John Mandrola, MD

November 08, 2015

At the Samuel A Levine Young Clinical Investigators Award session here at the American Heart Association (AHA) 2015 Scientific Sessions, Dr Rajeev Pathak (University of Adelaide, Australia) presented results of the ARREST-AF substrate study.[1] This was a randomized controlled trial that asked whether aggressive risk-factor (RF) management results in a reversal of the substrate for AF.

The group's aim was to study the impact of RF management on electrical and anatomic properties of the atria, cardiac structure, platelet and endothelial function, and inflammation.

The original ARREST-AF cohort study (published in the Journal of the American College of Cardiology[2]) showed that patients enrolled in a physician-led RF-modification clinic were more likely to be free of AF after ablation. The elegance of the ARREST-AF cohort study was that basic lifestyle changes, such as weight loss, exercise, attention to sleep quality, and moderation of alcohol delivered immense antiarrhythmic benefits.

Yet cardiologists struggled with these results. How could lifestyle changes do things that drugs and catheters could not? How did it work? We wanted to understand the mechanisms. ARREST-AF substrate investigators set out to go beyond empiricism; they wanted to explain how RF management delivers its benefits.


Investigators screened consecutive overweight AF patients who presented to the University of Adelaide arrhythmia service. They randomized 67 patients to either a standard-care arm (n=34) or an aggressive RF-management clinic (n=33). They did baseline electrophysiology (EP) studies, cardiac MRI, and blood testing in all patients. After a mean follow-up of 12 months, they then did follow-up EP studies, MRI, and blood tests. Not all patients consented for the second set of tests. Follow-up studies were available in 26 control patients and 24 in the RF-management group.


The baseline characteristics of the two groups were evenly matched.

Impact on RF management. Compared with controls, patients in the RF-management group lost more weight, had lower blood pressure, better glycemic control, and more favorable lipid profiles while taking fewer meds. (That last phrase, "while taking fewer meds," stands out at a meeting in which the benefits of drug-induced lower blood pressure and lipid levels will be much discussed.)

AF burden. Using 7-day Holter monitors, patients in the RF-management group experienced fewer AF episodes and less total duration of AF. In the RF-management group, 40% of patients were AF-free without drugs or ablation.

Atrial electrical health. Regional effective refractory periods from both the right and left atrium were unchanged in the control arm but increased significantly in the RF-management group. Conduction velocity did not change in the control group but increased in the RF-management group. In pre- and postelectroanatomic maps, the RF-management group showed fewer numbers of fractionated signals and double potentials while bipolar voltage increased.

Structural changes. By echo, researchers noted significant decreases in LA volume, LV septal thickness, and E/e' ratio (diastolic function) in the RF-management group. By MRI, the RF-management group showed reduced LV mass and pericardial fat. And markers of systemic fibrosis (MMP-9, TIMP-1, and TGF-beta) dropped significantly in the RF-management group.

Platelets, endothelial function, and inflammation. Endothelial function (ADMA, ET-1), platelet function (PA to ADP, thrombin, collagen, and P-selectin), and inflammatory markers (hs-CRP, IL-6, MPO, BNP) decreased in the RF-management group but not in the control group.

The authors concluded that RF management reduced AF burden, caused marked structural improvements in the heart, improved electrical properties of the heart, and reduced thrombogenic and inflammatory markers.


AF is a progressive disease. The more risk factors, the stronger the association with advanced forms of AF. Basic science evidence supports the notion that obesity, sleep apnea, and hypertension promote a profibrillatory milieu in the atria—via myocyte stretch, disordered cell-cell conduction, fibrosis, and other mechanisms.

We know pericardial fat is far more than an innocent bystander in promoting AF.

And notwithstanding the excitement over LA-appendage closure, we know stasis is only one way AF increases the risk of stroke. The other part of Virchow's triad is that AF induces platelet/endothelial dysfunction and inflammation, which lead to a hypercoaguable state.

If confirmed by other studies, these findings will not only improve the health of patients with AF, but more important, they will have given the cardiology community permission to see lifestyle intervention as potent medicine.

Human-to-human RF modification led to improved basic health measures, favorable structural and electrical properties of the heart and a reduced the thrombogenic state of AF. That, my friends, is the essence of cardiology.

Pay attention to this study. I believe it will change the course of how we approach patients with atrial fibrillation.

And yes, Dr Pathak took the Young Investigators' Award among tough competition.



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