Authors:
Laith Alkukhun MD
Heart and Vascular Institute, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Samuel Sauerwein MD
Department of Medicine, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Amr Barakat MD
Heart and Vascular Institute, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Dylan Burbee BS
Vascular Medicine Department, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Adam Straub Phd
Vascular Medicine Department, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Steve Reis MD
Heart and Vascular Institute, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Oladipupo Olafiranye MD1, MS, Cameron Dezfulian
MD3, Samir Saba MD1.
Heart and Vascular Institute, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Cameron Dezfulian MD
Vascular Medicine Department, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Samir Saba MD
Heart and Vascular Institute, University of Pittsburgh Medical Center,
Pittsburgh, PA.
Address for correspondence:
Samir Saba MD
200 Lothrop street, South Tower, B355.6
Pittsburgh, PA 15213
Phone: 412-802-3372
Fax: 412-647-7979
The endothelium plays a critical role in determining vascular tone.
Endothelial dysfunction is characterized by an imbalance between
endothelium derived vasodilating and vasoconstricting effects (1).
Forearm artery endothelial function measured non-invasively is commonly
used as a surrogate marker for endothelial function of the coronary
arterial circulation (2) and has been used to assess the effect of
atrial fibrillation on peripheral arterial function. Studies have
demonstrated that atrial fibrillation is associated with endothelial
dysfunction of forearm arteries, which improves after successful
electrical cardioversion (3) or catheter ablation (4). Measurements of
endothelial function have often focused on flow within the larger
conduit arteries as opposed to the microcirculation. Most studies used
post occlusive reactive hyperemia (PORH) or flow mediated dilation which
are in part nitric oxide (NO)-dependent. Microcirculatory endothelial
function following AF treatment has not been studied.
Laser speckle contrast imaging (LSCI) is a technology that measures
blood flow in the skin microvasculature using laser beam light that
reflects off moving red blood cells (5). Iontophoresis is a method for
non-invasive transdermal drug delivery to the skin microvasculature
based on the transfer of charged molecules using a low-intensity
electric current (5). We hypothesized that the microvascular endothelial
function in AF patients improves after sustaining normal sinus rhythm
using antiarrhythmic drugs (AAD). We utilized LSCI to measure change in
blood perfusion after brief ischemia-reperfusion (post-occlusive RH
[PORH]) and used iontophoresis to transfer vasodilating agents to
the skin microcirculation (chemical RH).
This prospective cohort study was approved by the University of
Pittsburgh Institutional Review Board. All subjects provided written
informed consents. We recruited patients with symptomatic AF electively
admitted to the inpatient cardiac electrophysiology service for
initiation of sotalol or dofetilide. Measurements were repeated during
follow up outpatient visits after hospital discharge. Exclusion criteria
included age above 75 years old, history of clinical cardiovascular
disease, advanced organ failure, major trauma within the preceding 3
months, uncontrolled autoimmune disease, or inflammatory disease.
Prior to attaching electrodes, the forearm was gently cleaned with
alcohol wipes. The dispersive electrode was attached proximal to the
wrist. The drug delivery electrode was attached 10–15 cm from the
radial styloid process. Patients were kept in a supine position during
the test. After laying down for 15 minutes, their endothelium-dependent
vasodilation was assessed using iontophoresis (Perimed
Perilont, Järfälla, Sweden) to transmit acetylcholine 1%. Next, we used
iontophoresis to transmit sodium nitroprusside 2.5% for the purpose of
evaluating the endothelium independent vasodilation. Afterwards, PORH
was acquired as a measure of overall vascular function. To this end, we
inflated a blood pressure cuff around the patient’s arm to 50 mmHg above
systolic blood pressure and deflated the cuff after 5 minutes. The LSCI
camera (Perimed PeriScan, Järfälla, Sweden) was placed 20 cm above the
forearm. Resting flow (RF) was obtained for 1 minute. Peak flow (PF) was
obtained for 2 minutes after iontophoresis and after deflating the blood
pressure cuff (post-occlusive RH). We recorded resting flow (RF), peak
flow (PF) and calculated RH [(PF-RF)/RF].
We enrolled 12 patients with a median age of 69 (65-70) years (33%
men). Patients had a median BMI of 34 (28-36) kg/m2and a median CHADVASC score of 3 (IQR 2-3). Twenty five percent of
patients had paroxysmal atrial fibrillation. Three patients had moderate
to severe LA dilation. Half of the patients were started on sotalol and
the other half on dofetilide, as per the choice of the treating
electrophysiologist. We conducted this study between July 2019 and June
2020, during which time seven patients had AF recurrence. Two patients
with AF recurrence underwent pulmonary vein isolation and their AADs was
discontinued. Two other patients were scheduled to undergo ablation but
their AADs were continued. Three patients had decreased burden of their
symptoms despite recurrence and their AADs were continued.
As shown in Table 1, patients with or without recurrence of AF had no
significant change in chemical RH or PORH after treatment. RH before
starting AADs was not significantly different between patients who had
AF recurrence and patients who did not. Patients on sotalol had similar
RH to patients to the other study patients at time of follow up.
In summary, we found that microvascular endothelial NO dependent
function, endothelial NO independent function and PORH did not change in
AF patients after the initiation of class III AADs. This was true
regardless of whether normal sinus rhythm was maintained or not and for
both AADs used. Our study has limitations. The small number of patients
limits the statistical power of the data. Also, no continuous heart
rhythm monitoring was used in our cohort. Alteration of endothelium
derived vasoactive substances, other than NO, in AF requires additional
studies. Notwithstanding these limitations, an important finding of this
research suggests that atrial fibrillation’s effect on the
microcirculation is different from its effect on the larger conduit
arteries.