Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy.

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.

A Comprehensive 6A Framework for Improving Patient Self-Management of Hypertension Using mHealth Services: Qualitative Thematic Analysis.

BACKGROUND: Hypertension affects over 15% of the world's population and is a significant global public health and socioeconomic challenge. Mobile health (mHealth) services have been increasingly introduced to support hypertensive patients to improve their self-management behaviors, such as adherence to pharmacotherapy and lifestyle modifications. OBJECTIVE: This study aims to explore patients' perceptions of mHealth services and the mechanisms by which the services support them to self-manage their hypertension. METHODS: A semistructured, in-depth interview study was conducted with 22 outpatients of the General Hospital of Ningxia Medical University from March to May 2019. In 2015, the hospital introduced an mHealth service to support community-dwelling outpatients with self-management of hypertension. Content analysis was conducted by following a grounded theory approach for inductive thematic extraction. Constant comparison and categorization classified the first-level codes with similar meanings into higher-level themes. RESULTS: The patient-perceived mechanisms by which the mHealth service supported their self-management of hypertension were summarized as 6A: access, assessment, assistance, awareness, ability, and activation. With the portability of mobile phones and digitization of information, the mHealth service provided outpatients with easy access to assess their vital signs and self-management behaviors. The assessment results gave the patients real-time awareness of their health conditions and self-management performance, which activated their self-management behaviors. The mHealth service also gave outpatients access to assistance, which included health education and self-management reminders. Both types of assistance could also be activated by abnormal assessment results, that is, uncontrolled or deteriorating blood pressure values, discomfort symptoms, or not using the service for a long period. With its scalable use to handle any possible information and services, the mHealth service provided outpatients with educational materials to learn at their own pace. This led to an improvement in self-management awareness and ability, again activating their self-management behaviors. The patients would like to see further improvements in the service to provide more useful, personalized information and reliable services. CONCLUSIONS: The mHealth service extended the traditional hypertension care model beyond the hospital and clinician's office. It provided outpatients with easy access to otherwise inaccessible hypertension management services. This led to process improvement for outpatients to access health assessment and health care assistance and improved their awareness and self-management ability, which activated their hypertension self-management behaviors. Future studies can apply the 6A framework to guide the design, implementation, and evaluation of mHealth services for outpatients to self-manage chronic conditions.

Rates of Attrition and Dropout in App-Based Interventions for Chronic Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Chronic disease represents a large and growing burden to the health care system worldwide. One method of managing this burden is the use of app-based interventions; however attrition, defined as lack of patient use of the intervention, is an issue for these interventions. While many apps have been developed, there is some evidence that they have significant issues with sustained use, with up to 98% of people only using the app for a short time before dropping out and/or dropping use down to the point where the app is no longer effective at helping to manage disease. OBJECTIVE: Our objectives are to systematically appraise and perform a meta-analysis on dropout rates in apps for chronic disease and to qualitatively synthesize possible reasons for these dropout rates that could be addressed in future interventions. METHODS: MEDLINE (Medical Literature Analysis and Retrieval System Online), PubMed, Cochrane CENTRAL (Central Register of Controlled Trials), and Embase were searched from 2003 to the present to look at mobile health (mHealth) and attrition or dropout. Studies, either randomized controlled trials (RCTs) or observational trials, looking at chronic disease with measures of dropout were included. Meta-analysis of attrition rates was conducted in Stata, version 15.1 (StataCorp LLC). Included studies were also qualitatively synthesized to examine reasons for dropout and avenues for future research. RESULTS: Of 833 studies identified in the literature search, 17 were included in the review and meta-analysis. Out of 17 studies, 9 (53%) were RCTs and 8 (47%) were observational trials, with both types covering a range of chronic diseases. The pooled dropout rate was 43% (95% CI 29-57), with observational studies having a higher dropout rate (49%, 95% CI 27-70) than RCTs in more controlled scenarios, which only had a 40% dropout rate (95% CI 16-63). The studies were extremely varied, which is represented statistically in the high degree of heterogeneity (I2>99%). Qualitative synthesis revealed a range of reasons relating to attrition from app-based interventions, including social, demographic, and behavioral factors that could be addressed. CONCLUSIONS: Dropout rates in mHealth interventions are high, but possible areas to minimize attrition exist. Reducing dropout rates will make these apps more effective for disease management in the long term. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42019128737; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128737.

Guideline for the diagnosis and management of hypertension in adults - 2016.

The National Heart Foundation of Australia has updated the Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults (updated December 2010). Main recommendations For patients at low absolute cardiovascular disease risk with persistent blood pressure (BP) ≥ 160/100 mmHg, start antihypertensive therapy. The decision to treat at lower BP levels should consider absolute cardiovascular disease risk and/or evidence of end-organ damage, together with accurate BP assessment. For patients at moderate absolute cardiovascular disease risk with persistent systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, start antihypertensive therapy. Treat patients with uncomplicated hypertension to a target BP of < 140/90 mmHg or lower if tolerated. Changes in management as a result of the guideline Ambulatory and/or home BP monitoring should be offered if clinic BP is ≥ 140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome. In selected high cardiovascular risk populations, aiming for a target of < 120 mmHg systolic can improve cardiovascular outcomes. If targeting < 120 mmHg, close follow-up is recommended to identify treatment-related adverse effects including hypotension, syncope, electrolyte abnormalities and acute kidney injury. Why the changes have been made A 2015 meta-analysis of patients with uncomplicated mild hypertension (systolic BP range, 140-169 mmHg) demonstrated that BP-lowering therapy is beneficial (reduced stroke, cardiovascular death and all-cause mortality). A 2015 trial comparing lower with higher blood pressure targets in selected high cardiovascular risk populations found improved cardiovascular outcomes and reduced mortality, with an increase in some treatment-related adverse events.

Regulator of G-protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling.

RATIONALE: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation. OBJECTIVE: To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways. METHODS AND RESULTS: We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin-angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension. CONCLUSIONS: Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gαq-coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.

Diastolic function is a strong predictor of mortality in patients with chronic kidney disease.

BACKGROUND: Cardiovascular disease is a major cause of death in patients with stage 4-5 Chronic Kidney disease (CKD, eGFR < 30). There are only limited data on the risk factors predicting these complications in CKD patients. Our aim was to determine the role of clinical and echocardiographic parameters in predicting mortality and cardiovascular complications in CKD patients. METHODS: We conducted a prospective observational cohort study of 153 CKD patients between 2007 and 2009. All patients underwent echocardiography at baseline and were followed for a mean of 2.6 years using regular clinic visits and review of files and hospital presentations to record the incidence of cardiovascular events and death. RESULTS: Of 153 patients enrolled, 57 (37%) were on dialysis and 45 (78%) of these patients were on haemodialysis. An enlarged LV was present in 32% of patients and in 22% the LVEF was below 55%. LV mass index was increased in 75% of patients. Some degree of diastolic dysfunction was present in 85% of patients and 35% had grade 2 or higher diastolic dysfunction. During follow up 41 patients (27%) died, 15 (39%) from cardiovascular causes. Mortality was 24.0% in the non-dialysis patients versus 31.6% in patients on dialysis (p=ns). On multivariate analysis age >75 years, previous history of MI, diastolic dysfunction and detectable serum troponin T were significant independent predictor of mortality (P < 0.01). CONCLUSION: Patients with stage 4-5 CKD had a mortality rate of 27% over a mean follow up of 2.6 years. Age >75 years, history of MI, diastolic dysfunction and troponin T were independent predictors of mortality.

Cognitive and brain changes associated with ischaemic heart disease and heart failure.

AIMS: It is unclear whether the cognitive dysfunction associated with heart failure (HF) is due to HF or comorbid conditions such as ischaemic heart disease (IHD). This study aimed to determine whether, compared with controls with and without IHD, adults with systolic HF show evidence of cognitive impairment and cerebral grey matter (GM) loss. METHODS AND RESULTS: Cross-sectional study of 35 participants with HF, 56 with IHD, and 64 controls without either HF or IHD. Subjects were older than 45 years and free of overt cognitive impairment. We acquired magnetic resonance images and used SPM8 to determine regional differences in cerebral GM volume. Participants with HF had lower scores than controls without IHD on immediate memory, long delay recall and digit coding, whereas those with IHD had lower long delay recall scores than controls without IHD. Compared with controls without IHD, participants with HF showed evidence of GM loss in the left cingulate, the right inferior frontal gyrus, the left middle and superior frontal gyri, the right middle temporal lobe, the right and left anterior cingulate, the right middle frontal gyrus, the inferior and pre-central frontal gyri, the right caudate, and occipital-parietal regions involving the left precuneus. The loss of GM followed a similar, less extensive, pattern when we compared participants with HF and IHD. CONCLUSION: Adults with HF have worse immediate and long-term memory and psychomotor speed than controls without IHD. Heart failure is associated with changes in brain regions that are important for demanding cognitive and emotional processing.

Two-year course of cognitive function and mood in adults with congestive heart failure and coronary artery disease: the Heart-Mind Study.

BACKGROUND: Congestive heart failure (CHF) has been associated with impaired cognitive function, but it is unclear if these changes are specific to CHF and if they get worse with time. We designed this study to determine if adults with CHF show evidence of cognitive decline compared with adults with and without coronary artery disease (CAD). METHODS: A longitudinal study was carried out of 77 adults with CHF (ejection fraction, EF < 0.4), 73 adults with a clinical history of CAD and EF > 0.6, and 81 controls with no history of CAD. The Cambridge Cognitive Examination of the Elderly (CAMCOG) was the primary outcome measure. Secondary measures included the California Verbal Learning Test (CVLT), digit coding and copying, Hospital Anxiety and Depression Scale (HADS), and the short form health survey (SF36). Endpoints were collected at baseline and after 12 and 24 months. RESULTS: The adjusted CAMCOG scores of CHF participants declined 0.9 points over two years (p = 0.022) compared with controls without CAD. There were no differences between the groups on other cognitive measures. Participants with CHF and with CAD experienced similar changes in cognitive function over two years. Left ventricular EF and six-minute walk test results could not explain the observed associations. CONCLUSIONS: The changes in cognitive function and mood associated with CHF over two years are subtle and not specific to CHF.

Effect of transfer delay on left ventricular function after primary PCI for ST elevation myocardial infarction.

BACKGROUND: Primary PCI (PPCI) is superior to thrombolysis for treatment of acute ST Elevation Myocardial Infarction (STEMI). However, transfer to a PCI centre results in a treatment delay compared to those presenting directly to such hospitals. The aim of this study was to investigate the influence of transfer delay on LV function and clinical outcomes in PPCI patients. METHODS: Of 113 consecutive PPCI patients, 69 presented directly to the PCI centre and 44 were transferred. Echocardiography was performed at day 1 and after 6 weeks to assess LV function using the Wall Motion Score Index (WMSI). Patients were followed for a mean of 3.51 years. RESULTS: There was no significant difference in WMSI at day 1 between local and transfer patients (1.52±0.36 and 1.48±0.34 respectively, p=ns). After 6 weeks the WMSI improved significantly in both groups (1.33±0.33 and 1.31±0.31 respectively, p<0.001 for both). On multivariate analysis, pain to balloon time>160 min, LAD stenosis and initial TIMI flow 0-1 were significant independent predictors of LV dysfunction. There was no significant difference in clinical events during long term follow up. CONCLUSIONS: Patients transferred for PPCI had similar LV function and clinical outcomes compared to those who presented directly to a PCI hospital.

Autonomic Afferent Dysregulation in Atrial Fibrillation.

OBJECTIVES: This study sought to evaluate the role of cardiac afferent reflexes in atrial fibrillation (AF). BACKGROUND: Efferent autonomic tone is not associated with atrial remodeling and AF persistence. However, the role of cardiac afferents is unknown. METHODS: Individuals with nonpermanent AF (n = 48) were prospectively studied (23 in the in-AF group and 25 in sinus rhythm [SR]) with 12 matched control subjects. We performed: 1) low-level lower body negative pressure (LBNP), which decreases cardiac volume, offloading predominantly cardiac afferent (volume-sensitive) low-pressure baroreceptors; 2) Valsalva reflex (predominantly arterial high-pressure baroreceptors); and 3) isometric handgrip reflex (both baroreceptors). We measured beat-to-beat mean arterial pressure (MAP) and heart rate (HR). LBNP elicits reflex vasoconstriction, estimated using venous occlusion plethysmography-derived forearm blood flow (∝1/vascular resistance), maintaining MAP. To assess reversibility, we repeated LBNP (same day) after 1-hour low-level tragus stimulation (in n = 5 in the in-AF group and n = 10 in the in-SR group) and >6 weeks post-cardioversion (n = 7). RESULTS: The 3 groups were well matched for age (59 ± 12 years, 83% male), body mass index, and risk factors (P = NS). The in-AF group had higher left atrial volume (P < 0.001) and resting HR (P = 0.01) but similar MAP (P = 0.7). The normal LBNP vasoconstriction (-49 ± 5%) maintaining MAP (control subjects) was attenuated in the in-SR group (-12 ± 9%; P = 0.005) and dysfunctional in the in-AF group (+11 ± 6%; P < 0.001), in which MAP decreased and HR was unchanged. Valsalva was normal throughout. Handgrip MAP response was lowest in the in-AF group (P = 0.01). Interestingly, low-level tragus stimulation and cardioversion improved LBNP vasoconstriction (-48 ± 15%; P = 0.04; and -32 ± 9%; P = 0.02, respectively). CONCLUSIONS: Cardiac afferent (volume-sensitive) reflexes are abnormal in AF patients during SR and dysfunctional during AF. This could contribute to AF progression, thus explaining "AF begets AF." (Characterisation of Autonomic function in Atrial Fibrillation [AF-AF Study]; ACTRN12619000186156).

Iodine staining outperforms phosphotungstic acid in high-resolution micro-CT scanning of post-natal mice cardiac structures.

Purpose: Micro-computed tomography (micro-CT) scan provides high-resolution three-dimensional images of mineralized tissues in small animal models. Contrast enhancement is essential to visualize non-mineralized tissues with micro-CT scan. We attempted to compare the two most common contrast agents to stain and image mouse cardiac structures. Approach: Ex-vivo micro-CT scan images of the mouse hearts were obtained following staining by potassium iodide or phosphotungstic acid (PTA). PTA-stained samples were imaged after various durations following staining (14 days, 25 days, 187 days, and 780 days), whereas iodine-stained samples were imaged after 72 hours. We compared median staining intensity between PTA and iodine at 0.1-mm intervals from the edge using the Mann Whitney test with correction for multiple comparisons. Results: Sixty post-natal mice hearts were stained with either PTA or iodine and imaged using micro-CT scan. Iodine proved to be faster and more uniform in complete enhancement of cardiac tissue in as short as 72 h, whereas PTA required a significantly longer time period to penetrate mouse cardiac structure ( > 150 days ). Median staining intensity with iodine was strongly higher than that with PTA from 0.1- to 1.5-mm distance from the epicardial edge (2-tailed P value < 0.01 or lower throughout). Conclusions: Iodine-stained soft tissue imaging by micro-CT scan provides a non-destructive, efficient, and accurate visualization tool for anatomical analysis of animal heart models of human cardiovascular conditions. Iodine is more efficient compared to PTA to achieve complete murine myocardial staining in a significantly shorter time period.

Multilevel modeling of geographic variation in general practice consultations.

OBJECTIVE: To test relatively simple and complex models for examining model fit, higher-level variation in, and correlates of, GP consultations, where known nonhierarchical data structures are present. SETTING: New South Wales (NSW), Australia. DESIGN: Association between socioeconomic circumstances and geographic remoteness with GP consultation frequencies per participant was assessed using single-level, hierarchical, and multiple membership cross-classified (MMCC) models. Models were adjusted for age, gender, and a range of socioeconomic and demographic confounds. DATA COLLECTION/EXTRACTION METHODS: A total of 261,930 participants in the Sax Institute's 45 and Up Study were linked to all GP consultation records (Medicare Benefits Schedule; Department of Human Services) within 12 months of baseline (2006-2009). PRINCIPAL FINDINGS: Deviance information criterion values indicated the MMCC negative binomial regression was the best fitting model, relative to an MMCC Poisson equivalent and simpler hierarchical and single-level models. Between-area variances were relatively consistent across models, even when between GP variation was estimated. Lower rates of GP consultation outside of major cities were only observed once between-GP variation was assessed simultaneously with between-area variation in the MMCC models. CONCLUSIONS: Application of the MMCC model is necessary for estimation of variances and effect sizes in sources of big data on primary care in which complex nonhierarchical clustering by geographical area and GP is present.

Green space and cardiovascular health in people with type 2 diabetes.

Associations between green space type and 9-year risk of incident cardiovascular disease (CVD) hospitalisations and deaths were analysed in 4166 people with type 2 diabetes in the Sax Institute's 45 and Up Study. Incidence of all-cause mortality, cardiovascular mortality, fatal or non-fatal CVD events and acute myocardial infarctions (AMI) were 14.67%, 7.23%, 47.36%, and 4.51%, respectively. After full adjustment, more tree canopy was associated with lower CVD mortality, lower fatal or non-fatal CVD events, and lower AMI risk. More open grass was associated with lower all-cause mortality, lower CVD mortality and lower fatal or non-fatal CVD events, but higher AMI risk.

Systemic vascular function, measured with forearm flow mediated dilatation, in acute and stable cerebrovascular disease: a case-control study.

BACKGROUND: Acute ischaemic stroke is associated with alteration in systemic markers of vascular function. We measured forearm vascular function (using forearm flow mediated dilatation) to clarify whether recent acute ischaemic stroke/TIA is associated with impaired systemic vascular function. METHODS: Prospective case control study enrolling 17 patients with recent acute ischaemic stroke/TIA and 17 sex matched controls with stroke more than two years previously. Forearm vascular function was measured using flow medicated dilatation (FMD). RESULTS: Flow mediated dilatation was 6.0 ± 1.1% in acute stroke/TIA patients and 4.7 ± 1.0% among control subjects (p = 0.18). The mean paired difference in FMD between subjects with recent acute stroke and controls was 1.25% (95% CI -0.65, 3.14; p = 0.18). Endothelium independent dilatation was measured in six pairs of participants and was similar in acute stroke/TIA patients (22.6 ± 4.3%) and control subjects (19.1 ± 2.6%; p = 0.43). CONCLUSIONS: Despite the small size of this study, these data indicate that recent acute stroke is not necessarily associated with a clinically important reduction in FMD.

Micro-CT scan with virtual dissection of left ventricle is a non-destructive, reproducible alternative to dissection and weighing for left ventricular size.

Micro-CT scan images enhanced by iodine staining provide high-resolution visualisation of soft tissues in laboratory mice. We have compared Micro-CT scan-derived left ventricular (LV) mass with dissection and weighing. Ex-vivo micro-CT scan images of the mouse hearts were obtained following staining by iodine. The LV was segmented and its volume was assessed using a semi-automated method by Drishti software. The left ventricle was then dissected in the laboratory and its actual weight was measured and compared against the estimated results. LV mass was calculated multiplying its estimated volume and myocardial specific gravity. Thirty-five iodine-stained post-natal mouse hearts were studied. Mice were of either sex and 68 to 352 days old (median age 202 days with interquartile range 103 to 245 days) at the time of sacrifice. Samples were from 20 genetically diverse strains. Median mouse body weight was 29 g with interquartile range 24 to 34 g. Left Ventricular weights ranged from 40.0 to 116.7 mg. The segmented LV mass estimated from micro-CT scan and directly measured dissected LV mass were strongly correlated (R2 = 0. 97). Segmented LV mass derived from Micro-CT images was very similar to the physically dissected LV mass (mean difference = 0.09 mg; 95% confidence interval - 3.29 mg to 3.1 mg). Micro-CT scanning provides a non-destructive, efficient and accurate visualisation tool for anatomical analysis of animal heart models of human cardiovascular conditions. Iodine-stained soft tissue imaging empowers researchers to perform qualitative and quantitative assessment of the cardiac structures with preservation of the samples for future histological analysis.

Atrial Fibrillation Is Associated With Syncope and Falls in Older Adults: A Systematic Review and Meta-analysis.

OBJECTIVE: To examine the potential association of atrial fibrillation (AF) to syncope and falls, we undertook a systematic review and meta-analysis given the increasing prevalence of AF in older adults as well as emerging data that it is a risk factor for dementia. PATIENTS AND METHODS: CENTRAL, PubMed, and EMBASE databases were searched from inception to January 31, 2019, to retrieve relevant studies. Search terms consisted of MeSH, tree headings, and keywords relating patients with "AF," "falls," "syncope," and "postural hypotension." When possible; results were pooled using a random-effects model. RESULTS: A total of 10 studies were included, with 7 studies (36,444 patients; mean ± SD age, 72±10 years) reporting an association between AF and falls and 3 studies (6769 patients; mean ± SD age, 65±3 years) reporting an association between AF and syncope. Pooled analyses demonstrate that AF is independently associated with falls (odds ratio, 1.19; 95% CI, 1.07-1.33; P=.001) and syncope (odds ratio, 1.88; 95% CI, 1.20-2.94; P=.006). There was overall moderate bias and low-moderate heterogeneity (I2=37%; P=.11) for falls and moderate bias with low statistical heterogeneity (I2=0%; P=.44) for syncope. Persistent AF, but not paroxysmal AF, was associated with orthostatic intolerance in 1 study (4408 patients; mean ± SD age, 66±6 years). CONCLUSION: AF is independently associated with syncope and falls in older adults. Further studies are needed to delineate mechanistic links and to guide management to improve outcomes in these patients. TRIAL REGISTRATION: PROSPERO: trial identifier: CRD4201810721.