Management of Hypertension in Fabry Disease

Abstract

Fabry disease (FD), a rare X-linked lysosomal storage disorder that depletes alpha-galactosidase A (α-GalA), is caused by mutations in the GLA gene. Diminished α-GalA enzyme activity results in the accumulation of Gb3 and lyso-Gb3. The pathophysiology of hypertension in FD is complex and unclear. The storage of Gb3 in arterial endothelial cells and smooth muscle cells is known to produce vascular injury by increasing oxidative stress and inflammatory cytokines as a primary pathophysiological mechanism. In addition, Fabry nephropathy developed, resulting in a decrease in kidney function and contributing to hypertension.

The prevalence of hypertension in patients with FD was between 28.4% and 56%, whereas hypertension in patients with chronic kidney disease ranged between 33% and 79%. A study using 24-hour ambulatory blood pressure monitoring (ABPM) to measure blood pressure (BP) indicated a high prevalence of uncontrolled hypertension in FD. Thus, 24-hour ABPM ought to be considered for FD hypertension assessments.

Appropriate treatment of hypertension is believed to reduce mortality in patients with FD caused by kidney disease, cardiovascular disease, and cerebrovascular disease because hypertension significantly impacts organ damage. Up to 70% of FD patients have been reported to have kidney involvement, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prescribed for proteinuria are recommended as first-line therapy with antihypertensive drugs. In conclusion, hypertension should be controlled appropriately, given the different morbidity and mortality caused by significant organ involvement in FD patients.

INTRODUCTION

Fabry disease (FD) is a rare multisystemic and X-linked lysosomal storage disease. It is caused by mutations in the galactosidase alpha (GLA) gene, resulting in a deficiency of alpha-galactosidase A (α-GalA) enzyme function1). The reduced or absent α-GalA activity causes the progressive accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3; also abbreviated as GL3) and the deacylated Gb3 (globotriaosylsphingosine [lyso-Gb3, also lyso-GL3]) in various cell types and organs, including the kidney, heart, skin, blood vessels, peripheral nerves, and central nervous system. The prevalence of FD ranges between 1:40,000 and 1:117,0002,3,4), and the clinical symptoms are nonspecific and highly variable.

FD can be classified into two phenotypes: "classic" and "later-onset, also called non-classic." In the classic phenotype, affected males have a total, or almost total, absence of α-GalA activity, and the symptoms typically appear in childhood or adolescence1). These symptoms include peripheral neuropathic pain, hypohidrosis, cutaneous angiokeratomas, lenticular and corneal verticillata, gastrointestinal symptoms including abdominal pain and diarrhea, microalbuminuria, and proteinuria. As patients age, they may develop serious complications, such as chronic kidney disease, cardiomyopathy, arrhythmias, and cerebrovascular diseases, which can lead to severe morbidity and higher mortality5,6,7).

Later-onset or non-classic phenotypes of Fabry patients have variable levels of residual α-GalA activity and heterogeneity in clinical presentations. Therefore, the onset of clinical symptoms is typically between the fourth and sixth decades of life; however, they may manifest in childhood with very different symptoms than the classic phenotype. They are also milder than in the case of the classic phenotype. They are frequently limited to a single organ (usually the heart or kidney)8,9). Adult-onset cardiac (cardiomegaly, left ventricular hypertrophy, cardiomyopathy, hypertrophic cardiomyopathy, and myocardial infarction) and renal (end-stage kidney disease) variants are more prevalent10,11,12).

Similarly to other X-linked genetic disorders, hemizygous males display more severe clinical symptoms than females. In females, X-linked gene expression is mosaic due to X-chromosome inactivation, which involves the random transcriptional silencing of one X-chromosome in each cell1). Consequently, based on penetrance and expression, females can exhibit various symptoms ranging from mild to severe.

The primary pathophysiological mechanism of FD is the storage of Gb3 in lysosomes, which causes cellular dysfunction by inhibiting autophagy and initiating apoptosis13). Eliminating accumulated Gb3 using enzyme replacement therapy (ERT) was anticipated to prevent disease progression and alleviate organ damage. Despite ERT treatment, advanced FD showed progressive major organ damage. It may be related to a secondary pathway via increased oxidative stress and induce an immunological response by activating the renin-angiotensin system(RAS) through the storage of lyso-Gb3.

Since it is generally accepted that FD is associated with a low prevalence of hypertension, very few studies have been conducted on it. On the other hand, due to the recent publication of studies on hypertension, there is a growing awareness of the significance of treating hypertension. Thus, we will review the prevalence of hypertension in FD patients, its pathophysiological mechanism, the impact of hypertension on organ damage, and therapies through a review of the literature.

Blood Pressure in Fabry Disease

Patients with FD are known to have significantly lower blood pressure (BP) than the general population14), despite the high prevalence of heart, kidney, and nervous system diseases associated with high BP. The most plausible explanation is autonomic dysfunction, which includes impaired sweating, reduced saliva and tear production, altered gastrointestinal motility, arrhythmia, and orthostatic hypotension15,16).

Several factors have been proposed as mechanisms of autonomic dysfunction. First, there is evidence of accumulation of glycosphingolipids and lipid-stained inclusions in central autonomic nuclei and peripheral nerves17). And somatic epidermal and dermal autonomic nerve fiber reductions were observed in skin biopsy18). FD vasculopathy, including smooth muscle cell hypertrophy with stored glycolipid, also affects autonomic dysfunction by constricting small neural blood vessels19). Baroreflex-mediated vasoconstriction due to the dysfunction of sympathetic vasomotor fibers in patients with FD is another known mechanism, as reported by Hilz et al.20). In addition, an insufficient increase in heart rate despite physical activity causes exercise intolerance and orthostatic hypotension in advanced stages21).

Considering these autonomic dysfunctions, it is controversial whether the definition of hypertension in patients with FD can be used for the general population. The autonomic nervous system primarily regulates BP variability14). The classification of BP and the definition of hypertension is unchanged from previous European guidelines and is defined as an office systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg, which is equivalent to a 24-h ambulatory BP monitoring (ABPM) average of ≥130/80 mmHg, or a home BP monitoring average ≥135/85 mmHg22). Considering the characteristics of low BP in patients with FD, it has been reported that even slightly elevated SBP can be associated with organ damage even if BP does not meet the criteria for hypertension23). BP variability was higher in FD patients compared with controls, while there was a decrease in heart rate variability and more non-dipper in FD14).

In a recent study by Rossi et al. on outpatient monitoring, 18.8% of 31 patients with FD had increased BP, and three had masked hypertension24).

Pathophysiology of Hypertension

The pathophysiological mechanisms underlying hypertension in FD are poorly understood due to the limited number of clinical and basic investigations on the mechanism of hypertension in FD. The accumulation of Gb3 in arterial endothelial cells and smooth muscle cells is considered the key pathophysiologic mechanism for inducing hypertension-related vascular injury (Fig. 1)19,25).

Fig. 1. The proposed pathophysiology of hypertension in Fabry disease. Mutations in the GLA gene reduced alpha-galactosidase A (α-GalA) activity, resulting in the progressive accumulation of Gb3 and lyso-Gb3 in plasma, endothelial cells, and vascular smooth muscle cells, which damages major organ damage. The cellular dysfunction produced by the storage of Gb3 in the lysosome leads to secondary injury, including immunological response through increased reactive oxygen species (ROS) and renin-angiotensin system activation. Chronic kidney disease resulting from FD nephropathy contributes to the development of hypertension. The solid line is a hypothesis based on clinical trials or basic research on Fabry disease. In contrast, the dotted lines reflect an assumed theory based on the mechanism of essential hypertension.

Essential hypertension is associated with an elevation of reactive oxygen species (ROS), which induce pro-inflammatory cytokines and vascular remodeling26). Gb3 loading into endothelial cells causes intracellular ROS and increases the expression of cell adhesion molecules27). Increased ROS production eventually triggers an increase in pro-inflammatory cytokines, resulting in vascular remodeling. In a study targeting FD cardiomyopathy, interleukin-6 (IL-6), interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), which is the pro-inflammatory cytokine, were significantly higher than those of the control group, suggesting that pro-inflammatory cytokines affect hypertension in FD28).

FD patients may have a potential relationship between the RAS system and hypertension, as the activation of angiotensin II can reduce the activity of endothelial nitric oxide synthase (eNOS) activity, leading to vasoconstriction and elevated BP, a mechanism also observed in the general population29). Additionally, research by Fujii et al. indicates that Gb3 and angiotensin-converting enzyme (ACE) are expressed in the same location in the proximal tubules, while Batista et al. found that α-GalA infusion inhibits ACE activity, leading to a temporary reduction in BP in Fabry patients after ERT30,31). However, the effects were compensated with upregulated ACE activity and increased plasma angiotensin II two weeks later. Bothou et al. also found a positive correlation between elevated renin and lyso-Gb3 levels in men with FD, while Shu et al. demonstrated that aortic endothelial cells lacking α-GalA had decreased eNOS activity and nitric oxide availability32,33). While these findings suggest a potential role of the RAS system in hypertension development in FD patients, further research is needed to confirm this relationship.

In addition, Gb3 is known to stimulate cell proliferation and fibrosis in smooth muscle cells, leading to inflammation and elevated BP. Storage of lyso-Gb3 within the medial layer of the arteries may also promote smooth muscle cell proliferation, with the fibrotic remodeling of the arterial wall leading to arterial wall stiffness34). Aerts et al. report that lyso-Gb3 dramatically increased the plasma of affected FD patients and tissues of FD mice and induced smooth muscle cell proliferation in vitro34). Barbey et al. showed that plasma from FD could stimulate the proliferation of vascular smooth muscle cells and cardiomyocytes35). The resulting shear stress may increase the expression of angiotensin I and II receptors in endothelial cells, increasing ROS, and decreasing NO synthesis19). These factors may initiate an inflammatory cascade with pro-thrombotic and pro-inflammatory effects on endothelial cells and vascular smooth muscle cells19,36).

Pinto et al. reported that an immune response causes hypertension in patients with FD, and innate immunity also plays a major role37). The innate immune system recognizes danger signals through pattern recognition receptors, such as toll-like receptor 4 (TLR4)>, expressed primarily on the surface of macrophages and dendritic cells. Glycolipids such as lyso-Gb3 can bind to TLR4 in FD, which in turn activates the NF-κB pathway to release pro-inflammatory cytokines and trigger systemic and local inflammatory responses38,39).

As FD nephropathy advances, CKD occurs, contributing to hypertension development. Kidney involvement is already known to be extremely prevalent in FD, and Gb3 deposition in the kidney is a primary cause40). In addition, high BP itself contributes to kidney damage; hence, high BP and kidney damage are tightly linked. In general, untreated patients present three clinical stages of FD nephropathy, depending on their age. In the first stage (infancy and adolescence), there is glomerular hyperfiltration. In the second (adult) stage, it is kidney-related with proteinuria and lipiduria, and in the third stage, severe kidney and cardiovascular complications develop, resulting in hypertension41).

Hypertension is a progressive disease whose prevalence increases with advancing age. It is also known that the prevalence of hypertension increases with age in FD. In particular, the prevalence of kidney and cardiovascular diseases, which are highly related to hypertension, increases with age, so this effect is thought to have an impact42,43).

Prevalence of Hypertension in Fabry Disease

According to a meta-analysis of the general European population, the prevalence of hypertension was 44.2%44). In a study of patients in the United States, the prevalence of hypertension in patients with chronic kidney disease was between 80 and 85 percent45). The prevalence of hypertension in patients with FD has been observed to range between 28% and 63.5% (Table 1)14,24,40,41,46,47,48,49,50,51). In the study by Lenders, hypertension was as high as 63.5%, which is attributed to the fact that the average age was older than in earlier studies, and the group with albuminuria reached 75.0%50).

Table 1. Prevalence of hypertension in Fabry patients.

ABPM, Ambulatory blood pressure monitoring; ACEi, Angiotensin-Converting Enzyme Inhibitors; ARBs, Angiotensin II receptor blockers; FOS, Fabry Outcome Survey registry; HTN, hypertension; CKD, chronic kidney disease

The majority of the research that reported the prevalence of hypertension was based on cross-sectional studies, and because of this, it was not able to adequately estimate the prevalence of hypertension using information such as medical history and the use of antihypertensive medicines. Two studies found that when the BP of FD patients was measured using ABPM, the prevalence of hypertension was 31-40%14,24). Considering that 5% to 41% of the patients had a glomerular filtration rate of less than 60, including other cross-sectional studies, hypertension in patients with FD was lower than in the general population.

Conversely, there is evidence that patients with FD have a high prevalence of uncontrolled hypertension. Kleinert et al. reported that among 391 patients with FD, 57% of males and 47% of females had uncontrolled hypertension when hypertension was defined as SBP ≥130 mmHg and DBP ≥90 mmHg51). Rossi et al. demonstrated the importance of ABPM by reporting that hypertension was detected in three (9.4%) patients by normal clinic measurements, while increased BP was found in six (18.8%) patients by ambulatory monitoring, which revealed three cases of masked hypertension24).

There may be heterogeneity in the reported data due to differences in study group age and kidney function at baseline. Hypertension prevalence increases with age in Fabry Outcome Survey (57.7% aged ≥75 years; 48.2% aged 65-74; 41.9% aged 50-64; 21.8% aged 18-49)47). According to Branton and colleagues, hypertension was not a prominent feature in this population, often not manifesting until patients experienced a decline in kidney function, and they proposed that hypertension is more likely to be essential or secondary to pre-existing kidney disease46).

The incidence of hypertension in patients with FD often increases with decreased kidney function. Patients with a glomerular filtration rate of less than 60 mL/min/1.73 m² had higher BP, according to a study by Ortiz et al.40). Schiffman et al. also reported that approximately 80% of patients with CKD had hypertension, whereas about 50% had a glomerular filtration rate of ≥60 mL/min/1.73 m²41). Dincer et al. reported the 24-hour BP determined by ABPM was significantly different between GFR <60ml/min and greater than 60, while the proportions of patients taking antihypertensive drugs were similar14).

Many studies show gender does affect hypertension. Ortiz et al. reported no difference between genders in the eGFR <60 and ≥60 groups40). In the group under 40 years old, however, there was a substantially higher frequency of hypertension among males (51%) than females (35%; p=0.0003) with CKD stages 1 or 240). These results might suggest organ involvement is associated with hypertension rather than gender.

Considering that the BP of FD patients is lower than that of the general population, the prevalence of hypertension is likely to be higher than estimated; therefore, additional research is necessary. In addition, since most studies have diagnosed hypertension by taking a patient's medical history and prescribing medication, tests such as ABPM should be considered to prevent major organ damage and active treatment of hypertension in patients with FD.

Hypertension and Major Organ Damage

The major consequences of hypertension are myocardial infarction, heart failure, stroke, and kidney failure. In the general population, for every 20 mmHg increase in SBP or 10 mmHg increase in DBP, the risk of cardiovascular disease doubles52).

Hypertension contributes to the disease burden of FD, just as it contributes to the disease burden of many other conditions in the general population. Due to the high prevalence of kidney, cardiac, and neurological diseases in FD, hypertension has detrimental effects on disease progression and prognosis despite the low prevalence of hypertension in patients with FD compared to the general population53).

Fabry nephropathy presents with a wide range of disease severity in males and females, proteinuria is typically a manifestation of podocyte injury, and urinary protein excretion is strongly associated with Fabry nephropathy progression40,54). A high prevalence of uncontrolled BP was reported in patients with FD and deteriorating CKD in the Fabry Outcome Survey Registry and the Fabry Registry40,51). Otiz et al. found SBP was higher with lower eGFR in Fabry patients40). Proteinuria in kidney disease is generally recognized as a risk factor for disease progression40,55). These findings suggest that hypertension may contribute to the decline of kidney function.

There is also evidence of an association between hypertension and cardiovascular disease in FD. Cardiovascular disease was the most common cause of death in both genders, accounting for 40% of men and 41.7% of women5). Linhart et al. evaluated the cause of death on 113 affected relatives of 714 patients with FD56). Cardiovascular mortality rate was most frequent in 41 female, while that was the second cause in 72 men. In a study by Patel et al., hypertension increased the odds of a cardiovascular event (myocardial infarction, heart failure, or heart-related death) by 7.8 in men and 4.5 in women57).

Hypertension has been considered the most crucial risk factor for cerebrovascular disease (CVD) in FD58). At the Fabry Registry, patients with CVD were more likely than FD patients without CVD to report a history of hypertension, 52.9% versus 20.5%, respectively59). A greater proportion of female stroke patients reported a history of hypertension than male stroke patients (32 of 52, 61.5%).

Management of Hypertension

As described above, as few as 30% to as many as 50% or more of FD patients are accompanied by hypertension14,24,46,47,48,49). Appropriate treatment of such hypertension contributes to the reduction of mortality due to kidney, cardiovascular, and cerebrovascular diseases in FD patients and, consequently, may positively affect the disease progression and prognosis of FD, so active hypertension treatment is recommended40,51).

The European Society of Hypertension-European Society of Cardiology guidelines suggest that a target BP in patients with FD with proteinuria >1 g/day should be less than 125/75 mmHg, whereas a target BP in patients with FD with proteinuria of 0.25-1 g/day should be 130/80 mmHg60,61). In addition to ERT, the current treatment guidelines published by Eng et al. emphasize the importance of managing hypertension in patients with kidney disease62).

When treating hypertension in patients with FD, it may be beneficial to consider medications that offer organ-protective effects, such as for the kidney, heart, and brain. Medications for hypertension in Fabry patients may include angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), calcium channel blockers (CCBs), or beta-blockers. Additionally, sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have recently emerged as a potential new antihypertensive drug, can also be considered.

ACEi/ARBs are the primary medications prescribed for hypertensive patients with FD. This is because proteinuria is very common in patients with FD, and it is the first-line treatment for proteinuria. Management of proteinuria is a critical feature in preserving kidney function in patients with FD. A consistent antiproteinuric therapy with ACEi or ARBs was shown to decrease the progression of kidney disease in FD63,64). Table 1 shows that ACEi/ARBs were used (16.7-71%) for organ damage in patients with FD.

Monitoring BP while using ACEi/ARBs is essential because sudden hypotension can impair kidney function. Although patients with hypertension were not targeted, Muntze's study reported that kidney function deteriorated after using ACEi/ARBs65). They said that migalastat was used as a treatment drug, and the left ventricular mass index significantly decreased in 14 patients while eGFR significantly deteriorated. The authors observed a significant correlation between the initiation of ACEi and SBP drop below 120, leading to a higher risk of kidney function deterioration. Hence, when BP falls below SBP 120 during the initiation of antihypertensive medications like ACEi, it is crucial to closely monitor BP to prevent any potential kidney function decline.

CCBs may be considered as a potential treatment option for hypertension in FD, but evidence for their use is lacking66). However, chest pain is a common symptom in FD patients, with up to 60% of hemizygous males and heterozygous females experiencing it67). For treating angina and left ventricular outflow tract obstruction, CCBs like verapamil and diltiazem should be considered68).

Beta-blockers with high cardiac selectivity are recommended for patients with angina pectoris, myocardial infarction, or tachycardia69,70). But when prescribing beta-blockers to patients with FD, caution is necessary due to the increased risk of bradyarrhythmias and chronotropic incompetence71). A high prevalence of symptomatic heart failure (47 out of 116 patients, 69 classic types and 47 late-onset) was reported in FD patients by Rob et al., with beta-blockers being the most frequently used medication (51%), followed by ACEi (43%), diuretics (28%), ARBs (15%), and MRAs (8.5%)72).

Steroidal and non-steroidal MRAs are recommended for their kidney protective effects, which include reducing proteinuria, as well as their cardioprotective effects in patients with heart failure69,73,74). However, it should be noted that there are risks of hyperkalemia or acute kidney injury, so caution must be taken when administering these medications as part of hypertension treatment.

SGLT2 inhibitors have demonstrated the potential to lower BP, suggesting their use as new antihypertensive drugs75). Even in patients with FD, SGLT2 inhibitors, similar to RAS blockade, may provide optimal kidney protection and control of systemic and intrarenal BP76). While recent findings suggest no risk of acute kidney injury associated with SGLT2 inhibitors, caution should still be exercised when using these drugs in patients with altered kidney function due to volume depletion77). Although there are no direct study results on the effect of SGLT2 inhibitors on FD, clinical studies are scheduled to be conducted and results are anticipated78).

Since a high-sodium diet can reduce the effectiveness of ACEi/ARBs79) and is associated with an increased risk of progression to end-stage kidney disease in patients with proteinuria80), a low-sodium diet is strongly recommended for FD patients with proteinuria81).

The FD-specific current treatments are ERT and chaperone therapy, which reduce intracellular Gb3 accumulation. ERT involves exogenous supplementation of α-GalA enzymes such as Fabrazyme and Replagal. Migalastat hydrochloride is an oral pharmacological chaperone that corrects the misfolded endogenous α-GalA and promotes the transport of α-GalA into lysosomes. Other future therapies, such as matrix reduction therapy, mRNA-based therapy, and gene therapy, are under development81).

Two studies found that ERT treatment improved hypertension and decreased proteinuria82,83). However, it is difficult to fully explain the effect of ERT alone, given that the patients who participated in these studies were also getting ACEi or ARBs medication. ACEi and ARBs are routinely used to protect the kidneys in FD. There are reports that ERT can reduce inflammation by regulating the immune system. FD leads to the activation of the pro-inflammatory pathway associated with hypertension. ERT may modulate the immune system to reduce the level of inflammation.

In conclusion, the improved treatment of hypertension has probably contributed to the decline in kidney and cardiovascular disease-related mortality in FD patients. All Fabry patients should have adequate control over their BP. As indicated previously, because of uncontrolled hypertension, 24-hour BP measurements and oral medications such as ACEi/ARBs should be considered while monitoring BP.