Cardiovascular Complications in Patients with Klinefelter’s Syndrome

Abstract

: More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement in restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease

“…For example, compared with XY men, Klinefelter men, who carry an additional copy of the X chromosome (XXY), have increased cardiovascular mortality. 37 The role of the extra X chromosome in bringing about the increased CVD risk is unclear, since these individuals have hypogonadism (which may be treated with testosterone supplementation), may have congenital cardiovascular abnormalities, and are more susceptible to CVD risk factors such as visceral obesity and type 2 diabetes. Likewise, identifying the role of the sex chromosomes in CVD susceptibility in Turner syndrome (XO) patients is confounded by the high prevalence of congenital cardiovascular abnormalities (such as bicuspid aortic valve, left-handed heart obstructive disease, enlargement of the thoracic aorta) and early onset hypertension, ischemic heart disease, and stroke.…”

Testosterone deficiency and metabolic disturbances in men who fathered a child by use of donated spermatozoa

“…Possible explanation for our findings might be the inclusion of men who have Klinefelter syndrome-the most frequent genetical cause of NOA 6 . This group of men is known to have higher cardiovascular and cardiometabolic morbidity and mortality according to most studies [21][22][23] despite some showing lower mortality rates for e.g. ischaemic heart disease 24 .…”

Metabolic and Nutritional Aspects in Paediatric Patients with Klinefelter Syndrome: A Narrative Review

“…Besides cardio-metabolic outcomes, there is evidence that KS is associated with an increased risk of congenital heart malformations [ 11 ], although their frequency is still not particularly high [ 44 ]. Different congenital cardiovascular anomalies have been observed among KS adults, including transposition of the great arteries, patent ductus arteriosus, partial atrioventricular canal defect and cleft of the anterior leaflet of the mitral valve, tetralogy of Fallot and hypertrophic cardiomyopathy with sick sinus syndrome and coronary arteriovenous fistula [ 44 , 45 ].…”

“…These were found to be significantly higher in KS adults compared to controls, yet testosterone therapy has a potential role in reducing them [ 31 ]. Moreover, the role of circulating endothelial progenitor cells should be elucidated since alterations were observed in KS patients [ 3 , 16 , 45 , 46 ].…”

“…These pathological conditions seem difficult to reverse once established; thus, it is important to prevent their flourishing by establishing healthy behaviours as early as possible. In this regard, KS patients are more likely to develop NCDs compared to the healthy population [ 16 , 17 , 18 , 19 , 45 ], and prevention is crucial throughout life.…”