© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12759
Echocardiography
ORIGINAL INVESTIGATION
Left Ventricular Diastolic Dysfunction in Type I Gaucher Disease: An Echo Doppler Study Francesco Lo Iudice, M.D.,* Antonio Barbato, M.D.,† Riccardo Muscariello, M.D.,† Carlo Di Nardo, M.D.,* Francesco de Stefano, M.D.,† Michelina Sibilio, M.D.,‡ Pasquale Strazzullo, M.D.,† Giovanni de Simone, M.D.,* and Maurizio Galderisi, M.D.* *Hypertension Research Center and Department of Medical Translational Sciences, Federico II University Hospital, Naples, Italy; †Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy; and ‡Division of Pediatrics and Neonatology, Moscati Hospital, Aversa (CE), Italy
Type I Gaucher disease (GD1) is an autosomal recessive lysosomal storage disease characterized by multiorgan damage. Left ventricular (LV) involvement has been rarely reported. Accordingly, the aim of the study was to evaluate LV geometry and function in a series of patients with GD1. Eighteen patients with GD1, 18 age- and sex-matched normal controls, and 18 age- and sex-matched hypertensive patients (HTN) were compared by standard echo Doppler examination. LV mass index, relative wall thickness and ejection fraction, transmitral E/A ratio, E velocity deceleration time (DT), atrial filling fraction (AFF = time-velocity integral of A velocity/time-velocity integral of total diastole 9 100), E/e0 ratio, and left atrial volume index were determined. Nine GD1 patients also exhibited arterial hypertension. The intergroup difference of LV mass index and relative wall thickness was not significant. Transmitral E/A ratio was lower in HTN than in normal controls and GD1 (P < 0.05). GD1 exhibited longer DT than NC and HTN (P = 0.009). AFF was higher in GD1 and HTN compared to NC (P = 0.034). After adjustment for heart rate, GD1 was associated with longer DT (P < 0.001) and greater AFF (P = 0.036), while HTN was associated only with AFF (P = 0.013). No interaction was found between GD1 and HTN. In conclusion, GD1 is associated with subclinical LV diastolic dysfunction, which is independent of the coexistence of arterial hypertension. Subclinical LV impaired relaxation in the context of myocardial infiltrative damage could be the mechanism underlying these alterations. (Echocardiography 2014;00:1–6) Key words: Gaucher disease, echocardiography, left ventricle, diastole, atrial filling fraction
Gaucher disease (GD) is an hereditary autosomal recessive lysosomal storage disease caused by deficiency of the enzyme b-glucosidase leading to accumulation of glucosylceramide—a sphingolipid mainly found in cell membranes—in macrophages (Gaucher cells). GD occurs in three different forms: a nonneuropathic form (Type I), an acute neuropathic form, fatal within the first years of life (Type II), and a subacute juvenile neuropathic form (Type III).1 In Type I GD (GD1), the main involvement is the accumulation of glucosylceramide in the liver, spleen, and bone marrow, which causes organomegaly, stimulates inflammatory pathways, and yields tissue fibrosis.2 The most frequent clinical manifestations of GD1 are hepatosplenomegaly, bone marrow Address for correspondence and reprint requests: Maurizio Galderisi, M.D., Echocardiography Laboratory, Hypertension Research Center, Federico II University Hospital of Naples, Via S. Pansini 5, Edificio 1, 80131 Naples, Italy. Fax: +39-81-5466152; E-mail: [email protected]
expansion, cortical bone mineral losses, and both hypoproductive- and consumptive-based anemia and thrombocytopenia.1 The lungs can be less frequently involved with pulmonary hypertension and consequent right ventricular overload.3 Clinically overt, direct involvement of the heart is uncommon.4–12 Cases of pericardial disease, with hemorrhagic or constrictive pericarditis and pericardial calcification have been observed.4 Valvular heart disease (mitral and aortic fibrocalcification and stenosis, often resembling rheumatic disease) has also been associated with GD,5,6 especially with the subtype of the subacute neuropathic form (Type IIIc).7 Clinically overt myocardial involvement is reported in few cases of dilated or restrictive cardiomyopathy.8– 11 Left ventricular (LV) hypertrophy and diastolic dysfunction at Doppler echocardiography have been described in individual cases of patients affected by GD1.12,13 However, no study has analyzed yet LV geometry and function in a series of consecutive GD patients. Accordingly, the aim 1
Lo Iudice, et al.
of the present study was to investigate whether subclinical LV myocardial abnormalities can be detected in a group of patients with GD1. Methods: Study Population: After obtaining informed consent, 18 consecutive patients with ascertained GD1 (7 males, 11 females) free of clinical symptoms and signs attributable to heart failure (mainly dyspnoea, palpitations, and peripheral edema) were studied. The mean age was 46 11 years; mean age at diagnosis of GD1 was 29 11 years. All GD1 patients, except one, were on enzyme replacement therapy, 15 with cerezyme and two with velaglucerase (mean duration 13 7 years, mean dose 28.8 9.8 IU/kg/14 days), 3 were splenectomized. Nine GD1 patients had comorbidity with arterial hypertension (6 treated with antihypertensive drugs, monotherapy, or multiple therapy including b-blockers [n = 3], RAS inhibitors [n = 3], thiazide diuretic [n = 3], and calcium channel blockers [n = 1]), 10 were dyslipidemic, 2 were affected by type 2 diabetes mellitus. Eighteen age- and sex-matched normal controls and 18 age- and sex-matched hypertensive patients were also studied. In the hypertensive group, 12 were under antihypertensive treatment (monotherapy or multiple therapy including b-blockers,5 RAS inhibitors,5 thiazide diuretics,7 and calcium channel blockers2). All subjects underwent standard echo Doppler examination at rest. Procedures: Standard echo Doppler examination: Echo Doppler examinations were performed by a Vivid E9 ultrasound scanner (GE, Milwaukee, WI, USA) equipped with a 2.5 MHz phased array transducer according to the standards of our laboratory.14,15 Two-dimensional measurements of LV end-diastolic and end-systolic volumes were done by the modified Simpson method (apical four- and two-chamber views) and ejection fraction was derived.16 Left atrial volume was measured at LV end-systole (measurements in apical four- and two-chamber views) by using the arealength method and indexed for body surface area (left atrial volume index).16 Transmitral pulsed Doppler was recorded in the apical four-chamber view at the tips level. Early (E) and atrial (A) peak velocities (m/sec) and their ratio, E velocity deceleration time (DT), and atrial filling fraction (AFF = time-velocity integral of A velocity/time-velocity integral of total diastole 9 100) 17 were measured. Pulsed tissue Doppler sample volume was placed at the septal and lateral mitral annulus in apical four-chamber
2
view; early diastolic velocity (e0 ) was measured at both septal and lateral annulus and averaged as recommended.18 The ratio of transmitral peak E velocity to peak e0 velocity was calculated as an estimate of LV filling pressure by averaging e0 of 2 sites (septal and lateral: E/e0 ratio).18 E/e0 ratio has been prognostically validated in patients with chronic and acute heart failure.18,19 All reported echo Doppler measurements were averaged from 3 cardiac cycles. Statistical Analysis: The analysis was performed using SPSS for Windows, release 14.0 (Chicago, IL, USA). All continuous variables were expressed as mean 1 standard deviation. Intergroup comparisons were done using one-way ANOVA, with post hoc analyses carried out using Ryan–Einot–Gabriel–Welsch F-test. Two-way ANOVA was used to establish the impact of both hypertension and GD1 and their interaction on the assessed parameters. Results: Clinical Characteristics: Table I summarized the clinical characteristics of the three study groups. They were homogeneous for anthropometrics. Both systolic blood pressure (P = 0.006) and diastolic blood pressure (P < 0.001) were significantly higher in hypertensive patients compared to GD1 patients and normal controls. Heart rate was also higher in the hypertensive group compared to the other two (P = 0.014). Calcification and Valve Involvement: Calcification was evident in 8 GD1 patients: 4 presented calcifications of the mitral subvalvular apparatus, 3 had calcification of the aortic valve cusps, and 1 had pericardial calcification. The total prevalence of calcification in our GD1 was 44% (n = 8/18). Mild mitral regurgitation was present only in 2 patients, whereas 9 had trivial mitral regurgitation. Only 1 patient had mild aortic regurgitation. LV and Left Atrial Geometry and Function: No significant difference in LV mass index and relative wall thickness was found among the 3 groups. Also, LV volumes, ejection fraction, and left atrial volume index did not show significant intergroup difference (Table II). LV Diastolic Function: Transmitral E/A ratio was lower in the hypertensive group compared to the other two (P < 0.05). E velocity DT was longer in GD1 patients compared to both hypertensive patients and normal controls (P = 0.009). AFF was greater
Gaucher Disease and Diastole
TABLE I Clinical Characteristics of the Study Groups
Parameter Age (years) Height (m) Weight (kg) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min)
NC (n = 18) 45.7 1.66 70.0 25.3 126.3 77.7 68.6
10.5 0.10 13.9 3.4 13.1 9.4 11.1
GD1 (n = 18) 46.4 1.67 75.1 26.7 133.7 80.7 66.0
10.2 0.10 14.6 4.2 10.8 8.3 9.3
HTN (n = 18) 47.6 1.65 73.2 26.7 147.1 92.3 77.1
10.1 0.11 13.2 3.2 25.7 13.1 13.3
P Overall NS NS NS NS 0.006
Echocardiography
ORIGINAL INVESTIGATION
Left Ventricular Diastolic Dysfunction in Type I Gaucher Disease: An Echo Doppler Study Francesco Lo Iudice, M.D.,* Antonio Barbato, M.D.,† Riccardo Muscariello, M.D.,† Carlo Di Nardo, M.D.,* Francesco de Stefano, M.D.,† Michelina Sibilio, M.D.,‡ Pasquale Strazzullo, M.D.,† Giovanni de Simone, M.D.,* and Maurizio Galderisi, M.D.* *Hypertension Research Center and Department of Medical Translational Sciences, Federico II University Hospital, Naples, Italy; †Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy; and ‡Division of Pediatrics and Neonatology, Moscati Hospital, Aversa (CE), Italy
Type I Gaucher disease (GD1) is an autosomal recessive lysosomal storage disease characterized by multiorgan damage. Left ventricular (LV) involvement has been rarely reported. Accordingly, the aim of the study was to evaluate LV geometry and function in a series of patients with GD1. Eighteen patients with GD1, 18 age- and sex-matched normal controls, and 18 age- and sex-matched hypertensive patients (HTN) were compared by standard echo Doppler examination. LV mass index, relative wall thickness and ejection fraction, transmitral E/A ratio, E velocity deceleration time (DT), atrial filling fraction (AFF = time-velocity integral of A velocity/time-velocity integral of total diastole 9 100), E/e0 ratio, and left atrial volume index were determined. Nine GD1 patients also exhibited arterial hypertension. The intergroup difference of LV mass index and relative wall thickness was not significant. Transmitral E/A ratio was lower in HTN than in normal controls and GD1 (P < 0.05). GD1 exhibited longer DT than NC and HTN (P = 0.009). AFF was higher in GD1 and HTN compared to NC (P = 0.034). After adjustment for heart rate, GD1 was associated with longer DT (P < 0.001) and greater AFF (P = 0.036), while HTN was associated only with AFF (P = 0.013). No interaction was found between GD1 and HTN. In conclusion, GD1 is associated with subclinical LV diastolic dysfunction, which is independent of the coexistence of arterial hypertension. Subclinical LV impaired relaxation in the context of myocardial infiltrative damage could be the mechanism underlying these alterations. (Echocardiography 2014;00:1–6) Key words: Gaucher disease, echocardiography, left ventricle, diastole, atrial filling fraction
Gaucher disease (GD) is an hereditary autosomal recessive lysosomal storage disease caused by deficiency of the enzyme b-glucosidase leading to accumulation of glucosylceramide—a sphingolipid mainly found in cell membranes—in macrophages (Gaucher cells). GD occurs in three different forms: a nonneuropathic form (Type I), an acute neuropathic form, fatal within the first years of life (Type II), and a subacute juvenile neuropathic form (Type III).1 In Type I GD (GD1), the main involvement is the accumulation of glucosylceramide in the liver, spleen, and bone marrow, which causes organomegaly, stimulates inflammatory pathways, and yields tissue fibrosis.2 The most frequent clinical manifestations of GD1 are hepatosplenomegaly, bone marrow Address for correspondence and reprint requests: Maurizio Galderisi, M.D., Echocardiography Laboratory, Hypertension Research Center, Federico II University Hospital of Naples, Via S. Pansini 5, Edificio 1, 80131 Naples, Italy. Fax: +39-81-5466152; E-mail: [email protected]
expansion, cortical bone mineral losses, and both hypoproductive- and consumptive-based anemia and thrombocytopenia.1 The lungs can be less frequently involved with pulmonary hypertension and consequent right ventricular overload.3 Clinically overt, direct involvement of the heart is uncommon.4–12 Cases of pericardial disease, with hemorrhagic or constrictive pericarditis and pericardial calcification have been observed.4 Valvular heart disease (mitral and aortic fibrocalcification and stenosis, often resembling rheumatic disease) has also been associated with GD,5,6 especially with the subtype of the subacute neuropathic form (Type IIIc).7 Clinically overt myocardial involvement is reported in few cases of dilated or restrictive cardiomyopathy.8– 11 Left ventricular (LV) hypertrophy and diastolic dysfunction at Doppler echocardiography have been described in individual cases of patients affected by GD1.12,13 However, no study has analyzed yet LV geometry and function in a series of consecutive GD patients. Accordingly, the aim 1
Lo Iudice, et al.
of the present study was to investigate whether subclinical LV myocardial abnormalities can be detected in a group of patients with GD1. Methods: Study Population: After obtaining informed consent, 18 consecutive patients with ascertained GD1 (7 males, 11 females) free of clinical symptoms and signs attributable to heart failure (mainly dyspnoea, palpitations, and peripheral edema) were studied. The mean age was 46 11 years; mean age at diagnosis of GD1 was 29 11 years. All GD1 patients, except one, were on enzyme replacement therapy, 15 with cerezyme and two with velaglucerase (mean duration 13 7 years, mean dose 28.8 9.8 IU/kg/14 days), 3 were splenectomized. Nine GD1 patients had comorbidity with arterial hypertension (6 treated with antihypertensive drugs, monotherapy, or multiple therapy including b-blockers [n = 3], RAS inhibitors [n = 3], thiazide diuretic [n = 3], and calcium channel blockers [n = 1]), 10 were dyslipidemic, 2 were affected by type 2 diabetes mellitus. Eighteen age- and sex-matched normal controls and 18 age- and sex-matched hypertensive patients were also studied. In the hypertensive group, 12 were under antihypertensive treatment (monotherapy or multiple therapy including b-blockers,5 RAS inhibitors,5 thiazide diuretics,7 and calcium channel blockers2). All subjects underwent standard echo Doppler examination at rest. Procedures: Standard echo Doppler examination: Echo Doppler examinations were performed by a Vivid E9 ultrasound scanner (GE, Milwaukee, WI, USA) equipped with a 2.5 MHz phased array transducer according to the standards of our laboratory.14,15 Two-dimensional measurements of LV end-diastolic and end-systolic volumes were done by the modified Simpson method (apical four- and two-chamber views) and ejection fraction was derived.16 Left atrial volume was measured at LV end-systole (measurements in apical four- and two-chamber views) by using the arealength method and indexed for body surface area (left atrial volume index).16 Transmitral pulsed Doppler was recorded in the apical four-chamber view at the tips level. Early (E) and atrial (A) peak velocities (m/sec) and their ratio, E velocity deceleration time (DT), and atrial filling fraction (AFF = time-velocity integral of A velocity/time-velocity integral of total diastole 9 100) 17 were measured. Pulsed tissue Doppler sample volume was placed at the septal and lateral mitral annulus in apical four-chamber
2
view; early diastolic velocity (e0 ) was measured at both septal and lateral annulus and averaged as recommended.18 The ratio of transmitral peak E velocity to peak e0 velocity was calculated as an estimate of LV filling pressure by averaging e0 of 2 sites (septal and lateral: E/e0 ratio).18 E/e0 ratio has been prognostically validated in patients with chronic and acute heart failure.18,19 All reported echo Doppler measurements were averaged from 3 cardiac cycles. Statistical Analysis: The analysis was performed using SPSS for Windows, release 14.0 (Chicago, IL, USA). All continuous variables were expressed as mean 1 standard deviation. Intergroup comparisons were done using one-way ANOVA, with post hoc analyses carried out using Ryan–Einot–Gabriel–Welsch F-test. Two-way ANOVA was used to establish the impact of both hypertension and GD1 and their interaction on the assessed parameters. Results: Clinical Characteristics: Table I summarized the clinical characteristics of the three study groups. They were homogeneous for anthropometrics. Both systolic blood pressure (P = 0.006) and diastolic blood pressure (P < 0.001) were significantly higher in hypertensive patients compared to GD1 patients and normal controls. Heart rate was also higher in the hypertensive group compared to the other two (P = 0.014). Calcification and Valve Involvement: Calcification was evident in 8 GD1 patients: 4 presented calcifications of the mitral subvalvular apparatus, 3 had calcification of the aortic valve cusps, and 1 had pericardial calcification. The total prevalence of calcification in our GD1 was 44% (n = 8/18). Mild mitral regurgitation was present only in 2 patients, whereas 9 had trivial mitral regurgitation. Only 1 patient had mild aortic regurgitation. LV and Left Atrial Geometry and Function: No significant difference in LV mass index and relative wall thickness was found among the 3 groups. Also, LV volumes, ejection fraction, and left atrial volume index did not show significant intergroup difference (Table II). LV Diastolic Function: Transmitral E/A ratio was lower in the hypertensive group compared to the other two (P < 0.05). E velocity DT was longer in GD1 patients compared to both hypertensive patients and normal controls (P = 0.009). AFF was greater
Gaucher Disease and Diastole
TABLE I Clinical Characteristics of the Study Groups
Parameter Age (years) Height (m) Weight (kg) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min)
NC (n = 18) 45.7 1.66 70.0 25.3 126.3 77.7 68.6
10.5 0.10 13.9 3.4 13.1 9.4 11.1
GD1 (n = 18) 46.4 1.67 75.1 26.7 133.7 80.7 66.0
10.2 0.10 14.6 4.2 10.8 8.3 9.3
HTN (n = 18) 47.6 1.65 73.2 26.7 147.1 92.3 77.1
10.1 0.11 13.2 3.2 25.7 13.1 13.3
P Overall NS NS NS NS 0.006
