Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability.

OBJECTIVE: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools. METHODS: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (ß) from linear regression, adjusted for BMI and sex, were calculated. RESULTS: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (ß = 0.041, p = 0.002), EFS (ß = 0.696, p = 0.026), and SRS-22r (ß = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (ß = 0.029, p = 0.028) and SRS-22r (ß = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (ß = 0.029, p = 0.037) and SRS-22r (ß = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031). CONCLUSIONS: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.

Characterization of persistent atrial fibrillation with non-contact charge density mapping and relationship to voltage.

BACKGROUND: Despite studies using localized high density contact mapping and lower resolution panoramic approaches, the mechanisms that sustain human persistent atrial fibrillation (AF) remain unresolved. Voltage mapping is commonly employed as a surrogate of atrial substrate to guide ablation procedures. OBJECTIVE: To study the distribution and temporal stability of activation during persistent AF using a global non-contact charge density approach and compare the findings with bipolar contact mapping. METHODS: Patients undergoing either redo or de novo ablation for persistent AF underwent charge density and voltage mapping to guide the ablation procedure. Offline analysis was performed to measure the temporal stability of three specific charge density activation (CDA) patterns, and the degree of spatial overlap between CDA patterns and low voltage regions. RESULTS: CDA was observed in patient-specific locations that partially overlapped, comprising local rotational activity (18% of LA), local irregular activity (41% of LA), and focal activity (39% of LA). Local irregular activity had the highest temporal stability. LA voltage was similar in regions with and without CDA. CONCLUSION: In persistent AF, CDA patterns appear unrelated to low voltage areas but occur in varying locations with high temporal stability.

Prescribing dronedarone for paroxysmal atrial fibrillation: how is it done across the UK and is it safe?

Dronedarone, a useful treatment for paroxysmal atrial fibrillation, is often only prescribed in secondary care. To support a protocol shared between primary and secondary care, dronedarone use was audited in our centre and prescribing practices across UK secondary care centres were reviewed. From 2010 to 2015, a total of 181 patients were started on dronedarone. There were no deaths or serious adverse events. Median cessation time due to adverse effects was 52 days and 88% stopped dronedarone within 6 months. Of 17 local prescribing protocols across the UK, 12 involved shared care and 5 purely secondary care follow-up. In our review, dronedarone was safe and well tolerated. The use of shared care protocols is well established in other UK centres. The development of a local shared care protocol between primary and secondary care is feasible with existing systems in place to support its introduction.

A minimal or maximal ablation strategy to achieve pulmonary vein isolation for paroxysmal atrial fibrillation: a prospective multi-centre randomized controlled trial (the Minimax study).

AIMS: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation of atrial fibrillation (AF). The intervenous ridge (IVR) may be incorporated into ablation strategies to achieve PVI; however, randomized trials are lacking. We performed a randomized multi-centre international study to compare the outcomes of (i) circumferential antral PVI (CPVI) alone (minimal) vs. (ii) CPVI with IVR ablation to achieve individual PVI (maximal). METHODS AND RESULTS: Two hundred and thirty-four patients with paroxysmal AF underwent CPVI and were randomized to a minimal or maximal ablation strategy. The primary outcome of recurrent atrial arrhythmia was assessed with 7-day Holter monitoring at 6 and 12 months. PVI was achieved in all patients. Radiofrequency ablation time was longer in the maximal group (46.6 ± 14.6 vs. 41.5 ± 13.1 min; P < 0.01), with no significant differences in procedural or fluoroscopy times. At mean follow-up of 17 ± 8 months, there was no difference in freedom from AF after a single procedure between a minimal (70%) and maximal ablation strategy (62%; P = 0.25). In the minimal group, ablation was required on the IVR to achieve electrical isolation in 44%, and was associated with a significant reduction in freedom from AF (57%) compared with the minimal group without IVR ablation (80%; P < 0.01). CONCLUSION: There was no statistically significant difference in freedom from AF between a minimal and maximal ablation strategy. Despite attempts to achieve PVI with antral ablation, IVR ablation is commonly required. Patients in whom antral isolation can be achieved without IVR ablation have higher long-term freedom from AF (the Minimax study; ACTRN12610000863033).

P wave morphology in guiding the ablation strategy of focal atrial tachycardias and atrial flutter.

Focal atrial tachycardias arise preferentially from specific locations within the atria. Careful analysis of the P wave can provide useful information about the chamber and likely site of origin within that chamber. Macro-reentrant atrial flutter also tends to occur over a limited number of potential circuits. In this case, the ECG usually gives a guide to the chamber of origin, but unless it shows a specific morphology it is less useful in delineating the circuit involved. Nonetheless, prior knowledge of the likely chamber of origin helps to plan the ablation strategy.

Atrial fibrillation in heart failure in the older population.

Atrial fibrillation (AF) is an important and often-underrecognized cause of cardiovascular morbidity and mortality. It is an arrhythmia that is commonly seen in the older patient; the median age of patients with AF in early studies was 75 years. Heart failure (HF) is also more frequently seen in the older patient with an approximate doubling of HF prevalence with each decade of life. There is clear interaction between AF and HF, with evidence that HF can lead to AF and AF exacerbates HF. This review focuses on the specific aspect of AF management in elderly patients with HF.

Effects of long-term ω-3 polyunsaturated fatty acid supplementation on paroxysmal atrial tachyarrhythmia burden in patients with implanted pacemakers: results from a prospective randomised study.

BACKGROUND: Sino-atrial node disease and aging increase AF risk. We investigated if long-term fish oil supplementation reduces paroxysmal atrial tachycardia/fibrillation (AT/AF) burden in patients aged ≥60 years with sinoatrial node disease and dual chamber pacemakers. METHODS: Following a run-in period of 6 months (p1) where AT/AF burden was logged,78 patients were randomised to control or fish oil group (total omega-3 6 g/d) and AT/AF burden evaluated after 6 months (p2; 39 controls, 39 fish oil) and 12 months (p3; 39 controls; 18 fish oil). A subset of 21 fish oil patients crossed over to controls in the final 6 months (crossover group). RESULTS: Median AT/AF burden increased significantly in controls (1.5%, 3.2%, 4.3%, P<.001) but not in fish oil patients at 6 months (1.4% to 2%, P=.46) or those continuing for 12 months (1.5%, 0.98%, 1%, P=.16). Time to first episode of AT/AF >1 min was not significantly different between the groups (P=.9). There was a rebound increase in AT/AF burden in p3 in cross over patients (2.2% to 5.8%, P=.01) reaching a level similar to controls (crossover vs. controls, 5.8% vs. 4.3%, P=.63) and higher than those who continued fish oil for 12 months (crossover vs. continued intake 5.8% vs. 1.2%, P=.02). Fish oil patients had shorter duration episodes of AT/AF with no difference in frequency compared to controls. CONCLUSION: Long-term fish oil supplementation did not suppress AT/AF burden but may have attenuated its temporal progression related to aging and sinus node disease.

Effects of high dose intravenous fish oil on human atrial electrophysiology: implications for possible anti- and pro-arrhythmic mechanisms in atrial fibrillation.

BACKGROUND: Intravenous omega-3 polyunsaturated fatty acids (ω-3 PUFAs) may prevent atrial fibrillation (AF) inducibility and perpetuation in animal models. We examined the effect of high dose IV ω-3 PUFAs on human atrial electrophysiology. METHODS AND RESULTS: We randomised 88 patients with no structural heart disease to receive saline (control group) or high dose IV ω-3 PUFA infusion prior to detailed atrial electrophysiologic evaluation. Biologically active components, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured in total lipids, free fatty acid and phospholipid (membrane incorporated) fraction pre and post infusion. Compared to pre-infusion values, EPA and DHA increased significantly in the total lipids and free fatty acid but were unchanged in the phospholipid fraction. IV ω-3 did not alter atrial refractory periods, however it slowed right, left and global atrial conduction (P<.05). Inducible AF was significantly less likely in ω-3 patients compared to controls (AF ≥ 5 min, 20% vs. 58%, P = .02) and was non-sustained (mean AF duration: 14s vs. 39 s, P<.001), however inducible and sustained atrial flutter was more common (≥ 5 min: 28% vs. 0%, P = .01). Organisation of AF into flutter was observed in a greater proportion of inductions in the ω-3 group (8.5% vs. 0.6%, P<.001). CONCLUSIONS: IV ω-3 PUFAs (as free fatty acids) cause acute atrial conduction slowing, suppress AF inducibility, organise AF into atrial flutter and enhance atrial flutter inducibility. These findings provide a novel insight into potential anti and pro-arrhythmic mechanisms of fish oils in human AF.

Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case-control, 3-T carotid artery MR imaging study.

OBJECTIVES: The goal of this study was to determine whether a 3-T magnetic resonance imaging (MRI) protocol combining carotid atherosclerotic plaque and brain imaging can identify features of high-risk acutely symptomatic plaque that correlate with brain injury. BACKGROUND: It has previously been demonstrated that, in asymptomatic patients, MRI can identify features of carotid plaque that are associated with stroke, such as the presence of a large lipid core. We hypothesized that the early phase (<7 days) after a cerebrovascular event, when risk of recurrence is highest, may be associated with particular plaque characteristics that associate with cerebral injury. METHODS: Eighty-one patients (41 presenting acutely with transient ischemic attack [TIA] or minor stroke and 40 asymptomatic controls) underwent multicontrast carotid artery MRI on 2 separate occasions, each accompanied by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging of the brain. RESULTS: Complex (American Heart Association [AHA] type VI) plaques were seen in 22 of 41 patients (54%) in the symptomatic group versus 8 of 40 (20%) in the asymptomatic group (p < 0.05). They were caused by intraplaque hemorrhage (34% vs. 18%; p = 0.08), surface rupture (24% vs. 5%; p = 0.03), or luminal thrombus (7% vs. 0%; p = 0.24). Noticeably, 17 of 30 (57%) cases of AHA type VI plaque were in vessels with <70% stenosis. At follow-up scanning (>6 weeks later), only 2 cases of symptomatic AHA type VI plaque showed evidence of full healing. The presence of fibrous cap rupture was associated with higher DWI brain injury at presentation and higher total cerebral FLAIR signal at follow-up (p < 0.05). CONCLUSIONS: Early carotid wall MRI in patients experiencing minor stroke or TIA showed a higher proportion of "complex" plaques compared with asymptomatic controls; a majority were in arteries of <70% stenosis. Fibrous cap rupture was associated with increases in DWI and FLAIR lesions in the brain. Combined carotid plaque and brain MRI may aid risk stratification and treatment selection in acute stroke and TIA.

Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. METHODS AND RESULTS: Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. CONCLUSIONS: Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states.

Multimodal cardiovascular magnetic resonance quantifies regional variation in vascular structure and function in patients with coronary artery disease: relationships with coronary disease severity.

BACKGROUND: Cardiovascular magnetic resonance (CMR) of the vessel wall is highly reproducible and can evaluate both changes in plaque burden and composition. It can also measure aortic compliance and endothelial function in a single integrated examination. Previous studies have focused on patients with pre-identified carotid atheroma. We define these vascular parameters in patients presenting with coronary artery disease and test their relations to its extent and severity. METHODS AND RESULTS: 100 patients with CAD [single-vessel (16%); two-vessel (39%); and three-vessel (42%) non-obstructed coronary arteries (3%)] were studied. CAD severity and extent was expressed as modified Gensini score (mean modified score 12.38 ± 5.3). A majority of carotid plaque was located in the carotid bulb (CB). Atherosclerosis in this most diseased segment correlated modestly with the severity and extent of CAD, as expressed by the modified Gensini score (R = 0.251, P < 0.05). Using the AHA plaque classification, atheroma class also associated with CAD severity (rho = 0.26, P < 0.05). The distal descending aorta contained the greatest plaque, which correlated with the degree of CAD (R = 0.222; P < 0.05), but with no correlation with the proximal descending aorta, which was relatively spared (R = 0.106; P = n. s.). Aortic distensibility varied along its length with the ascending aorta the least distensible segment. Brachial artery FMD was inversely correlated with modified Gensini score (R = -0.278; P < 0.05). In multivariate analysis, distal descending aorta atheroma burden, distensibility of the ascending aorta, carotid atheroma class and FMD were independent predictors of modified Gensini score. CONCLUSIONS: Multimodal vascular CMR shows regional abnormalities of vascular structure and function that correlate modestly with the degree and extent of CAD.

An unusual atrial tachycardia in a patient with Friedreich ataxia.

We present the unusual association of an atrial tachycardia with Friedreich ataxia. The arrhythmia was initially suspected to be focal in origin; however, use of a three-dimensional mapping system demonstrated that the tachycardia was macro-reentrant. This was subsequently treated successfully by linear ablation.

Atherosclerosis regression and high-density lipoproteins.

Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics.

Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study.

OBJECTIVES: Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function. BACKGROUND: NA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment. METHODS: We performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year. RESULTS: NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: -1.64 mm(2) [95% confidence interval: -3.12 to -0.16]; p = 0.03). Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for NA versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = -0.5, p = 0.02 for NA). CONCLUSIONS: In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531).

Reproducibility and accuracy of automated measurement for dynamic arterial lumen area by cardiovascular magnetic resonance.

Bright blood cine images acquired using magnetic resonance imaging contain simple contrast that is tractable to automated analysis, which can be used to derive a measure of arterial compliance that is known to correlate with disease severity. The purpose of this work was to evaluate whether automated methods could be used reliably on a clinically relevant population, and to assess the precision of these measurements so that it could be compared with expert manual assessment. In this paper we apply an algorithm similar to that used by Krug et al., and the exact processing steps are described in detail to allowing easy reproduction of our methods. Phantoms of different sizes have been assessed and the MRI measurements are found to correlate well (r = 0.9998) with physical measurement. Reproducibility assessment was performed on 33 CAD subjects in three anatomical locations along the aorta. Six normal volunteers and ten patients with more severe aortic plaques were investigated to assess reproducibility and sensitivity to pathological changes, respectively. The performance was also assessed on carotid vessels in 40 patients with known arterial plaques. In the human aorta the method is found to be robust (failing in only 7% of cases, all due to clear errors with image acquisition), and to be quantifiably consistent with expert clinical measurement, but showing smaller errors than that approach [<1.21% (5.62 mm(2)) manual vs. <0.58% (2.71 mm(2)) automated, for the aortic area] and with reduced bias, and operated correctly in advanced disease. We have proved over a large number of subjects the superiority of this automated method for evaluating dynamic area changes over the Gold-standard manual approach.

Nicotinic acid and the prevention of coronary artery disease.

PURPOSE OF REVIEW: Nicotinic acid is the most potent treatment clinically available for lowering LDL cholesterol and VLDL cholesterol and raising HDL cholesterol. The strong inverse relationship between coronary heart disease risk and HDL cholesterol at all levels of LDL cholesterol has, therefore, given renewed emphasis on the therapeutic potential of niacin. The purpose of this review is to evaluate advances in the elucidation of mechanisms by which nicotinic acid affects the lipoprotein profile and, more recently, emerging evidence of nonlipid-mediated anti-inflammatory effects. RECENT FINDINGS: Niacin treatment reduces cardiovascular events and the progression of atherosclerosis. Identification of G-protein-coupled receptor 109A as the receptor for nicotinic acid has provided insights into how treatment with this compound leads to a favourable alteration in HDL cholesterol. In addition, evidence of nonlipid-mediated anti-inflammatory effects of nicotinic acid such as direct enhancement of adiponectin secretion demonstrates a novel atheroprotective role. SUMMARY: Whether nicotinic acid use becomes routine in the treatment of atherosclerosis is likely to be determined by the results of two ongoing clinical outcome trials. In addition, further research is required to explore the 'pleiotropic' effects of nicotinic acid and will ultimately provide a platform for the development of newer molecules that are potentially beneficial but without the well known side-effects.

Atherosclerosis regression.

Atherosclerosis follows the deposition, retention, and oxidative modification of lipoproteins, especially low-density lipoprotein (LDL) in the walls of large arteries. Uptake of oxidized LDL results in the formation of macrophage foam cells. Proliferation of vascular smooth muscle cells and secretion of extracellular matrix contribute "fibrous" components of the plaque, whereas ongoing accumulation of lipid and inflammatory cell debris forms the necrotic lipid core of the mature atherosclerotic plaque. Both the size and composition of plaques determine the clinical course. In particular, a large lipid core, thin fibrous cap, dense inflammatory cell infiltrate, and proteolytic enzyme activity are associated with adverse risk. Atherosclerosis has often been considered a relentlessly progressive disease. However, new imaging techniques that can quantify plaque burden and provide insights into some of the specific plaque components have allowed regression to be mapped for the first time. In this article, drugs targeting atherosclerosis that have potential or proven benefit in atherosclerosis regression are discussed.