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A patient who did not read the textbook

Case presented by the Working Group on Myocardial and Pericardial Diseases


 

The Case

Presented by: Michael Arad MD, Heart Failure Institute, Leviev Heart Center, Sheba Hospital and Tel Aviv University, Israel

Case Presentation

A 67 year old woman of Jewish-Yemenite origin presented with pulmonary edema. She had diabetes from age of 50 with retinopathy and nephropathy. Other medical history included hypertension, allergy to iodide and her sister’s death from heart failure  at 60+ years. Brain MRI was performed to investigate dizziness and instability reported microinfarcts.

Picture 1


The ECG (see above) showed no dynamic changes. Echocardiography found normal ventricular size and wall thickness, pseudonormal filling and 'mild to moderate' left ventricular dysfunction. Because of slight troponin I elevation, coronary angiography was performed showing a 2-vessel coronary disease (video clips 1a, 1b). Stenting of a 70% narrowing in mid left anterior descending artery was accomplished.

During the next  2 years she had repeat hospitalizations for dyspnea or angina with no objective evidence of myocardial ischemia. At age 69, echocardiography revealed restrictive filling, LVEF 30%, no hypertrophy or dilatation, moderate pulmonary hypertension and 'moderate+' tricuspid regurgitation (video clips 2a, 2b). The BNP was 469 pg/ml.

Picture 2


Because of unexplained heart failure with persistent troponin elevation cardiac MRI was performed showing wall thickness of 6-10 mm, LVEF 46% and a widespread circular delayed gadolinium enhancement which could be compatible with amyloidosis.

Picture 3

Serum immunoglobulin electrophoresis and free light chains were normal and a fat pad biopsy was negative for amyloid. The patient refused to have endomyocardial biopsy. Tc DPD bone scan was weakly positive.

Picture 4

Questions

  1. What is the diagnosis?
  2. How to confirm the diagnosis?
  3. What is the therapy?

Part II

The patient was referred to hematologist. Bone marrow biopsy was negative for plasma cell dyscrasia but confirmed amyloid deposits around blood vessels. At this stage the niece of the patient brought a report from the National Amyloidosis Centre (UK) describing TTR cardiac amyloidosis and a S77Y TTR mutation in the late patient's sister.  The same mutation was then confirmed in the patient. No other family members agreed to be genotyped or thoroughly evaluated. The patient is currently in NYHA IV, is treated in the heart failure daycare, has no neuropathy and refuses to try any experimental therapy.  

Interestingly, we are familiar with another family of the exact same ethnic origin and the same mutation, who have an elderly onset familial polyneuropathy (TTR-FAP) but have no cardiomyopathy.

Comment

This case demonstrates the complexity of diagnosing AS/TTR amyloidosis in elderly patients with multiple comorbidities. In this case cardiac AS amyloidosis caused microvoltage, persistent troponin I elevation, decreased systolic and diastolic function and prominent tricuspid regurgitation but no ventricular hypertrophy. Once the diagnosis of amyloidosis is established, the type of amyloid needs to be defined by precise analytical methods such as mass spectroscopy. A strongly positive bone scan may probably be used as an alternative in appropriate cases. As demonstrated in our case, elderly age does not rule out a familial disease.

Familial TTR amyloidosis classically presents either as polyneuropathy and/or as cardiomyopathy. TTR-FAP is a common presentation in Portuguese patients with V30M mutation while other Europeans with the same mutation present with maturity-onset cardiomyopathy. In our case the S77Y mutation caused a completely different phenotype in 2 families of the same ethnic origin.

Accurate diagnosis of familial TTR amyloidosis is highly important not only for purpose of family planning but because novel therapies are already in use  and are being developed  to target this disease.

Further reading

Adam Castaño, et al. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs.

Heart Fail Rev. 2015 Mar;20(2):163-78. doi: 10.1007/s10741-014-9462-7.

The solution of the previous case of the month: Hypertrophic Cardiomyopathy with Extensive Left Ventricular Fibrosis and Severe Mitral Regurgitation

Presented by Regina Votavová, Lubor Golán, David Zemánek and Aleš Linhart

2nd Department of Internal Cardiovascular Medicine

First Medical Faculty, Charles University in Prague

General University Hospital in Prague

Czech Republic

Based on the typical distribution of scar tissue as seen on MRI and renal involvement, the patient was suspected of having Anderson Fabry disease (AFD).

Laboratory results confirmed low a-galactosidase A (AGALA) activity in plasma 0.22 (normal range 2.4-11.3 nmol/ml/h) and leukocytes 3.4 (normal values 32.2 – 89.0 nmol/ml/h). The genetic analysis revealed a missense mutation c.902G>A (p.Arg301Gln / p.R301Q).

At present the patient is being considered for mitral valve surgery while having his hepatic lesion and kidney involvement investigated. Renal biopsy is being considered. In the meantime he was started on enzyme replacement therapy (ERT) by agalsidase beta (Fabrazyme ®), 1 mg / kg / every other week.

Anderson - Fabry disease (AFD) (OMIM 301500) is an X-linked lysosomal storage disorder caused by a-gaalactosidase A gene (GAL) mutations resulting in decreased or absent level of a-galactosidase A enzymatic activity. This results in progressive accumulation of glycolipids, primarily globotriaosylceramide (Gb3) and its deacylated form lyso -Gb3 in a large spectrum of cells. Primarily the storage develops in vascular endothelium and smooth muscle cells, cardiac myocytes, conduction tissue calls, renal podocytes and multiple cell types in the kidneys, nervous system as well as in many other tissues throughout the body (Mehta 2004).

The classic phenotype of Fabry disease is characterized by early onset of symptoms, absent or severely reduced (<1% of normal average values) AGALA activity, and marked microvascular endothelial Gb3 accumulation (Desnick 2001). Many screening programs in neonates and in patients originally diagnosed with hypertrophic cardiomyopathy (HCM) revealed a later onset phenotype, which has a delayed onset and slower progression due to residual AGALA activity, minimal or absent vascular endothelial Gb3 accumulations, The predominant manifestation of late onset AFD is hypertrophic cardiomyopathy (Palecek et al. 2014; Spada et al. 2006; ). Heterozygous female patients may have a wide range of clinical phenotypes depending on mutation type and random X-chromosomal inactivation (Echevarria et al.2015).

A large spectrum of predominantly missense AGALA gene mutations is associated with late onset cardiac variants of the disease. These mutations maintain residual AGALA activity high enough to prevent massive endothelial storage. Most patients have minimal or absent signs and symptoms of the classical multisytemic AFD, therefore not complaining of pain, and not having extensive angiokeratomas, hypohidrosis, premature strokes and renal impairment. As heterozygous females carrying cardiac variant mutations may be oligosymptomatic or completely asymptomatic, the negative family history of our patient is not surprising (Desnick et al. 2001; Echevarria et al. 2015).

The mutation c.902G>A (p.Arg301Gln / p.R301Q) was described by Sakuraba back in 1990 and reported to be associated with isolated cardiac variant. In agreement with the results seen in our patient, hemizygous males carrying this mutation have an average residual enzyme activity of about 5.6±0.3 % of the average normal values (Sakuraba et al. 1990; Wu et al. 2011). This activity is relatively low compared to other cardiac variant genotypes (the best known mutation p.N215S (c.644A>G) was reported to have about three times more residual AGALA activity) (Wu et al. 2011). This may explain why in some patients other manifestations of AFD may develop. Although we hypothesize that the renal involvement of our patient is due to AFD, its exact nature should be elucidated. The observed transient elevation of serum creatinine coincided with elevated INR levels induced by warfarin therapy. This situation may be related to warfarin related nephropathy which should be taken into consideration as potential aggravating factor inducing abrupt and only partially reversible renal function decline in anticoagulated patients (Brodsky et al. 2011).

The enzyme replacement therapy, put in place in our patient, was shown to be effective in stabilizing the renal involvement in AFD (Banikazemi et al. 2007; Germain et al. 2015). In cardiac variants the treatment reduces the degree of LV hypertrophy and to some extent even the myocardial storage (Lin et al. 2013; Hsu et al. 2014). However, the evidence that ERT decreases the risk of cardiovascular complications is still lacking. In addition, ERT was shown less effective in subjects with extensive LV fibrosis (Weidemann et al. 2013). Therefore it is of great interest to prove that the renal disease of our patient is related to the damage caused by lysosomal storage within the kidney.

The AFD- associated cardiac fibrosis, as detected in our patient by LGE MRI and readily seen already on echocardiography, is typically developing in the mid-myocardial layer of the posterolateral basal segment. This characteristic distribution represents one of the “red flags” in HCM patients suggesting the presence of AFD (Weidemann et al. 2013). A similar extent of fibrosis and myocardial thinning as seen in our case was described in cardiac variant patients with an unfavorable outcome due to arrhythmias and heart failure (Takenaka et al. 2008). There is an ongoing debate on criteria that should be used for ICD indication in AFD. As in our patient, ICD is indicated in secondary prevention of sudden cardiac death. For others without evidence of malignant arrhythmias, the criteria currently proposed by HCM guidelines are inappropriate (Elliott et al., 2014). In absence of other clinical predictors, the extent and progression of fibrosis may be one of the parameters to be considered, as it was shown to be related to the arrhythmic events (Krämer et al. 2014).

In our case, the fibrosis is causing a systolic mitral leaflet restriction and severe mitral regurgitation. Although AFD is associated with direct valvular involvement as well (Linhart et al. 2000), we believe that in our patient the underlying mechanism is caused by mitral leaflets tethering by displaced papillary muscles. The indication for surgery should be carefully considered as AFD myocardial involvement may lead to complicated recovery even after an uneventful surgical procedure. Due to hypertrophied and fibrotic left ventricle with increased filling pressures, most of the operated patients suffer from signs of heart failure during recovery.

In conclusion, cardiac variants of AFD should be suspected in patients diagnosed with HCM, particularly in those with the typical distribution of fibrosis. The cardiac late-onset variants of AFD are caused mostly by missense mutations with some degree of preserved residual enzymatic activity. In general population, late-onset variants are more frequent than the classical disease phenotypes (Spada  et al. 2006). The indication of ERT in isolated cardiac variants without renal involvement remains controversial, particularly at stages associated with extensive fibrosis.

References


Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ; Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007 Jan 16;146(2):77-86.

Brodsky SV, Nadasdy T, Rovin BH, Satoskar AA, Nadasdy GM, Wu HM, Bhatt UY, Hebert LA. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int. 2011 Jul;80(2):181-9.

Desnick RJ, Ioannou YA, Eng CM. a-galactosidase A deficiency: Fabry disease. In:  Rosenberg RN. DiMauro S, Paulson HL, Ptácek L, Nestler EJ. The molecular and genetic basis of neurologic and psychiatric disease. 2001: 3733-3774.

Echevarria L, Benistan K, Toussaint A, Dubourg O, Hagege AA, Eladari D, Jabbour F, Beldjord C, De Mazancourt P, Germain DP. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2015 May 14. doi: 10.1111/cge.12613.

Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014 Oct 14;35(39):2733-79.

Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR. Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement. Genetics in Medicine 2006; 8: 539-548.

Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott R, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with FD. J Med Genet. 2015; 52: 353-8.

Hsu TR, Sung SH, Chang FP, Yang CF, Liu HC, Lin HY, Huang CK, Gao HJ, Huang YH, Liao HC, Lee PC, Yang AH, Chiang CC, Lin CY, Yu WC, Niu DM. Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4?+?919G>A) Orphanet J Rare Dis. 2014 Jul 1;9:96.

Krämer J, Niemann M, Störk S, Frantz S, Beer M, Ertl G, Wanner C, Weidemann F. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol 2014; 114: 895-900.

Lin HY, Liu HC, Huang YH, Liao HC, Hsu TR, Shen CI, Li ST, Li CF, Lee LH, Lee PC, Huang CK, Chiang CC, Lin CY, Lin SP, Niu DM. Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A).BMJ Open. 2013 Jul 16;3(7).

Linhart A, Palecek T, Bultas J, Ferguson JJ, Hrudová J, Karetová D, Zeman J, Ledvinová J, Poupetová H, Elleder M, Aschermann M. New insights in cardiac structural changes in patients with Fabry's disease. Am Heart J. 2000 Jun;139(6):1101-8.

Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004 Mar;34(3):236-42.

Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995; 333:288-93.

Niemann M, Rolfs A, St?rk S, et al. Gene mutations versus clinically relevant phenotypes : lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014: 7: 8-16.

Palecek T, Honzikova J, Poupetova H, Vlaskova H, Kuchynka P, Golan L, Magage S, Linhart A. Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: prospective Fabry cardiomyopathy screening study (FACSS). J Inherit Metab Dis. 2014 May;37(3):455-60

Sakuraba H, Oshima A, Fukuhara Y, Shimmoto M, Nagao Y, Bishop DF, Desnick RJ, Suzuki Y. Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet. 1990 Nov;47(5):784-9.

Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40.

Takenaka T, Teraguchi H, Yoshida A, Taguchi S, Ninomiya K, Umekita Y, Yoshida H, Horinouchi M, Tabata K, Yonezawa S, Yoshimitsu M, Higuchi K, Nakao S, Anan R, Minagoe S, Tei C. Terminal stage cardiac findings in patients with cardiac Fabry disease: an electrocardiographic, echocardiographic, and autopsy study. J Cardiol. 2008 Feb;51(1):50-9.

Weidemann F, Sanchez-Niño MD, Politei J, Fibrosis: a key feature of Fabry disease with potential therapeutic implications. Orphanet J Rare Dis. 2013; 8: 116.

Weidemann F, Niemann M, Störk S, Breunig F, Beer M, Sommer C, Herrmann S, Ertl G, Wanner C. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med. 2013 Oct;274(4):331-41.

Wu X, Katz E, Della Valle MC, Mascioli K, Flanagan JJ, Castelli JP, Schiffmann R, Boudes P, Lockhart DJ, Valenzano KJ, Benjamin ER. A pharmacogenetic approach to identify mutant forms of a-galactosidase A that respond to a pharmacological chaperone for Fabry disease. Hum Mutat. 2011 Aug;32(8):965-77.
 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.