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).

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.

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.

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.

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.

Neutralizing the pathological effects of extracellular histones with small polyanions.

Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.

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.

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.

Clinical evidence of autonomic dysfunction due to atrial fibrillation: implications for rhythm control strategy.

PURPOSE: The role of the autonomic nervous system in the genesis of atrial fibrillation (AF) has been well studied; however, the converse remains poorly understood. Pulmonary veins (PV) contain receptors important in cardiac reflexes. Here, we evaluated reflex responses in patients with paroxysmal AF (PAF) to lower body negative pressure (LBNP). METHODS: Thirty-four PAF patients (including 14 PAF patients post successful PV Isolation; PVI) were compared to 14 age and sex-matched controls. Mean arterial pressure (MAP), heart rate (HR), systemic vascular resistance index (SVRI), cardiac index (CI), and stroke volume index (SVI) were measured continuously during - 0, - 20, and - 40 mmHg LBNP. LBNP reduces venous return, deactivating atrial receptors, thereby eliciting a reflex increase in SVRI to maintain MAP. RESULTS: AF patients have higher BMI than the controls (p = 0.02). In control subjects, LBNP did not alter MAP as SVRI increased. In PAF patients, LBNP resulted in a reduction in MAP (- 4.8%) with attenuated SVRI response (+ 4.2%) compared to controls (p < 0.05). However, in the post-PVI group, SVRI increase was similar to controls (p = 0.12) although that was insufficient to maintain MAP. In all patients, both reduction in SVI and CI and increase in HR were similar in response to LBNP. CONCLUSIONS: This study provides novel clinical evidence of autonomic dysfunction in PAF patients. Successful PVI results in partial recovery of the cardiac reflex. Therefore, not only does autonomic disturbance predispose to AF but it is also a consequence of AF; potentially contributing to disease progression. This could help explain the dictum "AF begets AF."

A pilot study examining the effects of low-volume high-intensity interval training and continuous low to moderate intensity training on quality of life, functional capacity and cardiovascular risk factors in cancer survivors.

PURPOSE: The aim of this study was to evaluate the effects of low-volume high-intensity interval training and continuous low to moderate intensity training on quality of life, functional capacity and cardiovascular disease risk factors in cancer survivors. METHODS: Cancer survivors within 24 months post-diagnosis were randomly assigned into the low-volume high-intensity interval training group (n = 8) or the continuous low to moderate intensity training group (n = 8) group for 36 sessions (12 weeks) of supervised exercise. The low-volume high-intensity interval training (LVHIIT) group performed 7 × 30 s intervals (≥85% maximal heart rate) and the continuous low to moderate intensity training (CLMIT) group performed continuous aerobic training for 20 min (≤55% maximal heart rate) on a stationary bike or treadmill. RESULTS: Significant improvements (time) were observed for 13 of the 23 dependent variables (ES 0.05-0.61, p ≤ 0.05). An interaction effect was observed for six minute walk test (18.53% [32.43-4.63] ES 0.50, p ≤ 0.01) with the LVHIIT group demonstrating greater improvements. CONCLUSION: These preliminary findings suggest that both interventions can induce improvements in quality of life, functional capacity and selected cardiovascular disease risk factors. The LVHIIT program was well tolerated by the participants and our results suggest that LVHIIT is the preferred modality to improve fitness (6MWT); it remains to be seen which intervention elicits the most clinically relevant outcomes for patients. A larger sample size with a control group is required to confirm the significance of these findings.

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.

Glutathione transferase M2 variants inhibit ryanodine receptor function in adult mouse cardiomyocytes.

Release of Ca(2+) from the sarcoplasmic reticulum (SR) through the cardiac ryanodine receptor (RyR2) is an essential step in cardiac excitation-contraction coupling. Excess Ca(2+) release due to overactive RyR2 can cause arrhythmia that can lead to cardiac arrest. Fragments derived from the carboxy-terminal domain of human glutathione transferase M2 (GSTM2C) specifically inhibit RyR2 activity. Our aim was to further improve this inhibition by mutagenesis and to assess the therapeutic potential of GSTM2C based peptides to treat Ca(2+) release-based arrhythmia. We generated several mutant variants of the C-terminal fragment GSTM2C H5-8 and from those mutant proteins we identified two (RM13 and SM2) that exhibited significantly greater inhibition of cardiac SR Ca(2+) release and single RyR2 channel activity. Flow cytometry analysis showed that these two mutant proteins as well as GSTM2C H5-8 are taken up by isolated adult mouse cardiomyocytes without the aid of any additional compounds, Ca(2+) imaging and isolated cell contraction measurements revealed that GSTM2C H5-8, SM2 and RM13 reduce the SR Ca(2+) release rate and the fractional shortening of adult mouse cardiomyocytes, while importantly increasing the rate of Ca(2+) removal from the sarcoplasm. These observations indicate that peptides derived from GSTM2C inhibit RyR2 at a cellular level and thus they may provide the basis for a novel therapeutic agent to treat arrhythmia and heart attack.

Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia.

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.