Several morphological parameters based on the central aortic pressure waveform are proposed as cardiovascular risk markers, yet no study has definitively demonstrated the incremental value of any ...waveform parameter in addition to currently accepted biomarkers in elderly, hypertensive patients. The reservoir-wave concept combines elements of wave transmission and Windkessel models of arterial pressure generation, defining an excess pressure superimposed on a background reservoir pressure. The utility of pressure rate constants derived from reservoir-wave analysis in prediction of cardiovascular events is unknown. Carotid blood pressure waveforms were measured prerandomization in a subset of 838 patients in the Second Australian National Blood Pressure Study. Reservoir-wave analysis was performed and indices of arterial function, including the systolic and diastolic rate constants, were derived. Survival analysis was performed to determine the association between reservoir-wave parameters and cardiovascular events. The incremental utility of reservoir-wave parameters in addition to the Framingham Risk Score was assessed. Baseline values of the systolic rate constant were independently predictive of clinical outcome (hazard ratio, 0.33; 95% confidence interval, 0.13-0.82; P=0.016 for fatal and nonfatal stroke and myocardial infarction and hazard ratio, 0.38; 95% confidence interval, 0.20-0.74; P=0.004 for the composite end point, including all cardiovascular events). Addition of this parameter to the Framingham Risk Score was associated with an improvement in predictive accuracy for cardiovascular events as assessed by the integrated discrimination improvement and net reclassification improvement indices. This analysis demonstrates that baseline values of the systolic rate constant predict clinical outcomes in elderly patients with hypertension and incrementally improve prognostication of cardiovascular events.
The cause of perioperative myocardial infarction (PMI) is postulated to involve hemodynamic stress or coronary plaque destabilization. We aimed to evaluate perioperative factors in patients with ...peripheral artery disease (PAD) undergoing major vascular surgery to determine the likely mechanisms and predictors of PMI.
This was a prospective cohort study of 133 patients undergoing major vascular surgery including open abdominal aortic aneurysm (AAA) repair (n = 40) and major suprainguinal or infrainguinal arterial bypasses (non-AAA; n = 93). Preoperative assessment with history, physical examination, and peripheral artery tonometry was performed in addition to plasma sampling of biomarkers associated with inflammation and coronary plaque instability. The primary outcome was occurrence of a 30-day cardiovascular event (CVE; composite of PMI troponin I elevation >99th percentile reference of ≥0.1 μg/L, stroke, or death).
Of 133 patients, 36 patients (27%) developed a 30-day CVE after vascular surgery, and all were PMI. Patients with 30-day CVE were older (75 ± 8 years vs 69 ± 10 years, mean ± standard deviation; P = .001), had higher prevalence of hypertension (94% vs 79%; P = .01) and preoperative beta-blocker therapy (50% vs 29%; P = .02), and had longer duration of surgery (5.1 ± 1.8 hours vs 4.0 ± 1.1 hours; P < .0001). Significant elevations in cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin I, high-sensitivity troponin T, matrix metalloproteinase 3, and osteoprotegerin occurred in those who developed 30-day CVE (all P < .05). Multivariate binary logistic regression identified AAA surgery and log-transformed NT-proBNP to be independent preoperative predictors of 30-day CVE (area under the receiver operating characteristic curve = 0.81).
In patients with peripheral artery disease undergoing major vascular surgery, the likely mechanism of PMI appears to be the hemodynamic stress related to the type and duration of surgery. NT-proBNP was a useful independent predictor of CVE and thus may serve as an important biomarker of cardiovascular fitness for surgery.
Abstract Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the ...role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators' expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissect the role of MIF derived from different cellular sources in post-MI cardiac remodelling, we generated chimeric mice with MIF deficiency either in bone marrow derived-cells (WTKO ) or in somatic-cells (KOWT ). Compared to WT and KOWT mice, WTKO mice had reduced rupture risk and ameliorated cardiac remodelling, associated with attenuated regional leukocyte infiltration and expression of inflammatory mediators. In contrast, KOWT mice had delayed healing and enhanced expression of M1 macrophage markers, but diminished expression of M2 markers during the early healing phase. In conclusion, global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation. Leukocyte-derived MIF promotes inflammatory responses after MI, whereas cardiac-derived MIF affects early but not ultimate healing process.
Peripherally inserted central catheters (PICCs) are frequently used for prolonged drug administration, but their use is commonly complicated by the development of upper extremity deep venous ...thrombosis (UEDVT) requiring anticoagulation. Here, we compared the efficacy and safety profile of rivaroxaban (20 mg/d) with low molecular weight (LMW) heparin and vitamin K antagonists in the treatment of PICC-associated UEDVT.
Patients (N = 84) with PICC-associated UEDVT were studied. All had UEDVT identified by ultrasound scanning. Further ultrasound images were obtained at 1, 2, and 3 months after the start of treatment. Forty-four patients were treated with rivaroxaban and 40 with initial LMW heparin and vitamin K antagonist with continuation of vitamin K antagonists alone once international normalized ratio was therapeutic
In the rivaroxaban group mean (SD) age was 51 (16) years and 57% were men, whereas in the other group respective values were 50 (16) years and 56%. All patients were receiving treatment for cancer. Resolution of thrombus had occurred in 53.5% at 1 month, 76.1% at 2 months, and 92.6% at 3 months in the rivaroxaban-treated patients. Corresponding values in the LMW heparin/vitamin antagonist–treated patients were 34.2%, 55.5%, and 88.5%, respectively. Differences between groups were significant at 1 month (P < 0.01) and 2 months (P < 0.05). There were no major bleeds in either group, and cumulative bleeding rates by 3 months were 7.3% in the rivaroxaban group and 11.4% in the LMW heparin/vitamin K antagonist group.
Rivaroxaban led to faster resolution of PICC-associated UEDVT than LMW/vitamin K antagonists without any increase in bleeding.
Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is believed to be caused by abnormal host immune responses to the intestinal microbiome. However, ...the precise etiology of IBD remains unknown. Lipid metabolism and signaling are suggested to play important roles in inflammation with significant implications for IBD. In this study, we aimed to characterize lipidomic profiles in IBD with comparison between healthy controls, UC, and CD.
Patients with IBD (n = 40, UC: 16 and CD: 24) and age- and gender-matched healthy volunteers (n = 84) were recruited. Plasma lipid profiles containing 333 lipid species were measured using electrospray ionization-tandem mass spectrometry.
A total of 86 individual lipid species were significantly changed in CD compared with controls (78 decreased while 8 increased), with the majority belonging to the ether lipids including the alkylphospholipids (alkylphosphatidylcholine and alkylphosphatidylethanolamine) and plasmalogens (alkenylphosphatidylcholine and alkenylphosphatidylethanolamine). Of these 86 lipid species, 33 remained significantly and negatively associated with CD after adjusting for age, sex, waist circumference, current smoking, and diastolic blood pressure in logistic regression. In contrast, only 5 lipid species significantly differed between UC and controls.
We demonstrate that a number of ether lipids (alkylphospholipid and plasmalogens) are significantly and negatively associated with CD. These alterations of lipid profiles particularly plasmalogens may contribute to the pathogenesis of IBD.
Hypertension and aging are associated with large artery structural remodeling and stiffening, which are known to increase cardiovascular risk. Relaxin is a peptide hormone with potent antifibrotic ...action in multiple organs. Although relaxin is able to reduce peripheral vascular resistance and improve arterial compliance in rats, it remains unclear whether the improvement in compliance is indirectly attributed to a vasodilatory action or whether relaxin is able to reverse arterial remodeling and stiffening directly in aged hypertensive animals. Senescent spontaneously hypertensive rats (17 months old) were treated with relaxin for 2 weeks (0.5 mg/kg per day) followed by a 1-week washout period. We determined large artery compliance using in vivo and in vitro techniques and quantified arterial remodeling by morphological and chemical means. Relaxin therapy significantly reversed aortic remodeling (ie, increases in vessel size, wall thickness, and collagen content) and improved arterial compliance, effects independent of its vasodilatory action. In relaxin-treated spontaneously hypertensive rats, arterial collagen content showed a greater reduction (-31%; P<0.05) than that of elastin (-8%), resulting in an increased elastin:collagen ratio (0.63+/-0.03 versus 0.47+/-0.02; P<0.05). In conclusion, our results demonstrated that relaxin is potent in mediating reversal of arterial remodeling and improving arterial structural compliance in aged hypertensive rats.
Background:
The purpose of this study is to elucidate mechanism(s) by which the orally active PGI2 analog, Beraprost (BPS), ameliorates pulmonary hypertension (PH). Prostaglandins are an important ...treatment for PH. Mechanisms of their action are not fully elucidated in relation to receptor subtype and effects on O
2
sensitive Kv channels.
Methods:
Distal (3rd order and beyond) pulmonary arteries from chronically hypoxic rats and from humans with established PH were studied. Measurements included pulmonary haemodynamics and histology, vascular reactivity, prostanoid receptor expression and activity of the O
2
sensitive Kv channels.
Results:
Prostacyclin receptor (IP), prostaglandin receptor E3 (EP3) and prostaglandin receptor E4 (EP4) are the main pulmonary artery receptor subtypes in both rat and human pulmonary arteries. Circulating levels of PGI2 and PGE2 were reduced in PH. PH was also associated with reduced receptor expression of IP but not of EP4. The effects on IP expression were overcome with BPS. Dilatory responses in PH to BPS were reduced in the presence of EP4 blockade. Expression and activity of oxygen sensitive Kv channels were reduced in pulmonary artery smooth muscle cell from rats with PH and humans with PAH and were also overcome by administration of BPS. Effects of BPS on oxygen sensitive Kv channels were reduced in the presence of EP4 blockade implicating the EP4 receptor, as well as the IP receptor, in mediating BPS effects.
Conclusion:
Reduced expression of pulmonary IP receptors and reduced activity of O
2
sensitive Kv channels are found in PH in both humans and rats. The orally active prostacyclin analogue, BPS, is able to reverse these changes, partly through binding to the EP4 receptor.
We sought to investigate the effects of intensive cholesterol reduction on large artery stiffness and blood pressure in normolipidemic patients with isolated systolic hypertension (ISH).
Isolated ...systolic hypertension is associated with elevated cardiovascular morbidity and mortality and is primarily due to large artery stiffening, which has been independently related to cardiovascular mortality. Cholesterol-lowering therapy has been efficacious in reducing arterial stiffness in patients with hypercholesterolemia, and thus may be beneficial in ISH.
In a randomized, double-blinded, cross-over study design, 22 patients with stage I ISH received three months of atorvastatin therapy (80 mg/day) and three months of placebo treatment. Systemic arterial compliance was measured noninvasively using carotid applanation tonometry and Doppler velocimetry of the ascending aorta.
Atorvastatin treatment reduced total and low-density lipoprotein cholesterol and triglyceride levels by 36 ± 2% (p < 0.001), 48 ± 3% (p < 0.001) and 23 ± 5% (p = 0.003), respectively, and increased high density lipoprotein cholesterol by 7 ± 3% (p = 0.03). Systemic arterial compliance was higher after treatment (placebo vs. atorvastatin: 0.36 ± 0.03 vs. 0.43 ± 0.05 ml/mm Hg, p = 0.03). Brachial systolic blood pressure was lower after atorvastatin treatment (154 ± 3 vs. 148 ± 2 mm Hg, p = 0.03), as were mean (111 ± 2 vs. 107 ± 2 mm Hg, p = 0.04) and diastolic blood pressures (83 ± 1 vs. 81 ± 2 mm Hg, p = 0.04). There was a trend toward a reduction in pulse pressure (71 ± 3 vs. 67 ± 2 mm Hg, p = 0.08).
Intensive cholesterol reduction may be beneficial in the treatment of patients with ISH and normal lipid levels, through a reduction in large artery stiffness.
Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in ...mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of β2-adrenergic receptors (β2-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by ∼40%), hypertrophied hearts from SHR (by ∼80%), mice with TAC (at 1 and 3 weeks, by ∼50%), and β2-TG mice (by ∼20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy.
The coronavirus disease 2019 (COVID-19) outbreak within China has been well controlled and stabilized since early April 2020. Therefore, the current major focus in China is to prevent the ...introduction of COVID into China from international arrivals. To achieve this, pre-Hospital COVID-19 Response Teams (pHCRTs) have been established.
The pHRCTs were established in Xi'an, China in early 2020. During the 12 months covered in this report, there were 356 international flight arrivals with over 5,000 COVID-19 Nucleic Acid Test (NAT) positive people, 500 of them with symptomatic COVID-19 and requiring admission to special hospitals. All other arrivals were managed in dedicated facilities by pHRCTs. The outcome measure of this report was the number of positive cases among the pHRCT members.
Four hundred forty-two staff worked in the pHCRTs during the reporting period. Despite multiple throat swab PCR tests during their pHRCTs tour of duty, and the subsequent mandatory 14-day quarantine required before return to the general community, no staff became NAT positive.
The prevention of community transmission from imported cases is a vital part of the strategy to maintain the low numbers of cases in countries which have achieved control, or suppression of local internal cases. The program of pHCRTs described in this article gives successful protocols for transportation of patients who are infectious based on the minimal transmission of virus and staff safety. The strategies employed may prove useful in future pandemics.
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