Hyperbaric Oxygen Therapy in Patients With Chronic Stable Ischemic Heart Disease: An Option for Therapeutic Angiogenesis?


Ischemic heart disease is the leading cause of mortality in the United States and second most
common in Israel. Myocardial ischemia prevails when imbalance between oxygen demand and
delivery to the myocardium occurs: due to increased oxygen demand beyond what can be
delivered by increased coronary flow; due to restriction of blood flow from obstruction or
stenosis in the coronary circulation in the face of preserved oxygen demand; or combination
of these processes. There are two main causes for restricted blood supply to the myocardium:
Epicardial atherosclerotic coronary disease or dysfunctional coronary microcirculation. The
two processes are often co-occurring in the same patient given the similarities between the
risk factors underlying both. As the blood vessels fail to deliver adequate resting or
maximal coronary blood flow, either gradually over many years or abruptly during a course of
an acute event, myocardial segmental compromise and thus, global cardiac function

The functional hallmark of ischemic left ventricular (LV) segments is their inadequate
contractility, manifested as hypokinetic or akinetic segments when examined using either
invasive or non-invasive LV functional studies. Ischemic myocardial cells may progress to
cellular death, and irreversible scar formation. However, other cells may maintain viability.
These viable myocardial segments are of particular clinical importance given their ability to
resume contractility with adequate optimal medical therapy and/or revascularization

Gate SPECT technology allows evaluation of myocardial perfusion and myocardial segmental
viability in patients with chronic ischemic heart disease. Studies evaluating the ability of
myocardial perfusion studies to predict clinical outcomes are contradictory in that many have
shown ability to predict morbidity and mortality endpoints while others didn’t .

However, it is intuitively conceivable that invasive and non invasive approaches that are
able to reduce ischemic burden as determined by myocardial perfusion imaging, are an
important goal for the treatment of patients with chronic ischemic heart disease.

Different standard invasive approaches as percutaneous coronary angioplasty (PCI) and
coronary artery bypass grafting (CABG) have been shown to increase myocardial perfusion when
serial studies were compared before and after the intervention. Furthermore, non invasive
anti-anginal medications as calcium channel blockers, beta blocker and nitrates as well as
statins have been shown to similarly produce improvement in myocardial perfusion images as
are combinations of these treatments, as required by modern evidence-based guidelines. It is
presumed that these non-invasive approaches either decrease myocardial oxygen demand (e.g.
Beta blocker) or increase coronary dilation (e.g. Nitrates) as the therapeutic means by which
they contribute to ischemia reduction.

During the past decade or so, the concept of "therapeutic angiogenesis" has emerged out of
the observation that a significant number of patients are not candidates for standard
revascularization procedures or have incomplete revascularization with conventional
procedures like PCI or CABG. For example, in patients with two or three vessel coronary
artery disease, complete revascularization was successful in 23% and 9% of cases,
respectively in one report. The goal of therapeutic angiogenesis is the induction of new
coronary arterial vessels that can effectively provide blood supply to the area of myocardium
subtended by diseased or occluded native coronary arteries. These "native bypass" vessels
could then relieve myocardial ischemia, improve regional and global left ventricular
performance, lessen symptoms of angina, and potentially improve patient prognosis. Candidates
for pharmacological stimulation of therapeutic angiogenesis in cardiac ischemia include
angiogenic cytokines such as Fibroblast Growth Factors (FGF), Vascular Endothelial Growth
Factors (VEGF), Hepatocyte Growth /Scatter Factor (HGF/SF), CXC chemokines such as
interleukin 8 (IL8) and monocytes chemoattractant protein 1 (MCP-1), growth factors involved
in maturation of the vascular tree such as angiopoietins and Platelet Derived Growth Factor
(PDGF) and transcription factors that stimulate expression of angiogenic cytokines and their
receptors such as Hypoxia-Induced Factor 1α (HIF1α).

Following promising results from pre-clinical and non-controlled studies, several randomized
placebo-controlled trials in humans, using some of these candidates, have shown at best,
modest clinical endpoints improvement or perfusion enhancing capabilities. Although
therapeutic angiogenesis using angiogenesis-enhancing factors is an active research arena, it
is still in its infancy and no such strategy have yet achieved acceptance as adjuvant therapy
for chronic ischemic heart disease.

In this study, hyperbaric oxygen therapy (HBOT) is proposed as a possible in vivo angiogenic
stimulator for improving microvascular myocardial perfusion. Surprisingly, HBOT has not been
extensively evaluated in patients with chronic stable ischemic heart disease and to date, its
evaluation in cardiovascular diseases was primarily in the context of acute coronary
syndrome, amelioration of ischemic-reperfusion injury and stem cell research.

HBOT has been investigated for treatment of numerous diseases for more than 300 years.

The principal effect of HBOT is increasing the solubility of oxygen in plasma to a level
sufficient to support tissues with minimal oxygen supply carried on by hemoglobin. Transport
of oxygen to mitochondria, the main sites of oxygen utilization within each individual cell,
occurs by diffusion, via a stepwise decrease in the driving oxygen pressure gradient.
Diffusion oxygen gradient is a vector indicating the direction of the greatest rate of change
between oxygen dissolved in the blood and oxygen within the cell/entire tissue. As a whole,
breathing oxygen under hyperbaric conditions has been shown to be a potent means of
increasing arterial oxygen tension, as well as tissue oxygen tension. For example, at 2
absolute atmospheres (ATA), plasma O2 tension rises above 1110 mmHg, whereas at normal
environmental conditions, i.e. at the sea level, it reaches only 98 mmHg. As can be
concluded, hyperbaric conditions can provide about a ten-fold increase in the amounts of O2
reaching the hypoxic cardiac tissue. HBO therapy is well tolerated and has been considered
safe when used according to the standard protocols, with oxygen pressure not exceeding 3 ATA
and treatment sessions limited to a maximum of 120 min.

Multiple studies have suggested that HBOT can enhance angiogenesis but demonstrating enhanced
myocardial perfusion (presumably via therapeutic angiogenesis) in humans, have never been
attempted. The investigators hypothesized that chronically ischemic viable myocardial tissue
is in a state of chronic oxygen demand/delivery imbalance and that physiologic
ischemia-induced angiogenesis during regenerative/repair processes, aimed to restore oxygen
delivery, has been "burned out". Since all the regenerative/repair processes have common
denominator: they are all energy/oxygen dependent, it might be possible that HBOT can enables
the metabolic changes needed to reignite those regeneration processes, simply by supplying
the missing energy/oxygen.


After signing the informed consent, patients will be randomized in 1:1 manner into the
treated or the control-cross group. After the randomization, patients will be invited for
baseline evaluation that included full review of their medical status and complete physical
examination. Patients will be instructed to refrain from any changes in their chronic
medications or life style (e.g. exercise regimen) and to avoid new medications unless
clinically indicated and approved by the study investigators. Quality of life (QOL)
assessments (Seattle Angina Questionnaire [SAQ] translated to Hebrew) will be completed at
baseline and every 2 month in the control period or following the treatment period.

After their inclusion, all patients will undergo baseline myocardial perfusion study.
Afterwards, patients will be randomized to two groups: a treated group and a cross group.
Patients in the treated group will undergo HBOT treatment for 2 months and after that will
repeat the same-protocol myocardial perfusion study and questionnaire, before entering a 2
month control period. Patients in the cross group will be evaluated at baseline, after a 2
month control period of no treatment and after 2 month period of HBOT treatment (after the
cross to HBOT).

The following HBOT treatment protocol will be practiced: 40 daily sessions, 90 minutes of
100% oxygen at pressure of 2 ATA each, five days a week for 8 weeks.


Ischemic Heart Disease



Start Date:

July 2014


Assaf Harofeh MC

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