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.

Good at heart: Developing a tertiary perinatal cardiac service; the first eight years of experience.

BACKGROUND: Maternal cardiac disease is the most common cause of indirect maternal death, and women with pre-existing cardiac disease have complex medical, obstetric and anaesthetic requirements. Our hospital commenced a multidisciplinary perinatal cardiac service in 2009 to optimise outcomes in women with cardiac disease. AIM: To assess the maternal and perinatal outcomes of women referred to the clinic to evaluate clinical practice and inform future service provision. MATERIALS AND METHODS: This is a single-centre retrospective study of women referred to the perinatal cardiac service between 2009-2016. Data collected included: demographic details; cardiac diagnosis; pregnancy outcomes, including anaesthetic and delivery complications, and admission to intensive care unit (ICU)/high dependency unit (HDU). RESULTS: One hundred and fifty-two women were referred for care in 165 pregnancies. Congenital heart disease was the most common indication for referral (35%), followed by maternal cardiac arrhythmia (26%) and valvular disease (18%). The perinatal mortality rate was 2%, median gestational age at delivery was 38 weeks 4 days, fetal growth restriction (customised birthweight <10th centile) was 9% although 25 (17%) pregnancies resulted in preterm birth, 36% of which were spontaneous and 64% were iatrogenic. Maternal outcomes were favourable and there were no maternal deaths. However, 51% of women required a caesarean section, and 23% who achieved a live birth required ICU/HDU admission. CONCLUSION: This study confirmed that women with cardiac disease are at increased risk of preterm birth, and high acuity in the peripartum period but otherwise good maternal and perinatal outcomes. An integrated multidisciplinary perinatal cardiac service can optimise perinatal outcomes in these women.

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.

Late gadolinium enhancement identified with cardiac magnetic resonance imaging in sarcoidosis patients is associated with long-term ventricular arrhythmia and sudden cardiac death.

AIMS: Cardiac involvement with sarcoidosis is a major cause of morbidity and mortality in affected individuals. Cardiac magnetic resonance (CMR) imaging promises a new and more accurate assessment of cardiac sarcoidosis by identifying typical patterns of myocardial fibrosis. We assessed the utility of CMR in the prediction of adverse outcomes. METHODS AND RESULTS: One hundred and six CMR patients with biopsy-proven extracardiac and/or presumed cardiac sarcoidosis were enrolled. Late gadolinium enhancement (LGE) on CMR typical of sarcoidosis was used to determine the presence of cardiac involvement. Clinical endpoints and medical records were assessed and those with implantable cardioverter-defibrillators (ICDs) underwent device interrogation. Survival rates of patients with cardiac sarcoidosis were compared with those with only extracardiac disease. CMR identified 32 (30%) individuals as having cardiac sarcoidosis; the remaining 74 (70%) had only extracardiac disease. At a mean follow-up time of 36.8 ± 20.5 months, patients with cardiac sarcoidosis had a higher rate of the composite cardiac endpoint--comprising sudden cardiac death (SCD) and ventricular tachyarrhythmia--compared with those with only extracardiac disease (P < 0.001). There was a higher rate of SCD or ICD-aborted SCD in patients with cardiac sarcoidosis vs. those without (P = 0.005). In patients with cardiac sarcoidosis, the rate of SCD was lower in those with an ICD compared with those without (P < 0.02). CONCLUSIONS: Patients with evidence of cardiac sarcoidosis on CMR have higher rates of adverse cardiovascular events than those with only extracardiac disease. In patients with sarcoidosis detected on CMR, the presence of an ICD is associated with a lower rate of SCD.

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.

Is there an obesity paradox after percutaneous coronary intervention in the contemporary era? An analysis from a multicenter Australian registry.

OBJECTIVES: We sought to determine whether an obesity paradox exists in the contemporary era of percutaneous coronary intervention (PCI) and to explore potential clinical factors that might contribute. BACKGROUND: Previous studies have suggested that overweight and obese patients might have better outcomes after PCI than patients with a normal or low body mass index (BMI); however this "obesity paradox" remains poorly understood. METHODS: We evaluated 4,762 patients undergoing PCI between April 1, 2004 and September 30, 2007, enrolled in the MIG (Melbourne Intervention Group) registry. Patients were classified as underweight, normal, overweight, class I obese, and class II to III obese, BMI <20, 20 to 25, 25.1 to 30, 30.1 to 35, and >35 kg/m(2), respectively. We compared in-hospital, 30-day, and 12-month outcomes. RESULTS: As BMI increased from <20 to >35 kg/m(2), there was a statistically significant, linear reduction in 12-month major adverse cardiac events (MACE) (21.4% to 11.9%, p = 0.008) and mortality (7.6% to 2.0%, p < 0.001). Obesity was, with multivariate analysis, an independent predictor of reduced 12-month MACE and showed a trend for reduced 12-month mortality. At 12 months, obese patients had higher use of aspirin, clopidogrel, beta-blockers, renin-angiotensin system blockers and statins. CONCLUSIONS: Compared with normal-weight individuals, overweight and obese patients had lower in-hospital and 12-month MACE and mortality rates after PCI. Moreover, obese patients had a higher rate of guideline-based medication use at 12 months, which might in part explain the obesity paradox seen after PCI.