were scored for quality using our tool, quality scores were aggregated for each participant and were subsequently used to predict their recommendation. RESULTS: Exposure to statin-related benefits and management of side effects during the search was significantly associated with a higher probability of recommending that an older relative adhere to their physician's recommendation. Exposure to misinformation and side effects were not associated, nor were any other participant characteristics. Bigram analyses of the top reasons participants gave for their recommendation mirrored the statistical findings, except that among participants who did not recommend following the prescription order, myriad side effects were mentioned. CONCLUSIONS: Our findings suggest that units of information people see on health-related websites are not treated equally. Our methods offer new understanding at a granular level about the impact of Internet searches on health decisions regarding evidence-based recommended medications. Our findings may be useful to physicians considering ways to address non-adherence. Preventive care should include actively engaging patients in discussions about health information they may find on the web. The effectiveness of this strategy should be examined in future studies.

Plant-Dominant Low-Protein Diet for Conservative Management of Chronic Kidney Disease.

Chronic kidney disease (CKD) affects >10% of the adult population. Each year, approximately 120,000 Americans develop end-stage kidney disease and initiate dialysis, which is costly and associated with functional impairments, worse health-related quality of life, and high early-mortality rates, exceeding 20% in the first year. Recent declarations by the World Kidney Day and the U.S. Government Executive Order seek to implement strategies that reduce the burden of kidney failure by slowing CKD progression and controlling uremia without dialysis. Pragmatic dietary interventions may have a role in improving CKD outcomes and preventing or delaying dialysis initiation. Evidence suggests that a patient-centered plant-dominant low-protein diet (PLADO) of 0.6­0.8 g/kg/day composed of >50% plant-based sources, administered by dietitians trained in non-dialysis CKD care, is promising and consistent with the precision nutrition. The scientific premise of the PLADO stems from the observations that high protein diets with high meat intake not only result in higher cardiovascular disease risk but also higher CKD incidence and faster CKD progression due to increased intraglomerular pressure and glomerular hyperfiltration. Meat intake increases production of nitrogenous end-products, worsens uremia, and may increase the risk of constipation with resulting hyperkalemia from the typical low fiber intake. A plant-dominant, fiber-rich, low-protein diet may lead to favorable alterations in the gut microbiome, which can modulate uremic toxin generation and slow CKD progression, along with reducing cardiovascular risk. PLADO is a heart-healthy, safe, flexible, and feasible diet that could be the centerpiece of a conservative and preservative CKD-management strategy that challenges the prevailing dialysis-centered paradigm.

Fos-CreER-based genetic mapping of forebrain regions activated by acupuncture.

Acupuncture increasingly is accepted as a potential therapy for many diseases in the Western world. However, the mechanism of acupuncture is not well understood mechanistically. We have established that manual acupuncture (MA) at the Neiguan (P6) acupoint inhibits excitatory cardiovascular reflex responses through modulation of the autonomic nervous system in the brainstem. It is unclear whether P6 MA activates neurons in the brain regions beyond the brainstem. Thus, we mapped P6 specific neural activation by MA in the forebrain using the Fos-CreER; Ai9 mice model, which allows for enhanced sensitivity and efficiency compared to conventional immunohistochemical staining. Compared to sham-MA control without manual stimulation, we find that MA at P6 markedly increases c-Fos positive neurons in a number of the forebrain regions (n = 5 in each group). These activated regions include accumbens nucleus, caudate putamen, claustrum, bed nucleus of the stria terminalis, amygdaloid nucleus, ventral posterior division of the thalamic nucleus, paraventricular hypothalamic nucleus, arcuate hypothalamic nucleus, primary and secondary somatosensory cortex, ectorhinal cortex, and dorsolateral entorhinal cortex. As MA at P6 activates neurons in relatively broad brain networks beyond the brainstem, our data suggest that acupuncture at this acupoint has the potential to influence physiological functions associated with autonomic and non-autonomic nervous systems through its effects on multiple brain regions.

Role of opioid receptors in modulation of P2X receptor-mediated cardiac sympathoexcitatory reflex response.

Myocardial ischemia evokes powerful reflex responses through activation of vagal and sympathetic afferents in the heart through the release of ischemic metabolites. We have demonstrated that extracellular ATP stimulates cardiac sympathetic afferents through P2 receptor-mediated mechanism, and that opioid peptides suppress these afferents' activity. However, the roles of both P2 receptor and endogenous opioids in cardiac sympathoexcitatory reflex (CSR) responses remain unclear. We therefore hypothesized that activation of cardiac P2 receptor evokes CSR responses by stimulating cardiac sympathetic afferents and these CSR responses are modulated by endogenous opioids. We observed that intrapericardial injection of α,ß-methylene ATP (α,ß-meATP, P2X receptor agonist), but not ADP (P2Y receptor agonist), caused a graded increase in mean arterial pressure in rats with sinoaortic denervation and vagotomy. This effect of α,ß-meATP was abolished by blockade of cardiac neural transmission with intrapericardial procaine treatment and eliminated by intrapericardial A-317491, a selective P2X2/3 and P2X3 receptor antagonist. Intrapericardial α,ß-meATP also evoked CSR response in vagus-intact rats. Furthermore, the P2X receptor-mediated CSR responses were enhanced by intrapericardial naloxone, a specific opioid receptor antagonist. These data suggest that stimulation of cardiac P2X2/3 and P2X3, but not P2Y receptors, powerfully evokes CSR responses through activation of cardiac spinal afferents, and that endogenous opioids suppress the P2X receptor-mediated CSR responses.

Adenosine Receptor A2a, but Not A1 in the rVLM Participates Along With Opioids in Acupuncture-Mediated Inhibition of Excitatory Cardiovascular Reflexes.

Electroacupuncture (EA) can be used to lower high blood pressure (BP) in clinical practice. However, precise mechanisms underlying its effects on elevated BP remain unclear. Our previous studies have shown that EA at the P5-6 acupoints, overlying the median nerve, attenuates elevated BP induced by gastric distension (GD) through influence on rostral ventrolateral medulla (rVLM). Although adenosine is released during neuronal activation in the rVLM, its role in acupuncture-cardiovascular regulation is unknown. The purinergic system is involved in cardiovascular pressor and depressor responses, including via selective activation of A1 and A2 a rVLM receptors, respectively. The action of A2 a receptor stimulation in the central nervous system may be further regulated through an endogenous opioid mechanism. However, it is uncertain whether this putative action occurs in the rVLM. We hypothesized that adenosine in the rVLM contributes to EA modulation of sympathoexcitatory reflexes through an A2 a but not an A1 adenosine receptor-opioid mechanism. EA or sham-EA was applied at the P5-6 acupoints in Sprague-Dawley male rats subjected to repeated GD under anesthesia. We found that EA (n = 6) but not sham-EA (n = 5) at P5-6 significantly (P < 0.05) attenuated GD-induced elevations in BP. EA modulation of sympathoexcitatory cardiovascular reflexes was reversed significantly after rVLM microinjection (50 nl) of 8-SPT (10 mM; non-selective adenosine receptor antagonist; n = 7) or SCH 58261 (1 mM; A2 a receptor antagonist; n = 8; both P < 0.05), but not by DPCPX (3 mM; A1 receptor antagonist; n = 6) or the vehicle (5% dimethylsulfoxide; n = 6). Moreover, microinjection of an A2 a receptor agonist, CGS-21680 (0.4 mM; n = 8) into the rVLM attenuated GD-induced pressor responses without EA, which mimicked EA's inhibitory effects (P < 0.05). After blockade of opioid receptors with naloxone (1 mM) in the rVLM, SCH 58261's reversal of EA's effect on GD-induced pressor responses was blunted, and CGS-21680-mediated inhibitory effect on pressor responses was not observed. Furthermore, neurons labeled with adenosine A2 a receptors were anatomically co-localized with neurons stained with enkephalin in the rVLM. These data suggest that the involvement of rVLM adenosine A2 a receptors in EA modulation of GD-induced pressor reflexes is, at least in part, dependent on the presence of endogenous opioids.

Occurrence, mortality and predictors of complicated cardiac perforation in patients with CRT-D: Based on the National Inpatient Sample registry.

BACKGROUND: Cardiac Resynchronization Therapy Defibrillator (CRT-D) has been one of the most important therapies for patients with cardiomyopathy over the last decades. Cardiac perforation occurs infrequently but can be fatal. The occurrence of cardiac perforation after CRT-D implantation has not been studied well. The aim of study is to investigate the occurrence, mortality and predictors of cardiac perforation in patients receiving CRT-D during the index hospitalization. METHODS: Data were obtained from the National Inpatient Sample, the largest all-player inpatient dataset in the United States. Patients who received CRT-D from 2002 to 2012 were identified using ICD-9 codes. Multivariate analyses were used to identify predictors of cardiac perforation. Complications including in-hospital death and cardiac perforation were identified using ICD-9 codes. RESULTS: A total of 77,827 patients with CRT-D implantation were included into our analysis. After the CRT-D implantation, the in-hospital and rate of cardiac perforation was between 0.24 and 0.48% and had increased significantly (p = 0.02). Although occurrence of cardiac perforation is rare (0.32%), the mortality was 10.6% among those patients with cardiac perforation. In Multivariate analysis identified female as independent risk factors for cardiac perforation (OR: 2.628, 95% CI 1.926-3.585, p < 0.0001). CONCLUSION: Despite rapid progress of the tools and skills for CRT-D implantation, the occurrence of cardiac perforation has not improved. While cardiac perforation is rare, it carries the highest rate of mortality, especially in female patients. Implanting physicians should be familiar with the comorbidities and patient demographics that put them at a higher risk for complications.