Right Ventricular Hypertrophy, Systolic Function, and Disease Severity in Anderson-Fabry Disease: An Echocardiographic Study

Right Ventricular Hypertrophy, Systolic Function, and Disease Severity in Anderson-Fabry Disease: An Echocardiographic Study Francesca Graziani, MD, PhD, Marianna Laurito, MD, Maurizio Pieroni, MD, PhD, Faustino Pennestr
ı, MD, Gaetano Antonio Lanza, MD, Valentina Coluccia, MD, Antonia Camporeale, MD, Daniela Pedicino, MD, Elena Verrecchia, MD, Raffaele Manna, MD, and Filippo Crea, MD, Rome, Arezzo, and San Donato Milanese, Italy

Background: Right ventricular (RV) involvement has been described in Anderson-Fabry disease (AFD), especially in patients with established Fabry cardiomyopathy (FC). However, few and controversial data on RV systolic function are available, and there are no specific tissue Doppler studies. Methods: Detailed echocardiographic examinations were performed in 45 patients with AFD. FC, defined as maximal left ventricular wall thickness $ 15 mm, was present in 12. The Mainz Severity Score Index was calculated for each patient. Pulsed tissue Doppler was applied to the RV free wall at the tricuspid annular level and at the septal and lateral corners at the mitral annular level to obtain systolic tissue Doppler velocities (RV Sa, septal Sa, and lateral Sa, respectively). Twelve patients with amyloid light-chain cardiac amyloidosis were studied as a control group. Results: Echocardiography revealed RV hypertrophy (RVH) in 31% of patients with AFD, all but one of whom were male and all of whom had concomitant left ventricular hypertrophy (LVH). All patients with AFD had normal RV fractional area change (47.9 6 6.5%) and tricuspid annular plane systolic excursion (21.7 6 3.2 mm) and all but one also had normal RV Sa (13.2 6 2.2 cm/sec). RVH positively correlated with indices of LVH (r = 0.8, P = .0001, for all parameters evaluated), as well as with Mainz Severity Score Index (r = 0.70, P = .0001). Septal and lateral Sa were decreased in almost all patients (means, 7.7 6 1.8 and 7.9 6 1.9 cm/sec, respectively), irrespective of the presence of LVH. Compared with control subjects with cardiac amyloidosis, patients with FC showed better indices of RV systolic function (P < .001 for all: tricuspid annular plane systolic excursion, RV fractional area change, and RV Sa) despite similar RV wall thickness (6.2 6 1.2 vs 6.9 6 1.9 mm, P = NS). Conclusions: RVH is common in patients with AFD and correlates with disease severity and LVH. RVH, however, does not significantly affect RV systolic function. Patients with FC have better RV systolic function compared with those with cardiac amyloidosis with similar levels of RV thickness. The combination of low LV Sa values and normal RV Sa values might be helpful in the differential diagnosis of infiltrative heart disease. (J Am Soc Echocardiogr 2016;-:---.) Keywords: Fabry, Cardiomyopathy, RVH, LVH, Tissue Doppler

Anderson-Fabry disease (AFD) is a rare genetic lysosomal storage disorder caused by deficient activity of the enzyme a-galactosidase A, leading to progressive intracellular accumulation of neutral glycosphingolipids in different organs, including the heart.1 From the Department of Cardiovascular Sciences (F.G., M.L., F.P., G.A.L., V.C.,
D.P., F.C.) and the Department of Internal Medicine (E.V., R.M.), Universita Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; the Cardiovascular Department, San Donato Hospital, Arezzo, Italy (M.P.); and Multimodality Cardiac Imaging, San Donato Milanese Hospital, San Donato Milanese, Italy (A.C.). Reprint requests: Francesca Graziani, MD, PhD, Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli, Largo Agostino Gemelli 8, 00168 Rome, Italy (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2016 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2016.11.014

Cardiac involvement is common and remains one of the most important causes of morbidity and mortality in affected patients.2 Left ventricular (LV) hypertrophy (LVH) is the hallmark of cardiac involvement in AFD, and concentric hypertrophic cardiomyopathy (also called Fabry cardiomyopathy [FC]) is the classic cardiac phenotype, affecting mainly middle-aged men.3 Of note, although conventional measures of LV systolic function are usually within the normal range in patients with AFD,3 tissue Doppler (TD) studies revealed abnormal contraction velocities not only in patients with FC4 but also in carriers of the a-galactosidase A gene mutation without LVH.5 Although right ventricular (RV) involvement has been described in patients with AFD, few and conflicting data regarding RV systolic function are available,6,7 and none of them included TD. Thus, in this study we aimed to assess the prevalence of RV hypertrophy (RVH) and RV systolic function, as detected by standard echocardiography, as well as its relation with disease severity, in patients with AFD. 1

2 Graziani et al

Abbreviations

AFD = Anderson-Fabry disease

Journal of the American Society of Echocardiography - 2016

METHODS Study Population

We performed detailed echocardiographic examinations in 45 patients (25 men; mean age, FAC = Fractional area change 52 6 16) belonging to 20 different families, with docuFC = Fabry cardiomyopathy mented diagnoses of AFD, on GFR = Glomerular filtration the basis of reduced a-galactosirate dase A activity in peripheral blood lymphocytes and/or geLV = Left ventricular netic analysis. Exclusion criteria LVEF = Left ventricular included age < 18 years and ejection fraction inadequate image quality. LVH = Left ventricular Weight, height, blood pressure, hypertrophy and heart rate were measured at the time of echocardiography. MSSI = Mainz Severity Score All patients underwent extenIndex sive clinical and instrumental MWT = Maximal wall assessment of AFD manifestathickness tions, and the Mainz Severity PWT = Posterior wall Score Index (MSSI), as an expresthickness sion of disease severity, was obtained for each patient as RV = Right ventricular previously described.8 In brief, RVH = Right ventricular the MSSI is composed of four sechypertrophy tions, each assessing the general, neurologic, cardiovascular, and RVWT = Right ventricular wall renal involvement of the disease thickness (each with a 0- to 4-point score). SWT = Septal wall thickness Higher scores indicate more seTAPSE = Tricuspid annular vere involvement. The individual plane systolic excursion scores are summed to calculate the total MSSI score, on the basis TD = Tissue Doppler of which patients are classified as 2D = Two-dimensional having mild (<20), moderate (20–40), or severe (>40) AFD. Briefly, organ and system involvement was defined as follows: kidney involvement was defined as presence of glomerular filtration rate (GFR) < 60 mL/m2, microalbuminuria or proteinuria >300 mg/day, previous kidney transplantation, or need for hemodialysis. Brain involvement was defined by a history of cerebrovascular event requiring hospitalization or white matter lesions on magnetic resonance imaging compatible with AFD. Neuropathy was assessed clinically with acroparesthesia, diaphoresis, heat or cold intolerance, or fever pain crisis. Ear involvement was defined by tinnitus, vertigo, dizziness, high-frequency hearing loss, or sudden deafness. Eye involvement was defined as the presence of cornea verticillata, posterior subcapsular cataract, or tortuous vessels. Skin involvement was defined as the presence of angiokeratoma or telangiectasia. Gastrointestinal involvement was defined clinically by the presence of gastritis or ulcer, pancreatitis, or symptoms such as abdominal pain, nausea, vomiting, and diarrhea or constipation with no other explanation. The presence of FC was defined by echocardiographic LV maximal wall thickness (MWT) $ 15 mm.9 Patients with AFD were thus classified as FC+ (MWT $ 15 mm) or FC
(MWT < 15 mm). To assess whether RV characteristics were distinctive of FC, we compared echocardiographic data from FC+ patients with those of a group of patients (n = 12) with cardiac amyloidosis (CA) who also showed significant LVH (MWT $ 15 mm) on echocardiography. CA = Cardiac amyloidosis

All these patients had biopsy-proven diagnoses of systemic amyloid light-chain amyloidosis, with a clonal plasma cell disorder. The study was in compliance with the Declaration of Helsinki. The research protocol was approved by the local ethics committee, and informed consent was obtained from all participants. Echocardiography All echocardiographic studies were performed using a Toshiba Artida ultrasound system (TA-700; Toshiba, Tokyo, Japan) equipped with a 3.5-MHz probe according to American Society of Echocardiography guidelines.10 Patients were imaged and data analyzed by two independent operators; measurements were averaged over three heartbeats in sinus rhythm and five heartbeats in atrial fibrillation. The following echocardiographic M-mode and bidimensional parameters were evaluated: LV end-diastolic diameter, LV end-systolic diameter, septal wall thickness (SWT), and LV posterior wall thickness (PWT). LV end-diastolic and end-systolic volumes and LV ejection fraction (LVEF) were estimated using the biplane Simpson method. Pulsedwave Doppler recordings of mitral and tricuspid inflow velocities were obtained. A comprehensive assessment of RV geometry and systolic function was obtained from apical four-chamber (Figure 1A), RV-focused apical four-chamber, and modified apical four-chamber, left parasternal long- and short-axis, left parasternal RV inflow, and subcostal views.11 Two-dimensional (2D) linear and 2D-guided M-mode measurement of RV free wall thickness (RVWT) were performed from the subcostal view (Figure 1B) at end-diastole, below the tricuspid annulus, at a distance approximating the length of the anterior tricuspid leaflet when it was fully open and parallel to the RV free wall. Trabeculae, papillary muscles and epicardial fat were excluded from the measurement. Zoomed imaging with focus on the RV mid-wall and respiratory maneuvers were used to improve endocardial border definition. The two measures were averaged. RVH was defined as RV wall thickness (RVWT) > 5 mm.11 Tricuspid annular plane systolic excursion (TAPSE) was measured by 2D-guided M-mode tracing with the cursor optimally aligned along the direction of the tricuspid lateral annulus in the apical four-chamber view (Video 1 available at www.onlinejase.com). TAPSE < 17 mm was considered suggestive of RV systolic dysfunction. RV fractional area change (FAC) was assessed to provide an estimate of global RV systolic function, using the formula RV FAC (%) = 100  (end-diastolic area
end-systolic area)/end-diastolic area. Measurements were performed ensuring that the entire RV chamber was contained in the imaging sector, including the apex and the free wall, during both systole and diastole. While tracing the RV area, care was taken to include the trabeculae in the RV cavity. RV FAC < 35% was considered indicative of RV systolic dysfunction. TD was applied using pulsed spectral mode to record mitral annular velocities at septal (Figure 1C) and lateral corners. Systolic (septal Sa, lateral Sa), early diastolic (Ea), and late diastolic (Aa) TD velocities were measured. Normal septal Sa was considered >8.5 cm/ sec, and normal lateral Sa was considered >10 cm/sec.12 Pulsed spectral Doppler was also applied to the RV free wall (Figure 1D) at the tricuspid annular level (RV Sa). An RV Sa velocity < 9.5 cm/sec measured on the free wall side was considered suggestive of RV systolic dysfunction.10 Myocardial performance index was obtained by Color TD recordings by the sum of isovolumetric contraction and relaxation times divided by the ejection time, and a value >0.54 was considered

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Graziani et al 3

Figure 1 (A) Two-dimensional echocardiogram, apical four-chamber view, showing severe LVH (blue arrows) and RVH (red arrow). (B) Representative example of 2D measurement of the RV free wall from zoomed subcostal view (red arrow). (C) Pulsed-wave TD recording of septal annular mitral velocities showing significantly decreased systolic annular velocity (red arrow: septal Sa = 3 cm/ sec). (D) Pulsed-wave TD recording of the RV free wall at the tricuspid annular level showing normal systolic annular velocity (red arrow: RV Sa = 10 cm/sec). abnormal.10 RV diastolic function was defined according to American Society of Echocardiography guidelines.11 Statistical Analysis Continuous variables are expressed as mean 6 SD, and dichotomous variables are shown as numbers and percentages. Differences between groups were assessed using two-tailed unpaired Student’s t tests and c2 tests for continuous and dichotomous variables, respectively. Linear regression analysis was performed to correlate the echocardiographic parameters and the clinical variables, such as age and MSSI. Multivariate logistic regression analysis was performed to identify independent predictors of RV Sa in the AFD population. Variables with P values <.05 on univariate analysis were included in the model. Beta values and P values are reported. Statistical analyses were done using SPSS version 20.0 (SPSS Italia, Florence, Italy). Statistical significance was defined as P < .05. RESULTS General Characteristics of Patients with AFD Clinical characteristics and extracardiac manifestations in patients with AFD according to the presence or absence of FC are reported in Table 1. Causal mutations identified in the 20 families are reported in Table 2.

Kidney involvement was present in 24 patients (53%; 16 men), three of whom had undergone kidney transplantation and had GFRs <30 mL/min (all men). The remaining 21 patients had GFRs between 49 and 163 mL/min with some degree of proteinuria. Histories of cerebrovascular events (three ischemic, one hemorrhagic) were present in four patients. Other relevant findings included neuropathic pain in 20 patients (44%; 12 men), eye involvement (mainly cornea verticillata) in 19 (36%; 11 men), angiokeratoma in 11 (24%; eight men), and audiovestibular dysfunction in 18 (40%; 13 men). In terms of cardiac involvement, 29 patients were in New York Heart Association functional class I, 14 in class II, and two in class III (both men with severe LVH and on hemodialysis). None had been hospitalized for heart failure in the previous 4 years. Paroxysmal atrial fibrillation was documented in one patient, whereas permanent atrial fibrillation was present in two; episodes of nonsustained ventricular tachycardia were detected on Holter monitoring in five patients (all men). Four patients were on thiazide diuretic therapy for hypertension (two men), and no patients were on loop diuretics. Five patients (11%) had histories of typical angina, two of whom underwent percutaneous coronary intervention (both men), whereas three showed no obstructive coronary atherosclerosis (all men with severe LVH).

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Table 1 Clinical characteristics of the AFD population according to the presence or absence of FC and RVH Overall n = 45

FC
n = 33

FC+ n = 12

P

RVH
n = 31

RVH+ n = 14

P

Age (y)

52 6 16

48 6 16

61 6 10

*

49 6 17

58 6 12

*

Male/female

25/20

14/19

11/1

*

13/18

13/1

*

Weight (kg)

73.3 6 11.7

74 6 11

72 6 14

NS

73 6 11

74 6 14

NS

BMI (kg/m2)

24.9 6 3.8

25 6 3

24 6 4

NS

25 6 4

24 6 4

NS

Systolic BP (mm Hg)

121 6 14

121 6 14

124 6 16

NS

121 6 14

122 6 15

NS

Diastolic BP (mm Hg)

76 6 9

77 6 9

74 6 10

NS

77 6 9

76 6 10

NS

Hypertension

16 (36)

Diabetes Kidney Brain Neuropathy

8 (24%)

8 (67%)

* NS

8 (26)

8 (57)

* NS

2 (4)

1 (3%)

1 (8%)

1 (4)

1 (7)

24 (53)

14 (42%)

10 (83%)

*

12 (39)

12 (86)

7 (15)

5 (15%)

2 (17%)

*

6 (20)

1 (7)

NS

20 (44)

14 (42%)

6 (50%)

NS

11 (36)

9 (64)

NS

*

Ear

18 (40)

9 (28%)

9 (75%)

*

7 (23)

11 (79)

*

Eye

16 (36)

9 (28%)

7 (58%)

NS

7 (23)

9 (64)

*

Skin

11 (24)

8 (24%)

3 (25%)

NS

7 (23)

4 (29)

NS

Gastrointestinal

13 (29)

10 (30%)

3 (25%)

NS

9 (29)

4 (29)

NS

Creatinine (mg/dL)

1.0 6 0.56

0.8 6 0.2

1.5 6 0.9

†

0.8 6 0.2

1.5 6 0.8

†

GFR (mL/min)

98.2 6 36.1

110 6 28

62 6 34

†

112 6 29

70 6 33

†

Proteinuria (g/L)

0.3 6 0.4

0.25 6 0.46

0.41 6 0.34

NS

0.3 6 0.5

0.3 6 0.3

NS

MSSI

22 6 16

15 6 11

38 6 13

†

13 6 9

39 6 11

†

ERT

32 (71)

20 (60%)

12 (100%)

*

18 (58)

14 (100)

*

BMI, Body mass index; BP, blood pressure; ERT, enzyme replacement therapy. Data are expressed as mean 6 SD or as number (percentage). *P < .01. † P # .0001.

Echocardiographic Findings LV Findings in AFD. The main echocardiographic findings according to the presence of FC and RVH are summarized in Table 3. FC was found in 12 patients (27%; 11 men, six with MWT > 20 mm). No LVH (MWT < 12 mm) was found in 16 patients (35%; four men), whereas mild to moderate LVH (MWT 12–14.9 mm) was found in 17 (38%; 10 men). LVEF was lower in FC+ compared with FC
patients (56.4 6 5.8% vs 64.9 6 4.5%, P < .0001) (Figure 2A). All but four patients had normal LVEFs. The four patients with abnormal LVEFs showed only mild LVEF reduction (range, 48%–50%). All were male and had severe LVH (MWT ranging from 18 to 28 mm). Patients with FC also showed significantly lower values of septal as well as lateral Sa velocities compared with those without FC (5.6 6 1.5 vs 8.4 6 1.3 [P = .0001] and 6.8 6 2.0 vs 8.9 6 1.7, P = .008) (Figure 2B). Of note, Sa velocities at both septal and lateral corners were decreased in the majority of patients. Figure 3A shows the correlation between septal Sa and SWT. MSSI had significant positive correlations with all indices of LVH: PWT, SWT, and LV mass (r = 0.8, P = .0001, for all). MSSI negatively correlated with indices of LV systolic function (LVEF: r =
0.5, P = .0001; septal Sa: r =
0.7, P = .0001; lateral Sa: r =
0.5, P = .01). All the correlation analysis were confirmed after adjustment for age. Finally, grade I diastolic dysfunction was observed in 18 patients (40%) and grade II diastolic dysfunction in three patients (7%). No patient showed grade III diastolic dysfunction.

RV Findings in AFD. The main clinical findings in patients with or without RVH are summarized in Table 1, and echocardiographic data are shown in Table 2. RVH was found in 14 patients (31%), 13 of whom were male. All patients with RVH had some degree of LVH (11 had overt FC and three had mild to moderate LVH). All patients had normal RV FAC and TAPSE values. Similarly, all patients had normal RV Sa values, except one male patient who showed the most severe disease (MSSI = 60) and only mild RVH (RVWT = 5 mm). There was no difference in TAPSE (21 6 3.5 vs 22.2 6 2.7, P = .2; Figure 2C), whereas RV FAC (49.3 6 5.6 vs 44.6 6 7.3, respectively, P = .05) and RV Sa (12 6 2.6 vs 13.7 6 1.8, respectively, P = .04; Figure 2D) values showed slight differences. We found a strong correlation between RVH and LVH (r = 0.8, P = .0001, for the correlations between RVWT and SWT, PWT, MWT, and LV mass). Furthermore, RVWT also showed significant inverse correlations with indices of LV systolic function (LVEF: r =
0.5, P = .0001; septal Sa: r =
0.7, P = .0001; lateral Sa: r =
0.6, P = .0001). In contrast, TAPSE and RV FAC showed no correlation with indices of LV function or RVWT, and only a weak correlation of RVWT with RV Sa was found (r =
0.3, P = .03). Figure 3B shows the correlation between RV Sa and RVWT. MSSI significantly correlated with RVWT (r = 0.7, P = .0001). MSSI had no correlation with TAPSE or RV FAC but negatively correlated with RV Sa (r =
0.5, P = .001). All the correlation analyses were corrected for age. Moreover, we performed a multivariate analysis in

Graziani et al 5

Journal of the American Society of Echocardiography Volume - Number -

Table 2 GLA mutation and a-GAL-A activity a-GAL-A activity on leukocytes Family

Age/gender

(nmol/mg/hr)

1

44/F

—

1

79/M

6.9

2

41/F

—

3

63/M

4.4

3

65/F

—

4

28/M

6.1

5

57/M

4.0

5

56/M

5

(%)

—

GLA mutation

a-GAL A protein effect

Reference

c.937G>T

p.(Asp313Tyr)

Lenders et al., 2013

c.937G>T

p.(Asp313Tyr)

Lenders et al., 2013

—

c.868A>C

p.Met290Leu

Davies et al., 1993

13.6

c.647A>G

p.Tyr216Cys

Filoni et al., 2010

—

c.647A>G

p.Tyr216Cys

Filoni et al., 2010

14.4

c.644A>G

p.(ans215Ser)

Davies et al., 1993

9.5

c.548G>C

p. Gly183Ala

Filoni et al., 2010

0.9

2.2

c.548G>C

p. Gly183Ala

Filoni et al., 2010

29/F

—

—

c.548G>C

p. Gly183Ala

Filoni et al., 2010

5

26/F

—

—

c.548G>C

p. Gly183Ala

Filoni et al., 2010

6

40/M

3.1

7.2

c.123_126dupCATG

p.(Gly43Hisfs*14)

Morrone et al., 2003

7

47/M

5.1

c.644A>G

p.(ans215Ser)

Davies et al., 1993

8

43/F

—

—

c.758T>C

p.Ile253Thr

Scott et al., 2013

8

68/M

0.8

2.0

c.758T>C

p.Ile253Thr

Scott et al., 2013

9

44/M

4.1

9.7

c.1133G>A

p.Cys378Tyr

Topaloglu et al., 1999

10

70/F

—

—

c.644A>G

p.(ans215Ser)

Davies et al., 1993

11

52/M

2.1

4.9

c.639+1G>A

Splicing alteration

Rodriguez Mari et al., 2003

12

80/F

—

—

c.644A>G

p.(ans215Ser)

Davies et al., 1993

13

38/M

6.7

15.7

c.730G>A

p.(Asp244Asn)

Guffon et al., 1998

14

36/M

2.5

5.8

c907A>T

p.(Ile303Phe)

Novel

15

30/M

2.1

4.9

c.439G>A

p.(Gly147Arg)

Schafer et al., 2005

10

49/M

5.1

10

44/F

—

15

58/F

16

58/M

17

66/F

10

16

12

12

c.644A>G

p.(ans215Ser)

Davies et al., 1993

—

c.644A>G

p.(ans215Ser)

Davies et al., 1993

—

—

c.439G>A

p.(Gly147Arg)

Schafer et al., 2005

6.7

15.7

c.644A>G

p.(ans215Ser)

Davies et al., 1993

—

—

c.680G>A

p.(arg227Gln)

Eng et al., 1993

70/M

7.7

18.2

c.644A>G

p.(ans215Ser)

Davies et al., 1999

4

70/F

—

—

c.644A>G

p.(ans215Ser)

Davies et al., 1993

4

67/M

8.1

19.6

c.644A>G

p.(ans215Ser)

Davies et al., 1993

16

78/M

2.0

4.7

c.644A>G

p.(ans215Ser)

Davies et al., 1993

18

29/F

—

—

c.747C>A

p.(Ans249Lys)

Duro et al., 2014

18

25/F

—

—

c.747C>A

p.(Ans249Lys)

Duro et al., 2014

18

50/M

3.2

7.7

c.747C>A

p.(Ans249Lys)

Duro et al., 2014

18

31/F

—

—

c.747C>A

p.(Ans249Lys)

Duro et al., 2014

2

46/M

3.0

7.1

c.868A>C

p.Met290Leu

Davies et al., 1993

6

72/F

—

—

c.123_126dupCATG

p.(Gly43Hisfs*14)

Morrone et al., 2003

19

52/M

2.5

5.8

c.547+1G>T

Splicing alteration

Ashton-Prolla et al., 2000

19

54/F

—

—

c.547+1G>T

Splicing alteration

Ashton-Prolla et al., 2000

12

40/M

6.5

15.4

c.644A>G

p.(ans215Ser)

Davies et al., 1993

20

49/M

2.6

6.1

c.119C>T

p.Pro40Leu

Ashton-Prolla et al., 2000

2

63/F

—

—

c.868A>C

p.Met290Leu

Davies et al., 1993

2

74/F

—

—

c.868A>C

p.Met290Leu

Davies et al., 1993

2

71/F

—

—

c.868A>C

p.Met290Leu

Davies et al., 1993

17

39/M

0.6

1.5

c.680G>A

p.(arg227Gln)

Eng et al., 1993

17

42/M

6.1

14.4

c.680G>A

p.(arg227Gln)

Eng et al., 1993

The normal range for a-GAL-A activity is 20 to 65 nmol/mg/hr. a-GAL-A activity was not measured in female patients.

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Journal of the American Society of Echocardiography - 2016

Table 3 Echocardiographic variables according to the presence or absence of FC and RVH FC
n = 33

48 6 16

Age (yrs) Range

25–80

FC+ n = 12

61 6 10 49–78

P † †

RVH
n = 31

49 6 17 25–80

RVH+ n = 14

58 6 12 36–78

P

* *

LVEDD (mm)

47.3 6 4.2

48.2 6 4.3

NS

46.9 6 4.0

49.0 6 4.4

NS

LVESD (mm)

28.2 6 4.3

28.2 6 5.2

NS

27.9 6 4.3

28.8 6 5.1

NS

LVEF (%)

64.9 6 4.5

56.4 6 5.8

‡

64.5 6 4.7

58.5 6 7.1

†

LA diameter (mm)

34.9 6 4.8

40.4 6 5.2

†

34.6 6 4.7

40.3 6 4.9

†

SWT (mm)

10.7 6 2.1

20.3 6 3.9

‡

10.7 6 2.4

18.9 6 4.8

‡

PWT (mm)

10.2 6 1.9

17.7 6 3.4

‡

10.2 6 2.1

16.5 6 4

‡

LV mass (g)

181.4 6 59.4

446.3 6 123.2

‡

179.8 6 63.8

412.1 6 139.9

‡

96.1 6 27

243 6 70.7

‡

96.1 6 31.0

222.2 6 81.2

‡

2

LV mass index (g/m ) LV E wave (cm/sec)

74.8 6 17.9

65.3 6 18.6

NS

74.2 6 18.8

67.9 6 17.3

NS

LV A wave (cm/sec)

63.6 6 17.1

73.3 6 16.1

NS

64.6 6 17.9

69.6 6 15.7

NS

LV E/A ratio

1.3 6 0.6

0.9 6 0.3

*

1.26 6 0.6

1 6 0.3

LV E/E0 ratio

6.9 6 1.8

12.4 6 1.6

‡

6.9 6 1.9

11.6 6 5.9

‡

NS

55.2 6 19.9

80.7 6 25.5

*

55.4 6 20.7

78.2 6 25.7

*

Septal Sa (cm/sec)

8.4 6 1.3

5.6 6 1.5

‡

8.4 6 1.3

6.1 6 1.9

‡

Lateral Sa (cm/sec)

8.9 6 1.7

6.8 6 2.0

†

8.9 6 1.7

6.9 6 1.9

‡

RVWT (mm)

3.5 6 1.0

6.9 6 1.9

‡

3.2 6 0.6

6.9 6 1.5

†

LA volume (mL)

RV mid diameter (mm)

23.9 6 4.1

27 6 5.4

NS

23.7 6 4.4

27.3 6 4.6

NS

RV E wave (cm/sec)

49.7 6 16

41.9 6 7.6

NS

48.6 6 16.5

43.5 6 10.8

NS

40 6 8.3

NS

31.7 6 8.8

43.9 6 8.7

†

1.5 6 0.3

1 6 0.2

‡

RV A wave (cm/sec)

34 6 11.1

RV E/A ratio

1.4 6 0.4

1 6 0.2

†

RA volume (mL)

39.9 6 17.3

51.3 6 24.1

NS

36.2 6 15.8

52.9 6 22.1

NS

RV MPI

0.48 6 0.1

0.51 6 0.1

NS

0.45 6 0.05

0.52 6 0.05

NS

IVC size (mm)

13.8 6 4.4

10.4 6 4.2

NS

13.8 6 4.9

11 6 4.4

NS

TR jet velocity (cm/sec)

206 6 22

235 6 13.8

NS

197 6 19.9

230 6 11.4

†

TAPSE (mm)

21.8 6 2.6

21.5 6 4.5

NS

22.2 6 2.7

21 6 3.5

RV FAC (%)

49.3 6 5.9

44.8 6 7.3

NS

49.3 6 5.6

44.6 6 7.3

*

RV Sa (cm/sec)

13.5 6 1.8

12.1 6 2.7

NS

13.7 6 1.8

12 6 2.6

*

NS

IVC, Inferior vena cava; LA, left atrial; LVEDD, LV end-diastolic diameter; LVESD, LV end-systolic diameter; MPI, myocardial performance index; RA, right atrial; TR, tricuspid regurgitation. Data are expressed as mean 6 SD. *P < .05. † P < .01. ‡ P < .0001.

an attempt to account for effects of age and comorbidities on RV Sa. We included all variables that were significant on univariate analysis (age, sex, MSSI score, GFR, MWT, and RVWT), and we found that only MSSI score was significant on multivariate analysis (P = .016, b =
0.69). Impaired RV relaxation was found in four patients (89%). No pseudonormal or restrictive type of RV filling was detected in any subject. FC versus CA. The main differences between FC+ patients and those with CA are summarized in Table 4. Compared with FC+ patients, those with CA were older (P = .01). LV diastolic function distribution was as follows in patients with CA: four grade I, five grade II, and three grade III. FC+ patients were characterized by worse LVH (SWT, P = .01) and larger LV end-diastolic diameters (P = .02) compared with patients with CA. Indices of diastolic function were worse in patients with

CA compared with FC+ patients (LV E, P = .002; LV E/A ratio, P = .01; LV E/e0 ratio, P = .01; Table 4). RVH was found in 10 of 12 patients with CA (83%). There was no difference in terms of RVH between the two groups (RVWT, P = .3). Patients with CA had lower TAPSE (P = .0001), RV FAC (P = .0001), and RV Sa (P = .001) values, while there was no difference in terms of RV myocardial performance index (P = .40). Inferior vena cava size was larger (P = .001) and tricuspid regurgitant jet velocity was higher (P = .0001) in patients with CA compared with FC+ patients. In patients with CA, RVWT was significantly correlated with LVH (SWT: P = .006, r = 0.74; PWT: P = .03, r = 0.62) and right atrial volume (P = .02, r = 0.65). TAPSE was positively correlated with septal Sa (P = .001, r = 0.71) and LV E/E0 ratio (P = .001, r =
0.81), whereas RV FAC and RV Sa were not. Septal Sa was inversely correlated with LVH (SWT: P = .007, r =
0.73; PWT: P = .0001, r =
0.86) and E/e0 (P = .008, r =
0.72).

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Journal of the American Society of Echocardiography Volume - Number -

Figure 2 Individual data points for LVEF (A), septal Sa (B), TAPSE (C), and RV Sa (D). Bars represent mean and SD. Dashed red lines indicate the normal reference value for each parameter. In (B) the red panel displays the abnormal range for septal Sa values; note that the majority of patients had low septal Sa values, irrespective of the presence of FC. In (D) the green panel displays the normal range for RV Sa values; note that all but one patient had normal RV Sa independent of the presence of RVH.

Figure 3 (A) Correlation between septal Sa and SWT. (B) Correlation between RV Sa and RVWT. DISCUSSION Our study shows that RV involvement in patients with AFD parallels LV structural changes and is a feature of advanced disease, as suggested by the fact that RVH was detectable only in those with concomitant LVH and was associated with the disease severity score.

The most interesting finding of our study, however, is that RVH does not seem to significantly affect RV systolic function. Although RV Sa was indeed slightly lower in patients with than in those without RVH, all parameters of RV systolic function were within the normal range in our population, in sharp contrast with the data for the left ventricle. Moreover, compared with patients with amyloid light-

8 Graziani et al

Journal of the American Society of Echocardiography - 2016

Table 4 Echocardiographic data in patients with FC and control patients with CA FC+ (n = 12)

CA (n = 12)

P

LV findings LVEDD (mm)

48.2 6 4.3

41.3 6 5.2

*

LVESD (mm)

28.2 6 5.2

25.2 6 5.2

NS

LVEF (%)

56.4 6 5.8

58 6 5.7

NS

LA diameter (mm)

40.4 6 5.2

43.3 6 5.5

NS

SWT (mm)

20.3 6 3.9

17.1 6 1.5

†

PWT (mm)

17.7 6 3.4

15.9 6 2.3

NS

LV E wave (cm/sec)

65.3 6 18.6

93.5 6 21.2

†

LV A wave (cm/sec)

73.3 6 16.1

66.5 6 29.4

LV E/A ratio

0.9 6 0.3

1.8 6 1.2

†

LV E/E0 ratio

12.4 6 1.6

20.9 6 9.2

†

LA volume (mL)

NS

80.7 6 25.5

95.2 6 24.6

NS

Septal Sa (cm/sec)

5.6 6 1.5

5.4 6 1.4

NS

Lateral Sa (cm/sec)

6.8 6 2.0

6.4 6 1.2

NS

RVWT (mm)

6.9 6 1.9

6.2 6 1.3

NS

RV mid diameter (mm)

27 6 5.4

25 6 3.4

NS

45 6 12.3

NS

RV findings

RV E wave (cm/sec)

41.9 6 7.6

RV A wave (cm/sec)

40 6 8.3

33 6 15

NS

1 6 0.2

1.3 6 0.3

NS

RV E/A ratio RA volume (mL)

51.3 6 24.1

51.3 6 24.1

NS

RV MPI

0.51 6 0.1

0.52 6 0.1

NS

IVC size (mm)

10.4 6 4.2

17.1 6 2.7

†

TR jet velocity (cm/sec)

235 6 13.8

274 6 38.5

TAPSE (mm)

21.5 6 4.5

14.2 6 2.6

‡

RV FAC (%)

44.8 6 7.3

29 6 6.9

‡

RV Sa (cm/sec)

12.1 6 2.7

8.8 6 1.2

†

‡

IVC, inferior vena cava; LA, left atrial; LVEDD, LV end-diastolic diameter; LVESD, LV end-systolic diameter; MPI, myocardial performance index; RA, right atrium; TR, tricuspid regurgitation. Data are expressed as mean 6 SD. *P < .05. † P < .01. ‡ P < .0001.

chain CA, those with FC showed better RV systolic function, although the two groups were similar in terms of RVH. Pieroni et al.5 first demonstrated that reduced myocardial contraction TD velocities of the left ventricle are detectable even before LVH develops in patients with AFD. They also showed that myocardial TD dysfunction was more pronounced in patients with compared with those without LVH. We confirm these data, measuring low LV TD contraction velocities in almost all patients with AFD, including those with normal LV wall thickness, and thus confirming the role of TD dysfunction as early marker of myocardial involvement. It must be emphasized that the finding of impaired LV parameters even in patients without LVH may provide an earlier window to initiate specific therapy. We also found worse TD velocities in patients with FC than in those without, probably because of a more extensive accumulation of storage material and more prominent cardiomyocyte hypertrophy in subjects with significant LVH.

Surprisingly, opposite results were observed when considering RV structure and function. Indeed, we not only found normal values of conventional markers of RV systolic function in all patients, but we also showed normal TD contraction velocities in all but one patient, even when significant RVH was present. These findings have no clear explanation, as we are dealing with a progressive storage disease, but we can speculate that a different accumulation of Gb3 in the left ventricle compared with the right ventricle might contribute to the different behavior. The extensive involvement of the right ventricle in AFD was shown by Sheppard et al.,13 who reported that nearly all myocytes within the right and left ventricles were hypertrophied, with marked vacuolization of the cytoplasm in three patients with AFD. On the other hand Pieroni et al.14 demonstrated at histology that in the left ventricle, Gb3 storage is more prominent in subendocardial layers of the myocardial wall, represented by longitudinal fibers that have a greater influence on pulsed-wave TD velocities. RV architecture is quite different, with a prevalence of oblique and clockwise rotating fibers and with longitudinal fibers confined to trabeculae.15 We can speculate that accumulation of Gb3 in the longitudinal fibers, which are prevalent on the left ventricle, allows early detection of abnormality by TD, while the different fiber arrangement in the right ventricle could account for the difference we found. RV Involvement in AFD RV involvement in AFD was systematically examined in only two previous echocardiographic studies, with different results.6,7 Similar to our findings, both observed that RVH is common in patients with AFD (about one third of patients) and that RVH significantly increases with age. Moreover, the majority of patients with RVH also showed signs of LV geometric changes in both studies, suggesting that RV involvement in AFD accompanies LV changes and shares the same determinants of progression.3 We confirm these findings, as demonstrated by the strong correlation between different indices of LVH and RVWT. However, the two studies differ for the findings on RV systolic function, as Kampmann et al.7 found a high frequency of depressed RV systolic function, whereas Palecek et al.6 did not. The latter group observed that RVWT is not accompanied by impairment in RV systolic function, and this is in accordance with our data. However, Palecek et al.6 highlighted that using just one index of RV systolic function (TAPSE) may be not enough to unmask subtle RV systolic dysfunction, because of the observations already done on the left ventricle.4,5 We performed a more comprehensive evaluation of RV systolic function, by measuring three different parameters, and we confirm that RV systolic function is not significantly affected by RVH in the AFD population. However, RV Sa was the only parameter correlated with RVH as well as LVH and MSSI, suggesting additive value of TD over TAPSE and RV FAC. The Right Ventricle in Patients with CA In recent years, many studies have demonstrated the prognostic value of RV function in cardiovascular disease. RV function may be impaired in a number of cardiac conditions,16 and the prevalence of RV systolic dysfunction in patients with heart failure with preserved ejection fraction has been found to be as high as 33% to 50%.17 The importance of RV involvement in cardiomyopathies, neglected for a long time, has recently gained attention. RVH has been reported in up to 30% of patients with hypertrophic

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Journal of the American Society of Echocardiography Volume - Number -

cardiomyopathy,18 and its presence is associated with cardiovascular events in this setting.19 Bellavia et al.20 found that Doppler imaging is able to reveal abnormal RV systolic function in patients with amyloid light-chain amyloidosis compared with healthy subjects, despite normal standard 2D echocardiographic measurements; moreover, Doppler imaging measures were able to stratify the risk for death in this subset. Cappelli et al.21 showed that in patients with amyloid light-chain amyloidosis, RV involvement develops later than LV evidence of amyloid deposition, but when it occurs, prognosis dramatically worsens. To our knowledge, no studies have systematically explored RVH and function by TD in patients with FC, although normal RV function with no RV late enhancement has been reported in a cardiac magnetic resonance study on the impact of enzyme replacement therapy on the right ventricle in patients with AFD.22 In our study, patients with CA showed depressed RV systolic function compared with FC+ patients, although RVWT was similar between the two populations.

CONCLUSIONS RVH is common in patients with AFD and correlates with disease severity and LVH. RVH, however, does not significantly affect RV systolic function. The key finding of our study is that despite comparable levels of RVH, RV systolic function is preserved in patients with FC compared with those with amyloid cardiomyopathy. This observation could have a number of explanations: (1) possible heterogeneity of RV involvement, (2) the complexity of RV anatomy and its effect on RV performance, or (3) the limitations of the techniques used to assess RV systolic performance.26 The combination of low LV Sa values and normal RV Sa values may represent a helpful tool in the differential diagnosis of infiltrative heart disease.

SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.echo.2016.11.014.

Implications Our findings have two potential implications. First, our echocardiographic observation could explain why, despite biventricular involvement, there is a low burden of RV congestive heart failure signs and symptoms in patients with AFD,2 even when a severe form of FC is present. LV and RV involvement is evident in FC, but the magnitude of LV involvement is clearly predominant, whereas RV dysfunction occurs relatively late (when it occurs), so that symptoms of ‘‘RV dysfunction’’ are uncommon in these patients. Indeed, in our AFD population, no patient had been admitted for heart failure in the previous 4 years, none were on loop diuretics, and most of the patients were in New York Heart Association class I or II. Moreover, our findings suggest that in presence of biventricular hypertrophy, low LV Sa values associated with normal RV Sa values should prompt the hypothesis of FC instead of CA, where RVH is often associated with RV dysfunction.23 However, it must be emphasized that AFD diagnosis relies on a-galactosidase activity dosage and on genetic testing and that the peculiar echocardiographic features we describe should only alert physicians to suspect the disease and follow the conventional diagnostic process.

Limitations Some limitations of our study should be considered. First, our sample size was relatively small, and therefore, our data need to be confirmed in larger populations. Second, we cannot exclude that subtle RV abnormalities might have been detected in patients with AFD if more sensitive methods were used, a possibility that deserves assessment in appropriately designed studies. Indeed, infiltrative diseases might have preserved conventional systolic parameters but reduced strain values24,25: recently, Morris et al.24 found that speckle-tracking detects LV, RV, and left atrial functional myocardial alterations, even when conventional cardiac measurements are normal in patients with AFD. Finally, although in this study we found significant differences in RV function in patients with AFD compared with those with CA, whether similar differences also exist with other kinds of diseases characterized by LVH (such as hypertrophic cardiomyopathy and hypertensive heart disease) should be investigated in other studies.

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Journal of the American Society of Echocardiography - 2016

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