In this study, the majority of AFD patients (n = 22, 68.75%) were normotensive without specific blood pressure control therapy. Four (12.5%) patients previously diagnosed with hypertension and currently under anti-hypertensive treatment showed a well-controlled blood pressure, while six (18.75%) were diagnosed for the first time, due to the ABPM measurements, with uncontrolled hypertension. Half of them presented a non-dipping blood pressure pattern, which is shown to be associated with additional cardiovascular alterations and organ damage 24. Of note, half of these patients had normal blood pressure recordings in office and home measurements; masked hypertension was diagnosed with 24-hours blood pressure measurements highlighting the need of standardized long-term recordings, especially in patients with concomitant early signs of cardiomyopathy and/or nephropathy.
Our findings in the AFD population are in line with a recent presentation that shows that masked hypertension may have an average prevalence of about 40% in CKD-patients 25.
Apart from dyslipidaemia and sedentary lifestyle, the overall population revealed a low prevalence of well-known risk factors for the development of hypertension such obesity, glucose intolerance and diabetes, smoke habit and alcohol consumption.
The hypertensive group showed a higher prevalence of kidney involvement with the development of proteinuria and renal failure, supporting previous reports 7–11. Almost all of them presented electrocardiographic and echocardiographic alterations and the echocardiographic analysis highlighted that patients with uncontrolled hypertension showed a worse cardiac hypertrophy as compared to the well treated-hypertensive patients.
The majority of the hypertensive patients presented an unstable disease according to the FASTEX analysis, with progressive neurological, cardiac and renal involvement presumably connected with the development of high blood pressure. Moreover, untreated high blood pressure values represent an established risk factor for adverse cardiovascular and kidney outcomes 25,26.
In addition, hypertensive AFD patients showed a higher prevalence of classical mutations, related to a more severe phenotype compared with the late-onset ones, mainly involving one organ system such as the neuro-vegetative, cardiological or renal one 27.
In our study, the prevalence of hypertensive patients was lower as compared to several previous published papers 7–10. For instance, our results are in contrast to the report by Kleinert et al. 7 which showed a high overall rate of uncontrolled hypertension (57% in male patients) in a population of 391 patients affected by AFD. We described a lower prevalence of hypertension despite the average age of our patients being higher. Furthermore, the majority of our patients were female, and none of our patients had severe kidney failure, ESRD, needed dialysis or had received a kidney transplantation. In addition, the criteria for the diagnosis of hypertension differs slightly between the two studies. It is significant to point out that we analysed a smaller sample size, but our blood pressure monitoring was strictly structured.
Notably, our hypertensive patients were identified by automated and home blood pressure analyses, highlighting the need of well standardized blood pressure measuring routines in the follow-up of Fabry patients as half of them presented with normal office blood pressure. An important observation in our study is the association between non-controlled hypertension and clinically progressive disease, not seen in those patients where blood pressure was well controlled by antihypertensive agents at the time of inclusion. Of note, our observation also highlights the necessity of diagnosing the often-overlooked masked hypertension in AFD patients with early progressive cardiac or renal disease.
Moreover, a study on 10,051 individuals (53.2% female, age 56.2 ± 16.8 years) revealed that the prevalence of hypertension in Italy varies from 55–59% 28. Taking into account the limitations of a comparison between these studies, our data indicate that hypertension is not a frequent finding in stable and well-monitored AFD patients, who are likely to have a lower prevalence compared to the general population with the same age range. This is consistent with the general concept that Fabry disease often is accompanied by lower blood pressure levels, which in fact may limit the anti-proteinuric use of ACEi/RAS-blockade in many patients 29.
The mechanisms connecting Fabry disease to the development of hypertension have not been fully studied yet. Hypertension might be a consequence of an AFD associated vascular disease.
It is not known whether the vascular disease originates from the deposition of glycosphingolipids in endothelial cells or in smooth muscle cells in the arterial media layer 30,31. Growing evidence indicates that the deposition of Gb3 in the endothelium activates oxidative enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases leading to the production of reactive oxygen species (ROS) 32. Moreover, storage of glycosphingolipids in smooth muscle cells may promote cell proliferation with fibrotic remodelling of the arterial wall leading to arterial wall stiffness resulting in shear stress that may increase the expression of angiotensin 1 and 2 receptors in endothelial cells, increasing ROS, NF-kB, beta-integrin and cyclooxygenase 1 and 2 activity and decreasing nitric oxide synthesis 33. These mechanisms may lead to oxidative stress and inflammatory damage which promotes endothelial and vascular dysfunction leading to the development of hypertension 34.
Patients affected by Fabry disease may also develop hypertension due to a direct renal damage 8 caused by the accumulation of glycolipids within the tubular epithelial cells and the podocytes, leading to tubular atrophy, interstitial fibrosis and segmental and global glomerulosclerosis 35.
It has long been accepted the concept that renal impairment and hypertension are closely associated 36. Sustained and untreated high blood pressure values hasten the progression of kidney disease and, in turn, renal damage is clearly related to the development of hypertension 37.
Another theory speculates that hypertension may be a process unrelated to Fabry disease, such as in the case of essential hypertension 12. Additionally, kidney biopsy reports have shown concomitant renal diseases causing hypertension that may co-exist with Fabry disease (e.g. focal and segmental glomerular sclerosis, membranous or IgA nephropathy) 38–41.
However, we can speculate that glycolipids accumulation may also affect the autonomic nervous system causing an impairment of the arterial baroreflex function 42, leading to an altered blood pressure regulation, with possible orthostatic hypotension and predisposition to syncope 9 even if we did not diagnosed any orthostatic hypotension in our patients.
The purpose of a close blood pressure control in AFD population is important to reduce cardiovascular events and progressive deterioration of renal function.
We recommend the inclusion of ABPM for a reliable monitoring of BP in routine follow-up of AFD patients. Other studies in CKD patients confirm that the routine office BP measurements provide imprecise reflection of the actual BP load 25,43 as recommended by the ESC-ESH Guidelines 2018 44.
The limitations of our study are the small sample size of the population analysed and the higher prevalence of women compared to men. It is important to underline also the lack in the analysis of the patients eating habits, the sodium intake and natriuresis. Enlisting a control group of non-AFD patients would have helped to better develop the analysis.
The strength of the study are the accurate characterization of the patients and the meticulous BP monitoring according to current guidelines.