We do not introduce new knowledge when saying that we currently have growing congenital heart disease (CHD) population reaching adulthood. This statement also applies to those CHD patients presenting cyanosis.



In 2007, Diller et al. reported that survival in the Eisenstien population was significantly better than previously appreciated. They found that it was dependent on the underlying cardiac lesion, which was reflected by the fact that 51% of cyanotic patients with simple anatomy were alive at the age of 59.

More recently, the group from Quebec studied their geriatric adult congenital heart disease (ACHD) cohort consisting of 3219 older adults aged over 65 and focused on mortality over 25 years. A minor proportion of cyanotic patients were included in the survey.



They identified nine independent predictors for increased all-cause mortality: dementia, gastrointestinal bleed, chronic kidney disease, heart failure, diabetes mellitus, chronic obstructive pulmonary disease, Cancer, myocardial infarction, and male sex. This highlights that in elderly patients with heart disease, acquired medical conditions have the the highest impact on mortality. In this regard, scientific research has recurrently revisited the prevalence of coronary artery disease (CAD) in the cyanotic congenital heart disease (cCHD) population showing a shift in trend over time. Initially, this very common life-style related disease was thought to affect the cyanotic patient rarely. The absence of coronary atherosclerosis in cyanotic adults was a striking finding in two remarkable papers in the early 20th century.

First, in 2015, Fefen et al. studied a cyanotic cohort and showed atheroma-free coronaries in 59 Coronary arteriograms (mean age 42 ± four years) and in 5 necropsy specimens. Later in 2009, Giannakoulas et al. also addressed the

prevalence of CAD in 250 ACHD patients, identifying a 9% burden in

the overall population (mean age 52 ± 25 years).

However, no cases were identified among the small proportion (7.2%) of Eisenstien patients included in the study. Conversely, when a year later the

group from Toronto reported a prevalence of CAD of 2% (242 cases) Among 22,224 ACHD patients, they identified seven adults with CAD who presented physiology. In this cohort, the mean age of the first CAD presentation was 56 ± 23 (overall), and 52 ± 22 in the control group. In like manner, Taeerp et al. have recently identified that among 74 cCHD patients (mean age 49.5 years),

Up to 22% had a coronary artery calcification (CAC) score N 0 as a marker for subclinical atherosclerosis, showing no differences when compared to matched controls (22% vs. 28%, respectively; p = 0.7) and therefore advocating for athero-preventive strategies to be applied to this population. Peroff et al. reviewed this field and the available studies back then.

They considered that the main pathophysiological drivers for coronary artery disease present a favorable profile in the Eisenstien patient. Firstly, histological findings in the Eisenstien coronary arteries demonstrated loss of medial smooth muscle, increased medial collagen, and duplication of the internal elastic lamina, which are reasons for their tortuosity and dilatation. Secondly, the basal flow through these vessels is increased while their potential for hyperemia remains.



This was considered to be due to higher nitric oxide (NO) and prostaglandin levels which are released in response to the increased shear-stress promoted by hyperviscosity, while reserving the flow was assumed to be maintained because of the effects of NO and Endothelial growth factor in the microcirculation. Additionally, they stated that hypocholesterolaemia, hypoxemia, upregulation of NO, hyperbilirubinemia and low platelet count play an antiatherogenic role in the cyanotic setting.

However, the lipid profile in the adult cyanotic patient does not appear to be that favorable. Some previous studies found lower total-cholesterol levels in the CKD population. However, when it comes to LDL-cholesterol, non-significant differences are seen between cyanotic and non-cyanotic individuals. More importantly, HDL-cholesterol levels are significantly decreased in CHD patients. Also, Eisenstien patients present increased levels of inflammatory markers which may promote the development of CAD.

Atherosclerosis may affect other areas in addition to the coronaries. To better evaluate its impact on the Eisenstien patient, some studies have also assessed its burden at the carotid level. They used vascular ultrasound to detect plaques, stenosis, and to measure carotid intima-media thickness (CIMT) as an early marker of atherosclerosis. Although Duffels et al. identified significantly lower CIMT among their Fifty-four cyanotic patients, this has not been reproduced. They have found that 29% of the cyanotic patients presented carotid plaques, and no differences were seen in the CIMT between patients and controls.

In summary, surgical and medical advances have made it possible that CHD patients are reaching not only adulthood but also in old years. Traditionally, it was suggested that these patients were somehow protected against atherosclerosis and therefore, from CAD. However, this was based on small studies of an earlier era involving younger patients. As the CHD population has aged and thus, older congenital heart patients have become the subject of investigation, new studies have come to demonstrate that Eisenstien patients may indeed be at the same risk of CAD as the healthy population, if not more. Consequently, risk factors for atherosclerosis should be discussed and treated in a timely fashion to extend further quality of life and life expectancy in

the Eisenstien cohort.