Refractory Angina (RA) is an increasingly-prevalent issue worldwide. With increasing age, the number of patients who
might not undergo conventional myocardial revascularization with Coronary Artery Bypass Grafting (CABG) or Percutaneous
Coronary Interventions (PCI) is increasing steadily. The exact number of such patients has been ignored; but it has been estimated
that, in Europe, there are about 75,000 new cases annually [1], while in the United States, the reported incidence stands
at roughly 50,000 new cases/year and prevalence from 600,000 to 1,800,000 overall [2]. Due to limits in treatment, these patients
have been called “no-option” patients, their most common cause of unsuitability for CABG or PTCA being diffuse coronary
disease, either associated or not associated with small vessel disease. Comorbidities, excessively-old age, and the combination
of these two factors are further causes [3]. Apart from second- and third-line anti-anginal medications - like Nicorandil,
ivabradine, ranazoline, trimetazidine, perhexiliine, allopurinol, molsidomine, and fasudyl/hydroxyfasudil - several nonpharmacological
methods have been developed over the last 20 years. These include laser trans-myocardial revascularization,
shockwaves, spinal cord stimulation, stellate ganglion block, pro-angiogenic gene therapy, lipoprotein apheresis, stem cells,
external counter-pulsation and, quite recently, coronary sinus reducer devices [4]. Many of these techniques represent old ideas
and methods of revascularization, abandoned soon after the advent of cardiopulmonary bypass and coronary surgery, and resurrected
with modern technologies [5]. Two further options existed in the past, both involving the potential of Internal Mammary
Arteries (IMAs) to develop collaterals; and both surgical. One dates back to Arthur Vineberg, a Canadian surgeon who developed
a technique to implant an IMA into an intra-myocardial tunnel [6]. This allowed for neo-angiogenesis in the heart, next to
the site of the mammary artery implant, with the development of collaterals visible by coronary angiography. This technique,
after about 15 years of satisfactory results, was abandoned for some decades. Recently, a suggestion was made to resurrect it as
a way to address refractory angina [7].
Another old method involving the IMAs consisted of occluding them by ligature. This technique was invented by Davide
Fieschi, in 1939 [8], and reproduced by Cesare Battezzati [9, 10] and Robert Glover [11] in the fifties. The principle behind this
approach is that, if an IMA is ligated distal to its pericardiophrenic branch, blood flow might be redirected towards the heart
through a microvascular anastomotic network. This technique initially exhibited encouraging results, though conflicting opinions
existed [12, 13]. However, all discussions about this approach were abandoned, as well as Vineberg’s procedure, following
the advent of the heart-lung machine [14-16] and on-pump coronary surgery.
After 50 years of silence, since 2010, it has been proposed that ligating the IMA to develop collaterals, by occluding it distal
to the pericardiophrenic branch, could be adopted for patients with RA [17]. By the same year, it was suggested that this could be
achieved surgically, with or without the help of Vascular Endothelial Growth Factors (VEGF), or alternatively by endovascular
occlusion [18, 19]. An experimental study on dogs published in 2012, which included both a surgical approach and the injection
of VEGF, though inconclusive due to the high mortality rate among the dogs, opened the way to rediscovering therapeutic IMA
occlusion [20]. Subsequently, greater emphasis was placed upon IMA occlusion and, ultimately, a Swiss team adopted this
concept and has since published two papers, in 2014 and 2017, describing interesting results achieved in humans. In the first
study, they occluded the IMAs via balloon angioplasty, while simultaneously occluding the coronary vessels for a short period
of time [21]. In the second study, they caused persistent occlusion of the right internal mammary artery for six weeks [22].
They disclosed that, in patients with IMA occlusion, there were improvements in the collateral flow index, fractional flow reserve,
ECG intracoronary ST segment, and anginal symptoms. This improvement occurred ipsilaterally, meaning that occluding
the left IMA generated improvements if the left anterior descending artery was involved; as well, occluding the right IMA resulted
in improvement if the right coronary artery was involved. Conversely, the circumflex coronary artery exhibited no benefit
from occlusion of both the right and left IMAs. The investigators concluded that IMA occlusion could increase extracardiac
ipsilateral coronary supply to the point of reducing ischemia in the dependent but not contralateral myocardial region. What is
remarkable is that these conclusions are practically identical to those reported by Italian authors in 1939 and 1955.
Despite these modern demonstrations, occluding IMAs for therapeutic purposes is only a slowly-advancing concept within
the scientific community. In a recent editorial, this field of discovery was called an “undiscovered country” [23], and the author
of the current editorial certainly agrees [24]. The microvascular network that connects extra-cardiac vessels to the coronary
artery [25, 26], and the potential roles of IMA occlusion [27], remain almost ignored fields of research. As a result, in 2019 the
road towards therapeutic IMA occlusion for refractory angina [28], although re-opened after years being dormant, certainly
requires further studies and remains far from being an established therapeutic option.
