Objectives Assess the impact of end-stage renal disease (chronic kidney disease stage 5 (CKD5)) on cardiovascular outcomes in patients with Fabry disease on enzyme replacement therapy.
Background Fabry disease, an X-linked lysosomal storage disease, causes hypertrophic cardiomyopathy and cardiovascular dysfunction.
Methods Cardiac and renal function of 25 male patients with Fabry disease were analysed at 0, 1, 2, 5, 7 and 10 years after initiation of treatment. Patients were grouped at baseline into those with CKD5 (n=10) and those without (n=15). ECG and echocardiography were performed 6 and 12 monthly, respectively, while renal function was measured yearly.
Results After 10 years of treatment, cardiac and renal function in non-CKD5 patients remained unchanged. In contrast, CKD5 was associated with worse baseline cardiac parameters and progressive LV hypertrophy. LV mass index grew by 35.4±31.8 g/m2.7 in CKD5 versus 5.7±7.9 g/m2.7, p=0.044 in non-CKD5, predominantly due to increased interventricular septal wall thickness (7.7±5.5 mm vs 1.3±1.7 mm, p=0.003). Cardiovascular events, including sudden death, arrhythmia and pacing device insertion, occurred in 100% patients with CKD5 (21 events) and 26% non-CKD5 patients (7 events), p<0.0001. Additionally, estimated LV filling pressure (E/Ea) was significantly higher in patients having cardiovascular events (21.1±7.7 vs 12.5±4.5, p=0.008) irrespective of renal function.
Conclusions End-stage renal disease was the strongest indicator of cardiovascular disease progression in Fabry disease. Enzyme replacement initiated prior to CKD5 was associated with stability in cardiac and renal disease while patients with CKD5 showed ongoing deterioration. Additionally, E/Ea ≥15 may predict risk of cardiac events.
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Fabry disease is an X-linked disorder of glycosphingolipid metabolism with mutation in the GLA gene resulting in deficiency of the lysosomal enzyme α-galactosidase A (OMIM 301500)1 and resultant intracellular accumulation of globotriaosylceramide (Gb3). Gb3 accumulation ultimately results in cellular dysfunction and organ damage probably indirectly by inducing hypertrophy, fibrosis or inflammation.2 Clinical manifestations are widespread with involvement of vascular endothelium, heart, kidneys, cerebrovascular system, nerves and skin.3 ,4
Cardiac deterioration is associated with Gb3 accumulation in heart tissues, including cardiomyocytes, endothelial cells, vascular smooth muscle cells and fibroblasts.5 The classic cardiac phenotype is progressive thickening of cardiac walls, concentric LV hypertrophy (LVH) followed by increasing interstitial involvement and fibrosis.6 Clinical symptoms, including dyspnoea, palpitations, syncope or angina, occur in up to 78% of patients.6 ,7 Diastolic dysfunction is an early manifestation, but with disease progression systolic dysfunction and LV outflow obstruction can result. Ultimately progressive heart failure, conduction defects,8 bradycardia9 and mortality1 ,7 may result.
Enzyme replacement therapy with recombinant α-galactosidase A has been available in Australia since 2000. Multiple studies have demonstrated early tissue clearance of microvascular Gb3 deposits with enzyme replacement.5 ,10 Reductions in LV mass index (LVMI) and ventricular wall thickness have been demonstrated at all stages of disease.11–13 Results vary significantly between studies, and a direct relationship between LVMI reduction and improvement in cardiac function remains unproven. While clinical benefit of enzyme replacement in advanced structural cardiac disease remains in doubt, early treatment has shown significant impact. Potential benefits include improvement in conduction defects “eg normalization of QRS duration following development of bundle branch blocks, improvement in regional ventricular wall function and delayed progression of diastolic dysfunction”.13–16
Identification of patients with irreversible cardiac disease has recently focused on the presence of late enhancement on MRI and severity of cardiomyopathy.17 Currently, however, diastolic function or regional wall abnormalities determined by echocardiography and tissue Doppler imaging, in combination with ECG conduction system changes, are considered earlier and more reliable markers of cardiovascular outcomes.18
We assessed long-term cardiovascular outcomes of a Fabry patient cohort, with both mild and severe renal disease, undergoing enzyme replacement. Cardiac morphology (LVMI and ventricular wall thickness), systolic and diastolic function and cardiovascular events were included.
Data covering May 2000 to May 2014 obtained from medical records and the Fabry clinical database at the Royal Melbourne Hospital, the Fabry Centre for Victoria, Australia, were reviewed retrospectively. Inclusion criteria for review were men with confirmed genetic diagnosis, on enzyme replacement and available echocardiography and ECG results. Patients were not required to meet specific cardiac criteria for initiation of enzyme replacement. Informed consent was obtained for data analysis.
Standard 12-lead ECG was prospectively obtained prior to initiating enzyme replacement and 6 monthly thereafter. Routine measurements were manually taken at 25 mm/s and included PR interval, QRS duration, QT interval, corrected QT (QTc) interval using the Bazett formula and interventricular conduction delay, including bundle branch block pattern. LVH was determined using Sokolow–Lyon criteria (LVH present when the amplitude of S wave in lead V1 plus R wave in V5 is >35 mm).19
Measurements were performed according to the American Society of Echocardiography recommendations20 and included LV end-systolic diameter, LV end-diastolic diameter, end-diastolic thickness of the posterior wall (PWd), interventricular septal diameter (IVSd) and left atrial diameter. Studies were performed using standard echocardiographic equipment (General Electrics Vivid 7 (GE HealthcareGmbH, Solingen, Germany); Phillips IE33 (Phillips Healthcare, Hamburg, Germany)) by experienced radiologists and consultants in the Department of Cardiology, Royal Melbourne Hospital. LVMI were calculated with the Deveruex-modified cube formula,20 indexed to height. LVH was defined as LVMI >55 g/m.2.7 20 ,21 LV systolic function was assessed visually and EF measured using Simpson's biplane method. Standard assessment of diastolic function was performed, including pulsed-wave Doppler at the mitral valve tips, to determine mitral inflow pattern and to measure peak early (E) and late (A) wave velocities and deceleration time (DT). Tissue Doppler imaging of the mitral annulus was performed at the septal and lateral mitral valve annulus to allow direct measurement of E prime (Ea) an average measurement. Ratio of estimated LV filling pressure (E/Ea) was calculated giving an estimate LV filling pressure. Isovolumetric relaxation time (IVRT) was measured when additional information regarding myocardial relaxation was required.
Glomerular filtration rate, a marker of renal function, was measured yearly by renal clearance of radionuclide 51Cr-EDTA. Data were adjusted to body surface area.
Statistical analysis and graph presentation were conducted using GraphPad Prism V.6.0c for Mac OSX (1994–2013 GraphPad Software). Descriptive statistics were presented as median with range or mean and SD (in parenthesis). Shapiro–Wilk test assessed continuous variables for normality prior to data analysis. Pearson's correlation was used to assess correlations between continuous variables. Two-way analysis of variance was used to assess progressive long-term differences of individual parameters, comparing those with and without end-stage renal disease (chronic kidney disease stage 5 (CKD5)). Independent t-tests were performed to determine differences in LVMI, IVSd and PWd between CKD5 and non-CKD5 groups. Fisher's exact test assessed incidence of cardiovascular events at E/Ea ≥15. The Stata V.12 (StataCorp, Texas, USA) package was used for logistic regression analysis of the impact of CKD on cardiovascular events adjusted for age. A p value <0.05 was considered statistically significant.
In total, 110 patients with genetically confirmed Fabry disease attended the outpatient clinic. Of these, 40 were treated with enzyme replacement, but only 25 patients had cardiac outcome data available to 10 years after initiation of treatment. Ten patients were excluded, five having no echocardiographic data and five receiving <4 years of treatment. Five women were excluded due to paucity of data and confounding complications. Patients were separated at baseline in two groups, CKD5 (n=10) and non-CKD5 (n=15). Outcome data included eight patients (five with CKD5) who died during review period. One patient had a ‘cardiac’ variant mutation, but with biopsy-proven renal involvement. There were 21 missense disease-causing mutations, three deletions and one splice mutation. No correlation with mutation and outcome was detected.
Age was 37.7±10.9 years (range 18–59 years) at initiation of enzyme replacement. There was no significant age difference between CKD5 and non-CKD5 groups at baseline (43.6±8.8 vs 34.3±11.2, p=0.09). Patient characteristics are shown in table 1. Twenty patients (11 with non-CKD5, nine with CKD5) were treated with angiotensin blockade for its renoprotective and cardioprotective effect, with no statistical difference between groups. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg or on antihypertensive therapy. Lipid-lowering agent use was not significantly different between groups.
All 25 patients had renal involvement at initiation of enzyme replacement determined by the presence of proteinuria, lysosomal inclusions on renal biopsy or requirement for renal replacement therapy. Ten patients reached CKD5 requiring dialysis, with eight occurring prior to initiation of treatment. Two further patients were pre-dialysis on initiation of enzyme replacement but started haemodialysis within 2 years. The median age of starting haemodialysis was 40.3±7.1 (range 28–55.7). Six patients were transplanted prior to initiation of enzyme replacement and one patient transplanted after 1 year on treatment.
After 7 years of enzyme replacement, no patient was on dialysis, five were alive with functioning grafts and five deceased. Renal function in the non-CKD5 patients was stable over the 10 years (86.9±16.6 vs 82.2±25.4 mL/min/1.73 m2, p=0.57).
Bradycardia was highly prevalent, 15 patients (11 with non-CKD5) having a heart rate <60 bpm at baseline (table 1). Three patients with CKD5 had permanent pacing devices at baseline. Within the cohort (n=25), most PR and QRS intervals remained in normal range (table 2). One patient with CKD5 developed prolongation of the QRS interval and received a pacing device.
Standard ECG criteria for LVH were met for 100% of patients with CKD5 and 80% of non-CKD5 patients prior to initiation of enzyme replacement and no reversal occurred with treatment. After 2 years of treatment, all non-CKD5 patients showed LVH. QRS, QT and QTc were significantly longer in the CKD5 group and increased over the 10 years of treatment (p=0.004, p<0.0001 and p<0.0001, respectively). PR intervals remained unchanged.
LVH, defined as IVSd or PWd >10 mm in men,20 ,21 was present in 73% of patients at baseline. Progression of LVMI and cardiac chamber measurements are shown in table 3. One non-CKD5 patient had not completed the 10-year echocardiogram. Left atrial volume was not routinely available as this retrospective study pre-dated its routine measurement in clinical practice.
LVMI grew significantly in patients with CKD5 compared with non-CKD5 (35.4±31.8 vs 5.7±7.9 g/m2.7, p=0.044). The growth in LVMI was predominantly due to increased IVSd (7.7±5.5 mm vs 1.3±1.7 mm, p=0.003). Patients dying prior to 7 years of treatment were excluded from LVMI calculation. The CKD5 subgroup had worse cardiac baseline parameters and continued to decline despite enzyme replacement. In contrast, patients with preserved renal function had non-significant increases in LVMI, IVSd and PWd (table 3).
Markers of diastolic function E/Ea, IVRT and DT were significantly greater (all p<0.001) in the CKD5 subgroup (table 4). E/A was lower in the CKD5 group due to elevated late filling pressures. E/Ea was significantly higher in patients who had new cardiovascular events after initiating enzyme replacement (21.1±7.7 vs 12.5±4.5, p=0.008) irrespective of CKD stage. Furthermore, patients with E/Ea ≥15 were associated with increased cardiovascular events (11/13 vs 2/9, p=0.007) with three patients deceased prior to measurement of E/Ea.
LV systolic dysfunction occurred in six patients (four with CKD5). Only one of those six had ischaemic heart disease, having undergone a coronary artery bypass graft and aortic valve replacement. The other five had no other clear aetiology of systolic dysfunction, aside from Fabry disease and treated hypertension. All six patients had moderate to severe LVH with cardiac MRI data on two patients showing late gadolinium enhancement consistent with the fibrosis seen in Fabry disease. At initiation of enzyme replacement, three patients (two with CKD5) had EFs 20%–39% that did not improve with treatment. After 10 years of treatment, an additional three patients (two with CKD5) developed mild systolic dysfunction with EFs 40%–59%. Systolic dysfunction did not correlate with elevated E/Ea values.
Cardiovascular events, including mortality, conduction defects, pacing device requirement, cardiac arrest and cardiac valve dysfunction, were more frequent in patients with CKD5. Eight deaths occurred (five with CKD5), including six sudden cardiac deaths (one ventricular tachycardia arrest), one malignancy related and one suicide (non-CKD5 patient). The six cardiovascular deaths occurred in patients over the age of 40 years (range 43–59) with significant LVH at initiation of enzyme replacement. Mean duration of treatment prior to death was 46 months (range 18–84 months).
Conduction defects, including bundle branch blocks, atrial fibrillation or non-specific intraventricular conduction delay, were present in seven patients (five with CKD5) with four requiring pacemaker insertion (three with CKD5). A further five cardiovascular events occurred in the CKD5 group, including an acute cardiac syndrome necessitating percutaneous intervention, systolic dysfunction and severe aortic regurgitation.
Logistic regression analysis showed CKD5 predicted cardiovascular events completely with age having no impact. A Kaplan–Meier curve of cardiovascular event incidence after initiation of enzyme replacement is shown in figure 1. The cumulative burden of cardiovascular events diverges early in CKD5 and increases dramatically (figure 2).
Comparison of baseline CKD5 cohort with 10-year enzyme-treated non-CKD5 cohort
After 10 years of enzyme replacement, the mean age of the non-CKD5 cohort (n=12) closely resembled the CKD5 cohort (n=10) prior to initiation of treatment (41.1±9.2 vs 43.6±8.8, p=0.87). There was no difference in any ECG parameter between the groups. However, LVMI, IVSd and IVRT were all markedly greater in the CKD5 cohort (p=0.013, 0.016 and 0.03, respectively).
The presence of end-stage renal disease was strongly associated with cardiovascular disease progression in male patients with Fabry disease. Most patients in our cohort showed stabilisation or improvement in cardiac parameters LVMI, PWd, IVSd and diastolic function in the first 2 years after initiation of enzyme replacement in concordance with previous studies.13–15 After 2 years of treatment, a divergence of outcomes was evident in patients with CKD5. First, increased cardiovascular events, including death and conduction defects. Second, progressive LVH with increased LVMI predominantly driven by an increase in IVSd. A coincident rise in DT and IVRT suggested decreased ventricular compliance and delayed LV relaxation. Third, markedly elevated E/Ea consistent with elevated filling pressures. An E/Ea ≥15 also correlated with increased risk of cardiovascular events irrespective of renal function and cardiac wall thickness. In contrast, non-CKD5 patients at initiation of enzyme replacement showed stable renal and cardiovascular function over 10 years of treatment.
Concurrent severe cardiac and renal disease is likely to reflect the same pathological process. Whether Gb3-related end-organ damage or renal disease is the primary factor for cardiac deterioration is not clear from this study. Renal disease itself is a major risk factor for cardiovascular disease.22 However, more likely CKD5 marks the extent of multiorgan involvement in Fabry disease. Indeed, the severity of peripheral neuropathy in Fabry disease has been correlated with degree of renal impairment.23
Progressive cardiac dysfunction in the CKD5 subgroup is unlikely related to haemodialysis alone. Multiple studies have shown improvement or stabilisation in LVMI with haemodialysis.24 Furthermore, renal transplantation improved LVMI up to 2 years post-transplantation,25 including patients with Fabry disease.26 Diastolic dysfunction was prevalent in the CKD5 subgroup with most patients having grade 2 diastolic dysfunction, defined by Ea <8 and E/A 0.8–1.5.27 Furthermore, E/Ea was significantly higher in this CKD5 group. E/Ea is not increased by hemodialysis24 but elevated levels have identified patients at risk of cardiovascular events in dialysis cohorts.28 Cardiovascular events were significantly more frequent in patients with elevated E/Ea in our cohort. An elevated E/Ea correlates with adverse prognosis in patients postmyocardial infarction29 and with LV systolic dysfunction.30 Wang et al studied 174 patients with systemic hypertension and LVH and found a smaller early diastolic mitral annular velocity and smaller IVSd correlated with favourable prognosis. Our study is the first correlating elevated E/Ea with increased cardiac events in Fabry disease.
Debate persists about appropriate end-point measurements for improvement in cardiovascular function in Fabry disease. Structural damage and function loss appear later in disease, and recovery from damage is likely to take many years. There are few long-term studies of the response of cardiovascular disease to enzyme replacement to adequately assess potential end-point measures. Early response to enzyme replacement is suggested by decreases in LVMI and IVSd,13–15 ,17 but outcomes beyond 6 years remain undetermined. A review by Weidemann et al13 compared 40 patients’ progress after receiving 6 years of enzyme replacement with an untreated natural history group. Severe end-organ damage was not reversed with treatment, but symptom control was achieved. Absolute measures for irreversible disease were not detailed, but a reduction of IVSd was suggested as a marker of disease response.13 In our review, outcomes after 10 years of enzyme replacement were assessed. An early reduction in IVSd and PWd, while not statistically significant, did appear to herald better response to treatment. However, a wide variation in IVSd and PWd was seen and no clear point of irreversible disease could be determined by wall thickness alone. The extent of renal involvement at baseline may help identify those patients at risk of cardiovascular progression.
Several other observations were evident from this review. First, the non-CKD5 cohort after 10 years of enzyme replacement showed significantly better cardiac parameters and fewer cardiac events than the CKD5 cohort at initiation of treatment. Patients within these groups had three identical mutations and were very similar in age. This suggests early initiation of enzyme replacement may delay disease progression. Second, most patients were bradycardic at initiation of enzyme replacement with no improvement on treatment. Third, a high incidence of sudden cardiac death occurred, predominantly in patients with CKD5 prior to transplantation; this contrasts with low incidence previously reported.3 ,9 Fourth, no reduction in QT or QTc occurred with enzyme replacement in contrast to previous studies.8 Finally, QRS widths were also prolonged with a higher incidence of bundle branch block in patients with CKD5, but PR intervals remained within normal limits.
There are limitations inherent in a retrospective observational study. First, the population was heterogeneous in age and renal function. Second, numbers were small with a high incidence of mortality early, especially in patients with CKD5. Extrapolation of data within groups is consequently difficult. Third, data were collected from a clinical perspective and echocardiographic techniques continued to improve over follow-up. Furthermore, longitudinal and radial strain rate imaging is superior in assessing ventricular contractility and function,15 but until recently this research tool was not routinely performed in our centre. Fourth, echocardiographic measurement of wall thickness is limited by inter-operator variability. LVMI calculations are dependent on these measurements and have inherent inaccuracies. Fifth, cardiac MRI was not available for most patients after initiation of enzyme replacement and not possible for patients with permanent pacemakers. Myocardial fibrosis has been reported as a marker of irreversible cardiomyopathy.17 In our cohort, 10 patients (four with CKD5) had available cardiac MRI data, cardiac fibrosis was present in five patients (three with CKD5). Finally, a control group of patients of similar age and disease severity was not available for comparison.
Our review shows that initiating enzyme replacement prior to the onset of significant renal impairment was associated with reduced renal and cardiovascular disease progression. IVSd and PWd stability at 2 years of enzyme replacement may be a marker of cardiac progression. In addition, E/Ea ≥15 may identify patients at increased risk of cardiovascular events requiring increased cardiac follow-up. Poor cardiovascular response to enzyme replacement in patients with CKD5 does not preclude treating for other benefits, including neuropathic symptom relief and improved quality of life. Our data failed to give insight into whether enzyme replacement benefits Fabry patients with CKD5 despite their advanced disease load and higher risk of adverse outcome.
What is already known on this subject?
Fabry disease is associated with cardiac and renal deterioration, but current markers of disease progression are of limited utility in determining the highest risk cohort. In the general community, chronic kidney disease is associated with increased cardiovascular events and may be a potentially useful marker in Fabry disease.
What might this study add?
We identify chronic kidney disease as a potential marker of disease progression and increased risk of cardiovascular events. The use of enzyme replacement therapy prior to severe kidney injury may lead to prevention of cardiac and renal deterioration. In addition, estimated LV filling pressure may be a marker of increased risk of cardiovascular events.
How might this impact on clinical practice?
We add to the growing body of evidence for the benefit of early initiation of enzyme replacement to prevent or reduce cardiac and renal deterioration and hence mortality. Estimated LV filling pressure may be a marker of patients at increased risk of cardiovascular events requiring a closer follow-up. In addition, changes in posterior and interventricular wall thickness may be potential markers of better patient response to enzyme replacement.
The authors sincerely thank the patients who participated in the study, Elizabeth Di Sciascio for data collation and especially Alexandra Gorelik for assistance with statistical analysis.
Contributors AST was responsible for planning the study and the primary data interpretation, including statistical analysis and original manuscript preparation. NTL contributed to cardiac data collection and interpretation including manuscript editing. KMN consented all patients and was the primary clinician responsible for organisation and follow-up of cardiac investigations. She also contributed to data interpretation and original manuscript preparation.
Competing interests AST and KMN have received research support, honorariums and travel assistance from Shire Corporation, Sanofi Corporation, Amicus Therapeutics and/or Protalix Biotherapeutics. NTL has received travel assistance from Shire Corporation.
Patient consent Obtained.
Ethics approval All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000(5).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data from Fabry cohort are de-identified and entered onto International Fabry Registries—run separately by Genzyme (a Sanofi company) and Shire. No other additional unpublished data are available separate to this original research paper.