Paula Harvey

Impaired brachial artery endothelium dependent flow mediated dilation in systemic lupus erythematosus: preliminary observations.

Our objective was to compare brachial artery endothelium dependent and independent vasodilation in lupus patients and healthy females, by means of high-resolution noninvasive brachial artery ultrasound. Endothelially mediated vasodilation was estimated noninvasively by examination of brachial artery responses to postischemic reactive hyperemia and endothelial independent vasodilation from response to sublingual glycerlynitrate (GTN) using high-resolution external vascular ultrasound. Five patients with known coronary artery disease (CAD), five with subclinical CAD, five with no CAD and five control subjects were assessed. Endothelium dependent vasodilation was significantly blunted in lupus patients with CAD as compared with healthy female controls (0.11 versus 11.1%, P 1/4 0.018). Corresponding values for lupus patients with subclinical CAD and no CAD were 11 and 9.6%, respectively. For each subject, endothelium dependent vasodilation (EDV) was related to endothelium independent vasodilation (EIV) to adjust for varying vascular smooth muscle responses to GTN in individual subjects. This ratio was markedly depressed in lupus patients with CAD as compared with control subjects (0.12 versus 1.15). The corresponding EDV/EIV ratios for patients with subclinical CAD and no CAD were similar at 0.69 and 0.65, respectively. The conclusion was that flow mediated vasodilation in lupus patients with coronary artery disease is markedly depressed as compared to healthy subjects.

Women, cardiac syndrome X, and microvascular heart disease.

New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists.

Clinical review: Cardiovascular consequences of ovarian disruption: a focus on functional hypothalamic amenorrhea in physically active women.

CONTEXT Evidence indicates that hypoestrogenemia is linked with accelerated progression of atherosclerosis. Premenopausal women presenting with ovulatory disruption due to functional hypothalamic amenorrhea (FHA) are characterized by hypoestrogenemia. One common and reversible form of FHA in association with energy deficiency is exercise-associated amenorrhea (EAA). EVIDENCE ACQUISITION Articles were found via PubMed search for both original and review articles based on peer review publications between 1974 and 2011 reporting on cardiovascular changes in women with FHA, with emphasis placed on women with EAA. EVIDENCE SYNTHESIS Despite participation in regular exercise training, hypoestrogenic women with EAA demonstrate paradoxical changes in cardiovascular function, including endothelial dysfunction, a known permissive factor for the progression and development of atherosclerosis. Such alterations suggest that the beneficial effects of regular exercise training on vascular function are obviated in the face of hypoestrogenemia. The long-term cardiovascular consequences of altered vascular function in response to ovulatory disruption in women with EAA remain to be determined. Retrospective data, however, suggest premature development and progression of coronary artery disease in older premenopausal women reporting a history of hypothalamic ovulatory disruption. Importantly, in women with EAA, estrogen therapy, folic acid supplementation without change in menstrual status, and resumption of menses restores endothelial function. In this review, we focus on the influence of hypoestrogenemia in association with energy deficiency in mediating changes in cardiovascular function in women with EAA, including endothelial function, regional blood flow, lipid profile, and autonomic control of blood pressure, heart rate, and baroreflex sensitivity. The influence of exercise training is also considered. CONCLUSION With the premenopausal years typically considered to be cardioprotective in association with normal ovarian function, ovarian disruption in women with EAA is of importance. Further investigation of the short-term, and potentially long-term, cardiovascular consequences of hypoestrogenemia in women with EAA is recommended.

Variability over time and correlates of cholesterol and blood pressure in systemic lupus erythematosus: a longitudinal cohort study

IntroductionTotal cholesterol (TC) and blood pressure (BP) are likely to take a dynamic course over time in patients with systemic lupus erythematosus (SLE). This would have important implications in terms of using single-point-in-time measurements of these variables to assess coronary artery disease (CAD) risk. The objective of this study was to describe and quantify variability over time of TC and BP among patients with SLE and to determine their correlates.MethodsPatients in the Toronto lupus cohort who had two or more serial measurements of TC and systolic and diastolic BP (SBP and DBP) were included in the analysis. Variability over time was described in terms of the proportion of patients whose TC and BP profile fluctuated between normal and elevated (TC > 5.2 mmol/L; SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg), and also in terms of within- and between-patient variance quantified by using analysis of variance modeling. Generalized estimating equations (GEEs) were used to determine independent correlates of each of TC, SBP, and DBP, treated as continuous outcome variables.ResultsIn total, 1,260 patients, comprising 26,267 measurements of each of TC, SBP, and DBP, were included. Mean ± SD number of measurements per patient was 20.8 ± 20. Mean ± SD time interval between measurements was 5.4 ± 9.7 months. Mean ± SD time interval from the start to the end of the study was 9.3 ± 8.5 years. Over time, 64.7% of patients varied between having normal and elevated cholesterol levels, whereas the status of 46.4% of patients varied between normotensive and hypertensive. By using analysis of variance (ANOVA), the within-patient percentage of total variance for each of TC, SBP, and DBP was 48.2%, 51.2%, and 63.9%, respectively. By using GEE, independent correlates of TC and BP included age, disease activity, and corticosteroids; antimalarial use was negatively correlated with TC (all P values < 0.0001).ConclusionsTC and BP vary markedly over time in patients with SLE. This variability is due not only to lipid-lowering and antihypertensive medications, but also to disease- and treatment-related factors such as disease activity, corticosteroids, and antimalarials. The dynamic nature of TC and BP in SLE makes a compelling case for deriving summary measures that better capture cumulative exposure to these risk factors.

Impaired Vascular Function in Physically Active Premenopausal Women With Functional Hypothalamic Amenorrhea Is Associated With Low Shear Stress and Increased Vascular Tone

INTRODUCTION Exercise-trained hypoestrogenic premenopausal women with functional hypothalamic amenorrhea (ExFHA) exhibit impaired endothelial function. The vascular effects of an acute bout of exercise, a potent nitric oxide stimulus, in these women are unknown. METHODS Three groups were studied: recreationally active ExFHA women (n = 12; 24.2 ± 1.2 years of age; mean ± SEM), and recreationally active (ExOv; n = 14; 23.5 ± 1.2 years of age) and sedentary (SedOv; n = 15; 23.1 ± 0.5 years of age) ovulatory eumenorrheic women. Calf blood flow (CBF) and brachial artery flow-mediated dilation (FMD) were evaluated using plethysmographic and ultrasound techniques, respectively, both before and 1 hour after 45 minutes of moderate-intensity exercise. Endothelium-independent dilation was assessed at baseline using glyceryl trinitrate. Calf vascular resistance (CVR) and brachial peak shear rate, as determined by the area under the curve (SRAUCpk), were also calculated. RESULTS FMD and glyceryl trinitrate responses were lower (P < .05) in ExFHA (2.8% ± 0.4% and 11.6% ± 0.7%, respectively) than ExOv (8.8% ± 0.7% and 16.7% ± 1.3%) and SedOv (8.0% ± 0.5% and 17.1% ± 1.8%). SRAUCpk was also lower (P < .05) in ExFHA. Normalization of FMD for SRAUCpk (FMD/SRAUCpk) did not alter (P > .05) the findings. CBF was lower (P < .05) and CVR higher (P < .05) in ExFHA. After exercise, FMD and SRAUCpk were augmented (P < .05), but remained lower (P < .05), in ExFHA. FMD/SRAUCpk no longer differed (P > .05) between the groups. CBF in ExFHA was increased (P < .05) and CVR decreased (P < .05) to levels observed in ovulatory women. CONCLUSIONS Acute dynamic exercise improves vascular function in ExFHA women. Although the role of estrogen deficiency per se is unclear, our findings suggest that low shear rate and increased vasoconstrictor tone may play a role in impaired basal vascular function in these women.

Prevalence and associated factors of resting electrocardiogram abnormalities among systemic lupus erythematosus patients without cardiovascular disease

BackgroundElectrocardiogram (ECG) cardiovascular disease (CVD) abnormalities (ECG-CVD) are predictive of subsequent CVD events in the general population. Systemic lupus erythematosus (SLE) patients are vulnerable to CVD. We aimed to determine the prevalence of ECG-CVD in SLE patients and to examine the risk factors associated with ECG-CVD.MethodsA 12-lead resting supine ECG was performed on consecutive adult patients attending the clinic. One cardiologist interpreted the ECGs. ECG-CVD were defined as the presence of one or more of the following 4 elements (ECG-4): ST-segment and/or T-wave abnormalities, left ventricular hypertrophy (LVH), left axis deviation (LAD), left bundle branch block (LBBB) and right bundle branch block (RBBB). ECG-5 included the same elements as ECG-4 and the Q-wave. Repeated measurement data were created and the associations between ECG-4/ECG-5 and demographics were evaluated with univariate and multivariate Cox regression models.ResultsOf 487 SLE patients, 104 (21.4%) and 118 (24.2%) patients had one or more of the ECG-4 and ECG-5 elements, respectively. A higher prevalence of ECG-CVD was found in patients with a longer SLE disease duration, and the burden of ECG-CVD elements increased with age. Increased age, active SLE disease, and damage were associated with ECG4 and ECG-5, while treatment of hyperlipidemia was protective.ConclusionA high prevalence of ECG-4 (21.4%) and ECG-5 (24.2%) was found in this SLE cohort. Controlling SLE disease activity is important since it was associated with ECG-4 and ECG-5. Early identification of ECG-4 and ECG-5 in SLE patients might allow for better stratification and risk management.

Antimalarial-induced cardiomyopathy: a systematic review of the literature:

Background Antimalarials (AMs) are widely used in the treatment of connective tissue diseases. Their main side effect is retinal damage, while heart disease has been described in isolated cases. The aim of this study is to systematically review the existing literature on AM-induced cardiomyopathy (AMIC). Methods The PubMed database was searched for heart biopsy-confirmed AMIC cases. Information on demographics, clinical presentation, concomitant AM-related toxicity, cardiological investigations, treatment and outcome were collected. Descriptive statistics were used. Results Forty-seven cases (42 females) were identified with a mean age at diagnosis 56.4 ± 12.6 and mean AM treatment duration 12.7 ± 8.2 years. Systemic lupus erythematosus (n = 19) and rheumatoid arthritis (n = 18) were the most common primary diseases. Clinical presentation was that of congestive heart failure in 77%, while eight patients presented with syncope (17%). Complete atrioventricular block was reported in 17 patients; 24 received a permanent pacemaker (51%). Impaired systolic function was detected in 52.8%, bi-ventricular hypertrophy in 51.4% and restrictive filling pattern of the left ventricle in 18 patients. Cardiac magnetic resonance showed late gadolinium enhancement in seven cases, with a non-vascular pattern in the interventricular septum. Cardiomyocyte vacuolation was reported in all cases; intravacuolar lamellar and curvilinear bodies were observed in 46 (98%) and 42 (89.4%) respectively. Mortality rate was 45% (18/40). Conclusion AMIC is a rare, probably under-recognized, complication of prolonged AM treatment. It presents as a hypertrophic, restrictive cardiomyopathy with or without conduction abnormalities. Early recognition and drug withdrawal are critical with a survival rate of almost 55%.

Self-management of cardiac pain in women: an evidence map

Objective To describe the current evidence related to the self-management of cardiac pain in women using the process and methodology of evidence mapping. Design and setting Literature search for studies that describe the self-management of cardiac pain in women greater than 18 years of age, managed in community, primary care or outpatient settings, published in English or a Scandinavian language between 1 January 1990 and 24 June 2016 using AMED, CINAHL, ERIC, EMBASE, MEDLINE, Proquest, PsychInfo, the Cochrane Library, Scopus, Swemed+, Web of Science, the Clinical Trials Registry, International Register of Controlled Trials, MetaRegister of Controlled Trials, theses and dissertations, published conference abstracts and relevant websites using GreyNet International, ISI proceedings, BIOSIS and Conference papers index. Two independent reviewers screened using predefined eligibility criteria. Included articles were classified according to study design, pain category, publication year, sample size, per cent women and mean age. Interventions Self-management interventions for cardiac pain or non-intervention studies that described views and perspectives of women who self-managed cardiac pain. Primary and secondary outcomes measures Outcomes included those related to knowledge, self-efficacy, function and health-related quality of life. Results The literature search identified 5940 unique articles, of which 220 were included in the evidence map. Only 22% (n=49) were intervention studies. Sixty-nine per cent (n=151) of the studies described cardiac pain related to obstructive coronary artery disease (CAD), 2% (n=5) non-obstructive CAD and 15% (n=34) postpercutaneous coronary intervention/cardiac surgery. Most were published after 2000, the median sample size was 90 with 25%–100% women and the mean age was 63 years. Conclusions Our evidence map suggests that while much is known about the differing presentations of obstructive cardiac pain in middle-aged women, little research focused on young and old women, non-obstructive cardiac pain or self-management interventions to assist women to manage cardiac pain. PROSPERO registration number CRD42016042806.

Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea

Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P<0.05) and HF and total power were higher (P<0.05) in ExFHA than in eumenorrhoeic women. In all groups, LBNP decreased (P<0.05) SBP, HF and total power and increased (P<0.05) HR and LF/HF ratio. However, HF and total power remained higher (P<0.05) and HR, SBP and LF/HF ratio remained lower (P<0.05) in ExFHA than in eumenorrhoeic women, in whom measures did not differ (P>0.05). At each stage, HR correlated inversely (P<0.05) with HF. In conclusion, ExFHA women demonstrate augmented vagal yet unchanged sympathetic HR modulation, both at rest and during orthostatic stress. Although the role of oestrogen deficiency is unclear, these findings are in contrast with studies reporting decreased HRV in hypoestrogenic post-menopausal women.

Assessment of coronary risk based on cumulative exposure to lipids in systemic lupus erythematosus.

Objective. To quantify the independent role of each of low-density lipoprotein cholesterol (LDL-C), total cholesterol:high-density lipoprotein cholesterol ratio (TC:HDL-C), triglyceride (TG) level, and HDL-C as a marker of coronary risk in systemic lupus erythematosus (SLE). Methods. Patients with lipid measurements taken before a coronary event (or last clinic visit) were included. Mean and time-adjusted mean (TAM) levels were calculated for each lipid variable in each patient. Time-dependent proportional hazards regression models were used to quantify the risk of coronary event [myocardial infarction (MI) or angina], after adjustment for age. Results. Among 384 patients, over a mean (SD) followup of 3.81 (2.58) years, there were 21 “first” coronary events (6 MI, 15 angina). Mean and TAM LDL-C (HR 1.83, 95% CI 1.19–2.81, p = 0.006), TC:HDL ratio (HR 1.43, 95% CI 1.02–2.00, p = 0.04), and TG (HR 2.11, 95% CI 1.32–3.39, p = 0.0019) were predictive of coronary event at subsequent visits. In contingency table analysis, TAM LDL-C cutpoint of 2.0 mmol/l had a sensitivity and negative predictive value for coronary event of 85.7% (95% CI 63.7–97.0) and 93.9% (95% CI 83.1–98.7), respectively. However, at this cutpoint the specificity was only 12.7% (95% CI 9.4–16.5). Conclusion. This study links LDL-C, TC:HDL-C ratio, and TG to coronary risk in patients with SLE and quantifies the magnitude of this risk. SLE-specific risk assessment levels for lipids may be selected to optimize positive or negative predictive values.