18F-Sodium Fluoride Positron Emission Tomography Activity Predicts the Development of New Coronary Artery Calcifications.

OBJECTIVE: The coronary calcium score (CCS) predicts cardiovascular disease risk in individuals with diabetes, and rate of progression of CCS is an additional and incremental marker of risk. 18F-sodium fluoride positron emission tomography (18F-NaF PET) detects early and active calcifications within the vasculature. We aimed to ascertain the relationship between 18F-NaF PET activity and CCS progression in patients with diabetes. Approach and Results: We identified individuals between 50 and 80 years with diabetes and no history of clinical coronary artery disease. Those with a CCS ≥10 were invited to undergo 18F-NaF PET scanning and then repeat CCS >2 years later. 18F-NaF PET and CCS analysis were performed on a per-coronary and a per-patient level. We compared the proportion of CCS progressors in 18F-NaF PET-positive versus 18F-NaF PET-negative coronary arteries. Forty-one participants with 163 coronary arteries underwent follow-up CCS 2.8±0.5 years later. 18F-NaF PET-positive coronary arteries (n=52) were more likely to be CCS progressors, compared with negative coronary arteries (n=111; 86.5% versus 52.3%, P<0.001). Adjusting for baseline CCS, 18F-NaF PET-positive disease was an independent predictor of subsequent CCS progression (odds ratio, 2.92 [95% CI, 1.32-6.45], P=0.008). All subjects (100%, 15/15) with ≥2 18F-NaF-positive coronary arteries progressed in CCS. CONCLUSIONS: In subjects with diabetes, 18F-NaF PET positivity at baseline, independently predicted the progression of calcifications within the coronary arteries 2.8 years later. These findings suggest 18F-NaF PET may be a promising technique for earlier identification of patients at higher risk of cardiovascular events.

Effects of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients.

BACKGROUND: Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodeling. The ability to reverse this maladaptive remodeling by ligation of this AVF is unknown. We conducted the first randomized controlled trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients. METHODS: In this randomized controlled trial, kidney transplant recipients (>12 months after transplantation with stable graft function) were randomized to AVF ligation or no intervention. All participants underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, cardiac output/index, brachial flows (ipsilateral to AVF), and pulmonary artery velocity. RESULTS: A total of 93 patients were screened, of whom 64 met the inclusion criteria and were randomized to the AVF ligation (n=33) or control (n=31) group. Fifty-four participants completed the study: 27 in the AVF ligation group and 27 in the control group. On the second cardiac magnetic resonance scan, a mean decrease of 22.1 g (95% CI, 15.0-29.1) was observed in LV mass in the AVF ligation group compared with a small increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group ( P<0.001). Significant decreases in LV end-diastolic volumes, LV end-systolic volumes, cardiac output, cardiac index, atrial volumes, and NT-proBNP were also seen in the AVF closure group ( P<0.01). No significant changes were observed in LV ejection fraction ( P=0.93) and pulmonary artery velocity ( P=0.07). No significant complications were noted after AVF ligation. No changes in estimated glomerular filtration rate or systolic and diastolic blood pressures were observed between cardiac magnetic resonance scans. CONCLUSIONS: Elective ligation of patent AVF in adults with stable kidney transplant function resulted in clinically significant reduction of LV myocardial mass. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au . Unique Identifier: ACTRN12613001302741.

Bronchogenic stress cardiomyopathy: a case series.

Despite a growing awareness of stress (takotsubo) cardiomyopathy, the diversity in precipitants beyond emotional distress remains under-appreciated. Emerging data implicate a differential influence of precipitant type on the variable presentations of stress cardiomyopathy. We outline 5 cases of stress cardiomyopathy where the precipitant was an acute exacerbation of chronic obstructive pulmonary disease treated with high-dose bronchodilator therapy. In this setting, an atypical and insidious presentation of the stress cardiomyopathy was consistently observed that was difficult to distinguish from the acute airway exacerbation itself, with an absence of chest pain in particular. Scrutiny of published single-case reports reveals a similar atypical presentation; this supports the existence of a novel bronchogenic subgroup of stress cardiomyopathy. A key role of repeat ECG evaluation in distinguishing protracted but uncomplicated bronchospasm from bronchogenic stress cardiomyopathy is highlighted. Further data are now required to examine whether high-dose ß-agonist therapy is implicated in this association.

Protocol and rationale of the Australian multicentre registry for serial cardiac computed tomography angiography (ARISTOCRAT): a prospective observational study of the natural history of pericoronary adipose tissue attenuation and radiomics.

Background: Vascular inflammation plays a crucial role in the development of atherosclerosis and atherosclerotic plaque rupture resulting in acute coronary syndrome (ACS). Pericoronary adipose tissue (PCAT) attenuation quantified from routine coronary computed tomography angiography (CCTA) has emerged as a promising non-invasive imaging biomarker of coronary inflammation. However, a detailed understanding of the natural history of PCAT attenuation is required before it can be used as a surrogate endpoint in trials of novel therapies targeting coronary inflammation. This article aims to explore the natural history of PCAT attenuation and its association with changes in plaque characteristics. Methods: The Australian natuRal hISTOry of periCoronary adipose tissue attenuation, RAdiomics and plaque by computed Tomographic angiography (ARISTOCRAT) registry is a multi-centre observational registry enrolling patients undergoing clinically indicated serial CCTA in 9 centres across Australia. CCTA scan parameters will be matched across serial scans. Quantitative analysis of plaque and PCAT will be performed using semiautomated software. Discussion: The primary endpoint is to explore temporal changes in patient-level and lesion-level PCAT attenuation by CCTA and their associations with changes in plaque characteristics. Secondary endpoints include evaluating: (I) impact of statin therapy on PCAT attenuation and plaque characteristics; and (II) changes in PCAT attenuation and plaque characteristics in specific subgroups according to sex and risk factors. ARISTOCRAT will further our understanding of the natural history of PCAT attenuation and its association with changes in plaque characteristics. Trial Registration: This study has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621001018808).

Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men.

OBJECTIVE: Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. METHODS AND RESULTS: In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor L-NMMA, and norepinephrine. Flow-mediated vasodilatation (5.8%+/-0.4% vs 7.9%+/-0.5%; P=0.002) and CPC mobilization (CD34(+)/KDR(+) 53.2% vs 85.4%; P=0.001; CD133(+)/CD34(+)/KDR(+) 48.4% vs 73.9%; P=0.05; and CD34(+)/CD45(-) 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34(+)/KDR(+) -3.3% vs 68.4%; CD133(+)/CD34(+)/KDR(+) 0.7% vs 71.4%; and CD34(+)/CD45(-) -30.5% vs 77.8%; all P<0.001). CONCLUSIONS: In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.

Isolated Ventricular Septal Rupture in a Suicide Jumper.

Ventricular septal rupture is an extremely rare sequelae of blunt chest trauma, and is mostly diagnosed postmortem. We present a case of a large isolated traumatic ventricular septal rupture after a suicide attempt by jumping from a height of 5 stories, which was successfully treated with surgical closure. (Level of Difficulty: Intermediate.).

Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment for Post Infarct Angina in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries: A MINOCA-BAT Sub Study Rationale and Design.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients-The MINOCA BAT post infarct angina sub study. Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months. Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years. Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

Effects of renal sympathetic denervation on myocardial structure, function and perfusion: A serial CMR study.

BACKGROUND AND AIMS: Echocardiographic studies have shown improvements in cardiac indices associated with renal sympathetic denervation (RDN), however, the benefits on myocardial perfusion have never been assessed. This trial was designed to study the effects of RDN on myocardial perfusion using cardiac magnetic resonance (CMR) imaging. METHODS: A total of 14 patients with resistant hypertension were recruited for RDN and myocardial perfusion, alongside other CMR indices, was assessed at baseline and at 6 months. RESULTS: RDN showed significant reduction of mean office blood pressures from 181/100 ±â€¯19/16 mmHg to 147/85 ±â€¯19/17 mmHg, 6 months after the procedure (p < 0.0001). This was combined with significant improvement in regional aortic distensibility (p < 0.02) and associated with trends of improved myocardial perfusion reserve index (baseline = 2.2 ±â€¯1; 6 months = 2.9 ±â€¯1 units) (p = 0.08). Left ventricular end systolic volume index decreased from baseline to 6 months post procedure, 27 ±â€¯13 ml/m2vs. 22 ±â€¯10 ml/m2 (p = 0.03), but there was no significant change in left ventricular end diastolic volume index (p = 0.09). There was significant improvement in mean left ventricular ejection fraction from 68 ± 10% to 72 + 9%, 6 months post procedure (p = 0.04). T1 mapping failed to detect fibrosis in these patients at baseline and therefore no change was noted, however, extracellular volume percent improved from 46 ±â€¯4% at baseline to 41 ±â€¯8% at 6 months (p = 0.002). CONCLUSIONS: This study demonstrates that renal sympathetic denervation increased myocardial perfusion by 32% as assessed by CMR, and, this was associated with improvements in cardiac volumes and function. Larger well controlled and randomized studies are required to assess the clinical significance of these findings.

The impact of insulin resistance on endothelial function, progenitor cells and repair.

The structural and functional integrity of the vascular endothelium plays a critical role in vascular homeostasis. Insulin resistance, an important risk factor for cardiovascular disease, is thought to promote atherosclerosis through a reciprocal relationship with endothelial dysfunction. In health, cumulative damage to endothelial cells incurred by exposure to risk factors is mitigated by endogenous reparative processes. Disruption of the balance between endothelial damage and repair may mediate atherosclerotic progression. Bone marrow-derived 'endothelial progenitor cells' (EPC) have been identified as significant contributors to endogenous vascular repair. Insulin resistance is associated with a spectrum of biochemical abnormalities which have the potential to reduce the availability of EPCs and diminish their capacity for vascular repair. Many lifestyle and pharmacological interventions which improve insulin resistance also increase the numbers and functionality of EPCs. Cell-based therapies may also hold promise for the prevention and treatment of cardiovascular disease.

Renal sympathetic denervation increases renal blood volume per cardiac cycle: a serial magnetic resonance imaging study in resistant hypertension.

AIM: Preclinical studies have demonstrated improvements in renal blood flow after renal sympathetic denervation (RSDN); however, such effects are yet to be confirmed in patients with resistant hypertension. Herein, we assessed the effects of RSDN on renal artery blood flow and diameter at multiple time points post-RSDN. METHODS AND RESULTS: Patients (n=11) with systolic blood pressures ≥160 mmHg despite taking three or more antihypertensive medications at maximum tolerated dose were recruited into this single-center, prospective, non-blinded study. Magnetic resonance imaging indices included renal blood flow and renal artery diameters at baseline, 1 month and 6 months. In addition to significant decreases in blood pressures (p<0.0001), total volume of blood flow per cardiac cycle increased by 20% from 6.9±2 mL at baseline to 8.4±2 mL (p=0.003) at 1 month and to 8.0±2 mL (p=0.04) 6 months post-procedure, with no changes in the renal blood flow. There was a significant decrease in renal artery diameters from 7±2 mm at baseline to 6±1 mm (p=0.03) at 1 month post-procedure. This decrease was associated with increases in maximum velocity of blood flow from 73±20 cm/s at baseline to 78±19 cm/s at 1 month post-procedure. Notably, both parameters reverted to 7±2 mm and 72±18 cm/s, respectively, 6 months after procedure. CONCLUSION: RSDN improves renal physiology as evidenced by significant improvements in total volume of blood flow per cardiac cycle. Additionally, for the first time, we identified a transient decrease in renal artery diameters immediately after procedure potentially caused by edema and inflammation that reverted to baseline values 6 months post-procedure.

CT sizing for left atrial appendage closure is associated with favourable outcomes for procedural safety.

AIMS: We evaluated the utility of computerized tomography (CT) with respect to sizing work-up for percutaneous left atrial appendage (LAA) closure, and implications for procedural safety and outcomes. METHODS AND RESULTS: Contrast-enhanced multi-detector CT was routinely conducted to guide sizing for LAA closure in addition to transoesophageal echocardiography (TOE). Procedural safety and efficacy were prospectively assessed. Across 73 consecutive cases there were no device-related procedural complications, and no severe leaks. Systematic bias in orifice sizing by TOE vs. CT was significant on retrospective analysis (bias -3.0 mm vs. maximum diameter on CT; bias -1.1 mm vs. mean diameter on CT). Importantly, this translated to an altered device size selection in more than half of all cases, and median size predicted by CT was one interval greater than that predicted by TOE (27 mm vs. 24 mm). Of particular note, gross sizing error by TOE vs. CT was observed in at least 3.4% of cases. Degree of discrepancy between TOE and CT was correlated with LAA orifice eccentricity, orifice size, and left atrial volume. Mean orifice size by CT had the greatest utility for final Watchman device-size selection. CONCLUSIONS: In this single-centre registry of LAA closure, routine incorporation of CT was associated with excellent outcomes for procedural safety and absence of major residual leak. Mean orifice size may be preferable to maximum orifice size. A particular value of CT may be the detection and subsequent avoidance of gross sizing error by 2D TOE that occurs in a small but important proportion of cases.

The incremental impact of cardiac MRI on clinical decision-making.

OBJECTIVE: Despite a significant expansion in the use of cardiac MRI (CMR), there is inadequate evaluation of its incremental impact on clinical decision-making over and above other well-established modalities. We sought to determine the incremental utility of CMR in routine practice. METHODS: 629 consecutive CMR studies referred by 44 clinicians from 9 institutions were evaluated. Pre-defined algorithms were used to determine the incremental influence on diagnostic thinking, influence on clinical management and thus the overall clinical utility. Studies were also subdivided and evaluated according to the indication for CMR. RESULTS: CMR provided incremental information to the clinician in 85% of cases, with incremental influence on diagnostic thinking in 85% of cases and incremental impact on management in 42% of cases. The overall incremental utility of CMR exceeded 90% in 7 out of the 13 indications, whereas in settings such as the evaluation of unexplained ventricular arrhythmia or mild left ventricular systolic dysfunction, this was <50%. CONCLUSION: CMR was frequently able to inform and influence decision-making in routine clinical practice, even with analyses that accepted only incremental clinical information and excluded a redundant duplication of imaging. Significant variations in yield were noted according to the indication for CMR. These data support a wider integration of CMR services into cardiac imaging departments. ADVANCES IN KNOWLEDGE: These data are the first to objectively evaluate the incremental value of a UK CMR service in clinical decision-making. Such data are essential when seeking justification for a CMR service.

Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction.

BACKGROUND: Diabetes mellitus is associated with an increased risk of death and hospitalisation in patients with chronic heart failure. Better understanding of potential underlying mechanisms may aid the development of diabetes mellitus-specific chronic heart failure therapeutic strategies. METHODS: Prospective observational cohort study of 628 patients with chronic heart failure associated with left ventricular systolic dysfunction receiving contemporary evidence-based therapy. Indices of cardiac structure and function, along with symptoms and biochemical parameters, were compared in patients with and without diabetes mellitus at study recruitment and 1 year later. RESULTS: Patients with diabetes mellitus (24.2%) experienced higher rates of all-cause [hazard ratio, 2.3 (95% confidence interval, 1.8-3.0)] and chronic heart failure-specific mortality and hospitalisation despite comparable pharmacological and device-based therapies. At study recruitment, patients with diabetes mellitus were more symptomatic, required greater diuretic doses and more frequently had radiologic evidence of pulmonary oedema, despite higher left ventricular ejection fraction. They also exhibited echocardiographic evidence of increased left ventricular wall thickness and pulmonary arterial pressure. Diabetes mellitus was associated with reduced indices of heart rate variability and increased heart rate turbulence. During follow-up, patients with diabetes mellitus experienced less beneficial left ventricular remodelling and greater deterioration in renal function. CONCLUSION: Diabetes mellitus is associated with features of adverse structural and functional cardiac remodelling in patients with chronic heart failure.

Performance of 2014 NICE defibrillator implantation guidelines in heart failure risk stratification.

OBJECTIVE: Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic heart failure. METHODS: Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock. RESULTS: The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria. CONCLUSIONS: TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.

Left Atrial Appendage Eccentricity and Irregularity Are Associated With Residual Leaks After Percutaneous Closure.

OBJECTIVES: Predictors of residual leak following percutaneous LAA closure were evaluated. BACKGROUND: Left atrial appendage (LAA) closure aims to exclude this structure from the circulation, typically using a circular occluder. A noncircular orifice is frequently encountered however, and fibrous remodeling of the LAA in atrial fibrillation may restrict orifice deformation. Noncircularity may thus be implicated in the occurrence of residual leak despite an appropriately oversized device. METHODS: Pre-procedural multislice computerized tomography was used to quantify LAA orifice eccentricity and irregularity. Univariate predictors of residual leak were identified with respect to the orifice, device, and relevant clinical variables, with the nature of any correlations then further evaluated. RESULTS: Eccentricity and irregularity indexes of the orifice in 31 individuals were correlated with residual leak even where the device was appropriately oversized. An eccentricity index of 0.15 predicted a residual leak with 85% sensitivity and 59% specificity. An irregularity index of 0.05 predicted a significant residual leak ≥3 mm with 100% sensitivity and 86% specificity. Orifice size, device size, degree of device oversize, left atrial volume, and pulmonary artery pressure were not predictors of residual leak. CONCLUSIONS: Eccentricity and irregularity of the LAA orifice are implicated in residual leak after percutaneous closure even where there is appropriate device over-size. Irregularity index in particular is a novel predictor of residual leak, supporting a closer consideration of orifice morphology before closure.

Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology.

BACKGROUND: It is unclear whether diabetes mellitus (DM) is an adverse prognostic factor in chronic heart failure (CHF) of ischaemic and non-ischaemic aetiology managed with contemporary evidence-based care. METHODS: In total, 1091 outpatients with CHF with reduced ejection fraction were prospectively observed for a mean of 960 days. Total and cardiovascular mortality was quantified after accounting for potential confounders. RESULTS: In total, 25.7% of patients had DM; this group was more likely to have CHF of ischaemic aetiology and was more symptomatic. Patients with DM received comparable medical- and device-based therapies, except for greater doses of loop diuretic. DM was associated with approximately doubled crude and adjusted risk of total and cardiovascular mortality. The association of diabetes with these outcomes in patients with ischaemic and non-ischaemic cardiomyopathies was of similar magnitude. CONCLUSIONS: In spite of advances in the management of CHF, DM remains a major adverse prognostic feature, irrespective of ischaemic/non-ischaemic aetiology.