Aetiology of resuscitated out-of-hospital cardiac arrest treated at hospital.

INTRODUCTION: Precipitating aetiology of out-of-hospital cardiac arrest (OHCA), as confirmed by diagnostic testing or autopsy, provides important insights into burden of OHCA and has potential implications for improving OHCA survivorship. This study aimed to describe the aetiology of non-traumatic resuscitated OHCAs treated at hospital within a local health network according to available documentation, and to investigate differences in outcome between aetiologies. METHODS: Observational retrospective cohort study of consecutive OHCA treated at hospital within a local health network between 2011-2016. Cases without sustained ROSC (≥20 minutes), unverified cardiac arrest, and retrievals to external acute care facilities were excluded. A single aetiology was determined from the hospital medical record and available autopsy results. Survival to hospital discharge was compared between adjudicated aetiologies. RESULTS: In the 314 included cases, distribution of precipitating aetiology was 53% cardiac, 18% respiratory, 3% neurological, 6% toxicological, 9% other, and 11% unknown. A presumed cardiac pre-hospital diagnosis was assigned in 235 (84%) cases, 20% of which were incorrect after exclusion of unknown cases. Rates of survival to hospital discharge varied significantly across aetiologies: cardiac 64%, respiratory 21%, neurological 0%, toxicological 58%, other 32% (p < 0.001). A two-fold difference in survival was observed between cardiac and non-cardiac aetiologies (64% versus 29%, excluding unknown, p < 0.001). CONCLUSIONS: Non-cardiac aetiologies represented a substantial burden of resuscitated OHCA treated at hospital within a local health network and were associated with poor outcome. The results confirmed that true aetiology was not evident on initial examination in 1 in 5 cases with a pre-hospital cardiac diagnosis.

Steroid hormones and first trimester vascular remodeling.

Successful implantation and placentation require neoangiogenesis and the remodeling of the uterine spiral arteries. Progesterone and estradiol control various of the placental functions, but their role in vascular remodeling remains controversial. Therefore, this chapter aims to summarize the current knowledge regarding the role of steroid hormones in the uteroplacental vascular remodeling during the first trimester of gestation.

Carotid Artery Calcification on Orthopantomograms (CACO Study) - is it indicative of carotid stenosis?

It is unclear whether incidental carotid artery calcification (CAC) on radiographs has a defined relationship to clinically significant carotid artery stenosis, and therefore risk of stroke. The primary objective of this study was to ascertain the relationship between dental radiograph detected carotid calcification and carotid artery stenoses ≥50% on carotid duplex ultrasound. We carried out an observational study of patients undergoing routine dental orthopantomogram (OPG) examinations. Consecutive patients with CAC on OPG were prospectively matched to those without CAC based on age and gender. Ultrasound of the carotid arteries was performed to determine the presence of stenosis (≥50%) in either vessel. Of 5780 consecutive OPG examinations with suitable images for analysis, CAC was detected in 10.8%. A total of 233 patients underwent carotid ultrasound (130 with and 103 without CAC on OPG). The prevalence of a clinically significant (≥50%) carotid stenosis on ultrasound was 15.4% (20/130) in those with CAC and 5.8% (6/103) for those without CAC on OPG. Incidental CAC detected on routine OPG requires both radiological reporting and clinical follow-up since 1 in 7 patients will have a clinically significant carotid artery stenosis as compared with 1 in 20 patients who do not have CAC. Trial Registration: Australian and New Zealand Clinical Trials Registry website (U1111-1148-1066). http://www.ANZCTR.org.au/ACTRN12613001038785.aspx.

Roles for endothelial zinc homeostasis in vascular physiology and coronary artery disease.

The discovery of the roles of nitric oxide (NO) in cardiovascular signaling has led to a revolution in the understanding of cardiovascular disease. A new perspective to this story involving zinc (Zn) is emerging. Zn and its associated Zn transporter proteins are important for the integrity and functions of both the large conduit vessels and the microvascular resistance vessels. The Zn and NO pathways are tightly coordinated. Zn ions are required for the dimerization of endothelial nitric oxide synthase and subsequent generation of NO while generation of NO leads to a rapid mobilization of endothelial Zn stores. Labile Zn may mediate important downstream actions of NO including vascular cytoprotection and vasodilation. Several vascular disease risk factors (including aging, smoking and diabetes) interfere with Zn homeostatic mechanisms and both hypozincaemia and Zn transporter protein abnormalities are linked to atherosclerosis and microvascular disease. Some vegetarian diets and long-term use of certain anti-hypertensives may also impact on Zn status. The available evidence supports the existence of a Zn regulatory pathway in the vascular wall that is coupled to the generation and actions of NO and which is compromised in Zn deficiency with consequent implications for the pathogenesis and therapy of vascular disease.

Panic disorder and incident coronary heart disease: a systematic review and meta-regression in 1131612 persons and 58111 cardiac events.

BACKGROUND: Substantial healthcare resources are devoted to panic disorder (PD) and coronary heart disease (CHD); however, the association between these conditions remains controversial. Our objective was to conduct a systematic review of studies assessing the association between PD, related syndromes, and incident CHD. METHOD: Relevant studies were retrieved from Medline, EMBASE, SCOPUS and PsycINFO without restrictions from inception to January 2015 supplemented with hand-searching. We included studies that reported hazard ratios (HR) or sufficient data to calculate the risk ratio and 95% confidence interval (CI) which were pooled using a random-effects model. Studies utilizing self-reported CHD were ineligible. Twelve studies were included comprising 1 131 612 persons and 58 111 incident CHD cases. RESULTS: PD was associated with the primary incident CHD endpoint [adjusted HR (aHR) 1.47, 95% CI 1.24-1.74, p < 0.00001] even after excluding angina (aHR 1.49, 95% CI 1.22-1.81, p < 0.00001). High to moderate quality evidence suggested an association with incident major adverse cardiac events (MACE; aHR 1.40, 95% CI 1.16-1.69, p = 0.0004) and myocardial infarction (aHR 1.36, 95% CI 1.12-1.66, p = 0.002). The risk for CHD was significant after excluding depression (aHR 1.64, 95% CI 1.45-1.85) and after depression adjustment (aHR 1.38, 95% CI 1.03-1.87). Age, sex, length of follow-up, socioeconomic status and diabetes were sources of heterogeneity in the primary endpoint. CONCLUSIONS: Meta-analysis showed that PD was independently associated with incident CHD, myocardial infarction and MACE; however, reverse causality cannot be ruled out and there was evidence of heterogeneity.

Lysophosphatidic acid increases the production of pivotal mediators of decidualization and vascularization in the rat uterus.

INTRODUCTION: The decidual reaction and the formation of new vessels in the uterus are two crucial processes during embryo implantation. Previously, we observed that lysophosphatidic acid (LPA) increases cyclooxygenase-2 derived - prostaglandin E2 production during implantation in the rat uterus and that it augments the expression of decidualization (IGFBP-1) and vascularization (IL-10) markers. Both cyclooxygenase and nitric oxide synthase (NOS) are known enzymes involved in these processes. Thus, we became interested in studying which factors contribute to LPA receptor-specific role during the decidual and the vascular reaction at implantation. METHODS: We adopted a pharmacological approach in vitro incubating the uterus from rats on day 5 of gestation (day of implantation) with LPA, DGPP (a highly selective antagonist of LPA3, an LPA receptor) and cyclooxygenase and NOS selective and non-selective inhibitors. We determined NOS activity, prostaglandin E2 production and IGFBP-1 and IL-10 expression to evaluate decidualization and vascularization. RESULTS: We observed that LPA augmented the activity of the inducible NOS isoform through LPA1/LPA3. Inducible NOS activity participated in the induction of cyclooxygenase-2/prostaglandin E2 increase stimulated by LPA. Also, cyclooxygenase-2 derived prostaglandins mediated LPA-stimulatory action on NOS activity. Both cyclooxygenase-2 and inducible NOS mediated LPA effect on IGFBP-1 and IL-10 expression. CONCLUSIONS: These results suggest the participation of LPA/LPA3 in the production of crucial molecules involved in vascularization and decidualization, two main processes that prepare the uterine milieu for embryo invasion during implantation.

Reducing risk in coronary artery disease. Are Australian patients in general practice achieving targets? The Coronary Artery Disease in general practice study (CADENCE).

BACKGROUND: The benefits of secondary preventive measures for stable coronary artery disease are well established and risk factor treatment targets are defined. AIM: The aim of this study was to examine Australian general practitioners' (GP) perception and management of risk factors in chronic stable angina patients in primary care. METHODS: Using a cluster-stratified design, 2031 consecutive stable angina patients were recruited between October 2006 and March 2007 by 207 GP who documented their risk factors and reported if they were optimally controlled. RESULTS: Among the patients, 93% had objective evidence of coronary artery disease and 63% were male, and mean age was 71 ± 11 years. Based upon national guidelines, recommended targets were achieved in: 60% for blood pressure, 24% for body mass index, 23% for waist circumference, 17% for lipid profiles (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) and 54% of diabetics for haemoglobin A1c . However, GP perceived risk factors to be 'optimally controlled' in: 86% for blood pressure (kappa statistic (κ) = 0.37), 44% for weight (κ = 0.3), 70% for lipids (κ = 0.20) and 60% for haemoglobin A1c (κ = 0.74). CONCLUSIONS: In this representative cohort of chronic stable angina patients attending GP, cardiovascular risk factor control was frequently suboptimal despite being perceived as satisfactory by the clinicians. New strategies that raise awareness and address this treatment gap need to be implemented.

Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.

BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction.

BACKGROUND: Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial. METHODS AND RESULTS: The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non-infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183+/-59 versus 247+/-53 mg/dL, P<0.006) but showed a lower incidence of vasodilation (2% versus 9% of coronary segments) and a greater incidence of spasm after acetylcholine (47% versus 15% of arteries, P<0.00001). Incidence of spasm was higher in IRAs than in NIRAs in both populations (67% versus 39% and 23% versus 11%, respectively). Multivessel spasm was more common (64% versus 17%, P<0.02) and vasoconstriction of nonspastic segments was greater in Japanese patients (-23.4+/-14.9% versus -20.1+/-15.7%, P<0.02) in the presence of similar average basal coronary tone with respect to post-nitroglycerin dilation and of nonsignificant differences of coronary atherosclerotic score. CONCLUSIONS: Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.

Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients.

Japanese investigators have provided a substantial contribution in the understanding of coronary vasomotor reactivity. On occasions, their findings have been at variance with those undertaken on caucasian patients, raising speculation that vasomotor differences between races may exist. In a comparative review of the published literature, we evaluated the vasoreactive differences among Japanese and caucasian patients with variant angina or myocardial infarction. In variant angina, Japanese patients appear to have diffusely hyperreactive coronary arteries compared with caucasian people, manifested by their segmental rather than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These differences may reflect the increased basal tone among Japanese variant angina patients and may relate to controversial differences in endothelial nitric oxide production or autonomic nervous system activity. Provocative vasomotor studies of Japanese patients with a recent myocardial infarction report a higher incidence of inducible spasm than caucasian studies, an observation recently supported by a controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both non-infarct- and infarct-related vessels. These observations support the existence of racial coronary vasomotor reactivity differences but require confirmation in further prospectively conducted studies.

Evaluation of antibodies to beta2-glycoprotein 1 in the causation of coronary atherosclerosis as part of the antiphospholipid syndrome.

BACKGROUND: Anticardiolipin antibodies (aCL) are associated with accelerated coronary atherosclerosis. Beta2-glycoprotein 1 is a cofactor necessary for the binding of aCL. AIM: The aim of this study was to determine whether antibodies to beta2-glycoprotein 1 (anti-beta2GP1) predispose to coronary artery disease (CAD), and whether the measurement of anti-beta2GP1 will be more useful than aCL alone in the evaluation of coronary risk. METHODS: Persons who had undergone coronary angiography were invited to participate, and risk factors for coronary atherosclerosis recorded. IgG aCL and anti-beta2GP1 were measured and fasting triglyceride (TG) and total cholesterol (TC) levels were determined. Angiographic score (AS) was defined as the number of diseased vessels (0, 1, 2, 3), (>50% stenosis). Ethics Committee approval was obtained. Statistical comparison used the Student's t test and Chi-squared test. RESULTS: Ninety-seven subjects (63 male) with age range 38-81 years (mean 66.0) participated. There were 31 subjects with AS=0, 27 with AS=1, 22 with AS=2, and 17 with AS=3. The three subjects with positive aCL all had CAD, as did three of the four subjects with positive anti-beta2GP1. Among patients with CAD, there was an equal incidence (4.5%, three/66) of aCL and anti-beta2GP1, and an incidence of either aCL or anti-beta2GP1 of 7.6% (five/66). Compared to the group with AS=0, those with AS=1, 2 or 3 comprised a higher mean age (p=0.001) however, there was no significant difference in the prevalence of other coronary risk factors between the two groups. There was no difference in the proportions of patients with either aCL or anti-beta2GP1 in the group with AS=1, 2, or 3, compared to the group with AS=0 (5/66 c.f. 1/31, chi2=0.146, p>0.5). CONCLUSIONS: Our study has not supported an association between anti-beta2GP1 and CAD. The measurement of anti-beta2GP1 (or aCL) in the investigation of premature CAD is not justified on the basis of our results.

Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema.

BACKGROUND: Nitrates are superior to furosemide in the management of acute pulmonary edema associated with myocardial infarction; however, their role in the absence of infarction is unclear. METHODS AND RESULTS: A randomized comparison was undertaken of the relative effectiveness of primary therapy with either intravenous morphine/furosemide (men/women; n = 32) or nitroglycerin/N-acetylcysteine (NTG/NAC; n = 37) in consecutive patients with acute pulmonary edema. The primary end point was change in PaO2/FIO2 over the first 60 minutes of therapy. Secondary end points were needed for mechanical respiratory assistance (ie, continuous positive airway pressure via mask or intubation and ventilation) and changes in other gas exchange parameters. Both treatment groups showed improvement in oxygenation after 60 minutes of therapy; however, this reached statistical significance only with NTG/NAC therapy. There was no significant difference between groups in the assessed parameters (95% CI for differences in Pao2/FIO2: furosemide/morphine -12 to 23 and NTG/NAC 4 to 44), a finding also confirmed in 32 patients presenting with respiratory failure. Only 11% of the study group required mechanical ventilatory assistance (continuous positive airway pressure in 4 patients and intubation and ventilation in 3 patients). CONCLUSIONS: NTG/NAC therapy is as effective as furosemide/morphine in the initial management of acute pulmonary edema, regardless of the presence or absence of respiratory failure. The necessity for mechanical ventilatory assistance is infrequent in these patients, regardless of the initial medical treatment regimen.

Low incidence of serotonin-induced occlusive coronary artery spasm in patients with recent myocardial infarction.

Intracoronary infusion of serotonin has been reported to induce varying degrees of coronary vasoconstriction in different coronary syndromes, but it has never been studied in patients after myocardial infarction. In patients with recent myocardial infarction, we found a low incidence (11%) of serotonin-induced occlusive spasm only in the infarct-related artery (IRA), and a significantly higher vasoconstriction in the distal segment of the IRA than in the same segment of the non-IRA.

Differences in vasodilatory response to dipyridamole between patients with angina and normal coronary arteries and patients with successful coronary angioplasty.

BACKGROUND: Previous studies reported a reduced coronary blood flow reserve, assessed by the intravenous administration of dipyridamole, in patients with angina and normal coronary arteries, and early after successful coronary angioplasty, which suggests the presence of small coronary vessel dysfunction. This study aimed to establish whether the mechanisms of small coronary vessel disease in these two groups of patients are similar. METHODS: The effects of the intracoronary infusion of adenosine and dipyridamole (maximum dose 2.7 and 7.5 mg/min, respectively) on coronary blood flow velocity were assessed in 11 patients with angina and normal coronary arteries (group A) and in 12 patients immediately after successful coronary angioplasty (group B) using a 0.018" Doppler wire. RESULTS: Baseline coronary blood flow velocity was significantly higher in group B than group A (34 +/- 14 versus 19 +/- 8 cm/s; P = 0.001). In group A, coronary blood flow velocity was higher during adenosine than dipyridamole infusion (74 +/- 17 versus 58 +/- 21 cm/s; P < 0.001), whereas in group B velocities were similar (85 +/- 30 versus 78 +/- 32 cm/s; NS). CONCLUSIONS: In patients with angina and normal coronary arteries, a maximal dose of adenosine causes a greater coronary dilation than that of dipyridamole. Given that dipyridamole operates mainly through an inhibition of adenosine re-uptake, it can only dilate the arteriolar segments exposed to endogenous adenosine. Therefore, the lower response to dipyridamole than to exogenous adenosine observed in patients with angina and normal coronary arteries suggests an impairment of the pre-arterioles that are not influenced by endogenous adenosine, resulting in a limited flow-mediated dilation in response to arteriolar dilation. Such an impairment is not apparent immediately after successful coronary angioplasty, where the most obvious abnormality is an increase of baseline coronary blood flow velocity.

Characterization of a hair (wool) keratin intermediate filament gene domain.

In epithelial differentiation keratin intermediate filament genes are expressed in multifarious tissue-specific and stage-specific patterns. Pairs of type I and type II intermediate filament genes, belonging to multigene families, are coordinately regulated, and 4-5 genes of each type are expressed in the hair follicle. Accumulating chromosomal mapping data points to a major locus for each intermediate filament multigene family on separate chromosomes. In this report we describe the isolation of a sheep hair keratin cosmid by chromosome walking that overlaps two previously described cosmids and establishes a continuous 100-kb segment of cloned DNA containing three hair and three hair-like type II intermediate filament keratin genes. A new hair keratin type II intermediate filament gene, KRT2.11, is located in the middle of the cluster, and partial sequence data reveal a striking conservation of its predicted N-terminal region with other sheep hair keratin type II intermediate filament proteins. Expression analyses demonstrate the presence of a 2.4-kb KRT2.11 transcript in wool follicle RNA and show that expression occurs in the follicle cortical keratinocytes above the dermal papilla. The three hair genes are clustered within about 40 kb and flanked by hair-like genes that are not expressed in the hair follicle, thereby demarcating a hair keratin gene domain.

Site-specific transgene insertion: an approach.

Methods to improve the production of transgenic animals are being developed. Conventional transgenesis, involving microinjection of DNA into fertilized eggs, has a number of limitations. These result from the inability to control both the site of transgene insertion and the number of gene copies inserted. The approach described seeks to overcome these problems and to allow single copy insertion of transgenes into a defined site in animal genomes. The method involves the use of embryonic stem cells, gene targeting and the FLP recombinase system.