RNA-based therapy in the management of lipid disorders: a review.

This review focuses on antisense oligonucleotides and small interfering ribonucleic acid therapies approved or under development for the management of lipid disorders. Recent advances in RNA-based therapeutics allow tissue-specific targeting improving safety. Multiple potential target proteins have been identified and RNA-based therapeutics have the potential to significantly improve outcomes for patients with or at risk for atherosclerotic cardiovascular disease. The advantages of RNA-based lipid modifying therapies include the ability to reduce the concentration of almost any target protein highly selectively, allowing for more precise control of metabolic pathways than can often be achieved with small molecule-based drugs. RNA-based lipid modifying therapies also make it possible to reduce the expression of target proteins for which there are no small molecule inhibitors. RNA-based therapies can also reduce pill burden as their administration schedule typically varies from weekly to twice yearly injections. The safety profile of most current RNA-based lipid therapies is acceptable but adverse events associated with various therapies targeting lipid pathways have included injection site reactions, inflammatory reactions, hepatic steatosis and thrombocytopenia. While the body of evidence for these therapies is expanding, clinical experience with these therapies is currently limited in duration and the results of long-term studies are eagerly awaited.

Cardiology-cardiothoracic subspeciality training in South Africa: a position paper of the South Africa Heart Association.

Over the past decades, South Africa has undergone rapid demographic changes, which have led to marked increases in specific cardiac disease categories, such as rheumatic heart disease (now predominantly presenting in young adults with advanced and symptomatic disease) and coronary artery disease (with rapidly increasing prevalence in middle age). The lack of screening facilities, delayed diagnosis and inadequate care at primary, secondary and tertiary levels have led to a large burden of patients with heart failure. This leads to suffering of the patients and substantial costs to society and the healthcare system. In this position paper, the South African Heart Association (SA Heart) National Council members have summarised the current state of cardiology, cardiothoracic surgery and paediatric cardiology reigning in South Africa. Our report demonstrates that there has been minimal change in the number of successfully qualified specialists over the last decade and, therefore, a de facto decline per capita. We summarise the major gaps in training and possible interventions to transform the healthcare system, dealing with the colliding epidemic of communicable disease and the rapidly expanding epidemic of non-communicable disease, including cardiac disease.

Reduced right ventricular ejection fraction in endurance athletes presenting with ventricular arrhythmias: a quantitative angiographic assessment.

AIMS: Spontaneous or inducible sustained ventricular arrhythmias (VA) in endurance athletes frequently originate from the right ventricle (RV), even in the absence of familial arrhythmogenic RV cardiomyopathy (ARVC). The goal of this study was to determine whether the RV arrhythmogenic predilection in these patients is associated with RV functional abnormalities. METHODS AND RESULTS: Biplane RV angiography was performed in three groups: 22 endurance athletes with VA, 15 matched athletes without VA, and 10 non-athletes without VA. Four methods for quantitative RV angiographic analysis (area length, Boak, pyramid monoplane, and pyramid biplane) were used to calculate RV end-diastolic volume (EDV) and end-systolic volume (ESV) (both corrected for body surface area) and ejection fraction (EF). In addition RV outflow tract shortening fraction (SF) was determined. Although only 6 of 22 (27%) athletes with VA fulfilled the diagnostic criteria for ARVC, RV arrhythmogenic involvement was manifest or probable in 82%, based on a combination of electrophysiologic, electrocardiographic, and morphologic criteria. RV EDV in athletes was higher than in non-athletes (area length: 100.3 +/- 26.9 vs. 69.6 +/- 14.3 mL/m(2), P = 0.001), without significant difference between athletes with and without VA. RV ESV, in contrast, was significantly higher in athletes with VA than in athletes without VA (52.6 +/- 22.3 vs. 35.5 +/- 11.2 mL/m(2), P = 0.004), resulting in a significantly lower RV EF, a consistent finding across all methods (area length: 49.1 +/- 10.4 vs. 63.7 +/- 6.4%, P < 0.001). This functional impairment was also reflected in a lower RV outflow tract SF (SF right anterior oblique 32.2 +/- 10.1 vs. 40.0 +/- 11.6%, P = 0.09; SF left anterior oblique (LAO) 31.9 +/- 7.8 vs. 39.0 +/- 10.5%, P = 0.10). CONCLUSION: VA in high-level endurance athletes frequently originate from a mildly dysfunctional RV. This raises the question whether endurance exercise not only acts as a trigger for these arrhythmias but also as promoter of the RV changes.

Importance of measurements at or after the J-point for evaluation of ST-segment deviation and resolution during treatment for acute myocardial infarction.

BACKGROUND: Determination of ST-segment deviation (STdev) and its resolution (STR) by reperfusion strategies have become important tools in the assessment of patients with acute myocardial infarction (AMI). STdev has been measured at different time-points, i.e. at 20-80 ms after the J-point. There are no data comparing STR at different time-points. METHODS AND RESULTS: STdev was measured using a new computer-assisted workflow. The intraclass correlation coefficients (ICC) for validity and agreement vs. classical manual measurements (n=1020) were both 0.996 (p<0.0001). The reliability indices were 0.991 (95% CI 0.990-0.992) for the manual vs. 0.995 (95% CI 0.995-0.996) for the computer-assisted method, indicating superiority of the latter. 12-lead STdev were determined on ECGs before (baseline) and 180 min after start of thrombolytic therapy, measured both at the J-point (STdev(J)) and 20 ms after the J-point (STdev(J20); n=2400). STdev(J20) was on average 0.01+/-0.03 mV higher than STdev(J) (p<0.0001) with a tendency towards larger differences for higher ST-elevations (p<0.001). Although the average STR calculated from STdev(J20) and STdev(J) was not statistically different in any infarct location group, in 26% of the patients the difference was >10%, and 11% of the patients were classified into another ST-resolution group. Analysing STdev only in the single lead with the highest ST-elevation at baseline (a simplified measurement which may eliminate the confounding effect of ST-depressions) showed an even higher classification discordance (14% of the patients). CONCLUSIONS: The time-point of STdev measurement is an important variable to be accounted for when evaluating ST resolution data. Uncontrolled extrapolation of classification schemes based on STdev(J20) to other time-points cannot be justified.

Ablation of focally induced atrial fibrillation: selective or extensive?

INTRODUCTION: Focally induced atrial fibrillation (AF) often is due to ectopic activity in the pulmonary veins (PV). Although initial approaches were aimed at ablating only the ectopic foci, more extensive ablation approaches have evolved that isolate all PVs empirically and/or create circumferential ablation lines in the left atrium (LA). These techniques last longer and may be associated with more risks. We retrospectively evaluated the outcome and risks of ablation for focally induced AF in a single-center patient population. METHODS AND RESULTS: We report on 47 patients (32 men and 15 women; age 47 +/- 10 years) in whom 52 ablations were performed. In 19 patients (22 sessions), ablation was directed at the site(s) of overt ectopic activity ("selective" group), whereas in 28 patients (30 sessions) without sufficient ectopy to determine the culprit PV a mean of 3.5 PVs were empirically targeted for bidirectional disconnection from the LA ("extensive" group). On a preprocedural Holter recording, the "selective" group had significantly more isolated atrial ectopy (3,276 +/- 2,933 vs 620 +/- 937 beats/24 hours) and runs of atrial tachycardia (330 +/- 202 vs 53 +/- 87 runs/24 hours) than the "extensive" group (P < 0.01 for both). Only 11% had persistent AF before ablation. Acute procedural success was 81% (elimination of all ectopy) and 83%, respectively (bidirectional and fully circumferential isolation of all targeted PVs). Procedure and fluoroscopy times were significantly shorter in the "selective" group. There were no major complications, but 7 minor complications and 2 acute PV stenoses > 50% in the 30 "extensive" procedures were observed. Mean follow-up was 8.4 +/- 8.5 months (median 6.9). Kaplan-Meier analysis, excluding recurrences during only the first month ("delayed cure"), showed AF recurrence in 45% after 6 months and in 55% after 1 year. Outcome was not dependent on ablation approach ("selective" or "extensive") nor was time to first AF (22 +/- 64 days and 30 +/- 69 days). AF recurrence tended to be higher in patients with larger LA (P = 0.08), underlying heart disease or hypertension (P = 0.08), and those "extensive" patients in whom not all 4 PVs were targeted (P = 0.07). CONCLUSION: Trigger-directed ablation for focally induced AF is associated with a relatively high recurrence rate during follow-up. Apart from recurrence of the ectopic trigger, this may point to underlying structural changes in the atrial substrate not addressed by the ablation. Prospective evaluation of the risk-to-benefit profile of any technique (selective, extensive, including linear lines) is required.