Vulnerability to environmental and climatic health provocations among women and men hospitalized with chronic heart disease: insights from the RESILIENCE TRIAL cohort.

AIMS: We aimed to recruit a representative cohort of women and men with multi-morbid chronic heart disease as part of a trial testing an innovative, nurse-co-ordinated, multi-faceted intervention to lower rehospitalization and death by addressing areas of vulnerability to external challenges to their health. METHODS AND RESULTS: The prospective, randomized open, blinded end-point RESILIENCE Trial recruited 203 hospital inpatients (mean age 75.7 ± 10.2 years) of whom 51% were women and 94% had combined coronary artery disease, heart failure, and/or atrial fibrillation. Levels of concurrent multi-morbidity were high (mean Charlson Index of Comorbidity Score 6.5 ± 2.7), and 8.9% had at least mild frailty according to the Rockwood Clinical Frailty Scale. Including the index admission, 19-20% of women and men had a pre-existing pattern of seasonally linked hospitalization (seasonality). Detailed phenotyping revealed that 48% of women and 40% of men had ≥3 physiological factors, and 15% of women and 16% of men had ≥3 behavioural factors likely to increase their vulnerability to external provocations to their health. Overall, 61-62% of women and men had ≥4 combined factors indicative of such vulnerability. Additional factors such as reliance on the public health system (63 vs. 49%), lower education (30 vs. 14%), and living alone (48 vs. 29%) were more prevalent in women. CONCLUSION: We successfully recruited women and men with multi-morbid chronic heart disease and bio-behavioural indicators of vulnerability to external provocations to their health. Once completed, the RESILIENCE TRIAL will provide important insights on the impact of addressing such vulnerability (promoting resilience) on subsequent health outcomes. REGISTRATION: ClinicalTrials.org: NCT04614428.

Incidence and risk factors for stroke following percutaneous coronary intervention.

BACKGROUND: Stroke rates and risk factors may change as percutaneous coronary intervention practice evolves and no data are available comparing stroke incidence after percutaneous coronary intervention to the general population. AIMS: This study aimed to identify the incidence and risk factors for inpatient and subsequent stroke following percutaneous coronary intervention with comparison to age-matched controls. METHODS: Data were prospectively collected from 22,618 patients undergoing percutaneous coronary intervention in the Melbourne Interventional Group registry (2005-2015). The cohort was compared to the North-East Melbourne Stroke Incidence Study population-based cohort (1997-1999) and predefined variables assessed for association with inpatient or outpatient stroke. RESULTS: Inpatient stroke occurred in 0.33% (65.3% ischemic, 28.0% haemorrhagic, and 6.7% cause unknown), while outpatient stroke occurred in 0.55%. Inpatient and outpatient stroke were associated with higher rates of in-hospital major adverse cardiovascular outcomes (p < 0.0001) and mortality (p < 0.0001), as well as 12-month mortality (p < 0.0001). Factors independently associated with inpatient stroke were renal impairment, ST-elevation myocardial infarction, previous stroke, left ventricular ejection fraction 30-45%, and female sex, while those associated with outpatient stroke were previous stroke, chronic lung disease, previous myocardial infarction, rheumatoid arthritis, female sex, and older age. Compared to the age-standardized population-based cohort, stroke rates in the 12 months following discharge were higher for percutaneous coronary intervention patients <65 years old, but lower for percutaneous coronary intervention patients ≥65 years old. CONCLUSIONS: Risk of inpatient stroke following percutaneous coronary intervention appears to be largely associated with clinical status at presentation, while outpatient stroke relates more to age and chronic disease. Compared to the general population, outpatient stroke rates following percutaneous coronary intervention are higher for younger, but not older, patients.

The Receptor for Advanced Glycation End Products (RAGE) Is Associated with Persistent Atrial Fibrillation.

OBJECTIVE: Upregulation of the receptor for advanced glycation end products (RAGE) has been proposed as a pathophysiological mechanism underlying the development of atrial fibrillation (AF). We sought to investigate if soluble RAGE levels are associated with AF in Caucasian patients. METHODS: Patients (n = 587) were prospectively recruited and serum levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) measured. The patients included 527 with sinus rhythm, 32 with persistent AF (duration >7 days, n = 32) and 28 with paroxysmal AF (duration <7 days, n = 28). RESULTS: Patients with AF were older and had a greater prevalence of heart failure than patients in sinus rhythm. Circulating RAGE levels were higher in patients with persistent AF [median sRAGE 1190 (724-2041) pg/ml and median esRAGE 452 (288-932) pg/ml] compared with paroxysmal AF [sRAGE 799 (583-1033) pg/ml and esRAGE 279 (201-433) pg/ml, p ≤ 0.01] or sinus rhythm [sRAGE 782 (576-1039) pg/ml and esRAGE 289 (192-412) pg/ml, p < 0.001]. In multivariable logistic regression analysis, independent predictors of persistent AF were age, heart failure, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% confidence interval (CI) 1.0-1.1, p = 0.001] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.1-1.4, p < 0.001]. Heart failure and age were the only independent predictors of paroxysmal AF. In AF patients, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% CI 1.1-1.2, p = 0.007] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.0-1.5, p = 0.017] independently predicted persistent compared with paroxysmal AF. CONCLUSIONS: Soluble RAGE is elevated in Caucasian patients with AF, and both sRAGE and esRAGE predict the presence of persistent AF.

From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension.

Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An "alternate" arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.

Impact of renal function in patients with multi-vessel coronary disease on long-term mortality following coronary artery bypass grafting compared with percutaneous coronary intervention.

BACKGROUND: Comorbidities, such as diabetes, affect revascularization strategy for coronary disease. We sought to determine if the degree of renal impairment affected long-term mortality after percutaneous coronary intervention (PCI) compared to coronary artery bypass grafting (CABG) in patients with multi-vessel coronary disease (MVD). METHODS AND RESULTS: 8970 patients with MVD undergoing revascularization between 2004 and 2008, in two multi-center parallel PCI and CABG Australian registries were assigned to three groups based on their estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 (n=1678:839), 30-59 mL/min/1.73 m2 (n=452:226) and <30 mL/min/1.73 m2 (n=74:37). We used 2:1 propensity matching to compare 3306 patients undergoing primary CABG versus PCI. Shock, myocardial infarction (MI)<24 h, previous CABG, valve surgery or PCI were exclusions. Long-term mortality (mean 3.1 years) was compared with Cox-proportional hazard-adjusted modeling. Observed long-term mortality rates (CABG vs. PCI) were 4.5% vs. 4.3% p=0.84, 12.8% vs. 17.3% p=0.12, and 23.0% vs. 40.5% p=0.05 in the three strata, respectively. In patients with eGFR≥60 mL/min/1.73 m2, long-term mortality between PCI and CABG (HR 0.99, 95% CI 0.65-1.49, p=0.95) was similar. However, amongst patients with eGFR 30-59 mL/min/1.73 m2, there was a significant mortality hazard with PCI (HR 2.00, 95% CI 1.32-3.04, p=0.001). In patients with eGFR<30 mL/min/1.73 m2, there was a trend for hazard with PCI (HR 1.66, 95% CI 0.80-3.46, p=0.17). CONCLUSION: Long-term mortality in MVD patients with preserved renal function was very low and similar between PCI and CABG. However there was a long-term mortality hazard associated with PCI amongst patients with moderate renal impairment.