According to the definition of the European Society of Cardiology (ESC), “Restrictive cardiomyopathies are defined as restrictive ventricular physiology in the presence of normal or reduced diastolic volumes of one or both ventricles, normal or reduced systolic volumes, and normal ventricular wall thickness.”2 According to the definition of the American Heart Association (AHA), “Primary restrictive non-hypertrophied cardiomyopathy is a rare form of heart muscle disease and a cause of heart failure (HF) that is characterized by normal or decreased volume of both ventricles associated with biatrial enlargement, normal LV (left ventricular) wall thickness and AV (atrioventricular) valves, impaired ventricular filling with restrictive physiology, and normal (or near normal) systolic function.”3 Both definitions emphasize restrictive ventricular physiology, normal or reduced volume of one or both ventricles, and normal wall thickness. AHA further stipulates the presence of atrial dilation, normal AV valves, and normal systolic function.3 End-stage hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) may manifest restrictive physiology, but these forms are not assigned to distinct subgroups of cardiomyopathies.2 Precise epidemiology data are not available, but restrictive cardiomyopathy (RCM) is a less common form of cardiomyopathy. A nationwide epidemiologic survey in Japanese hospitals estimated a prevalence of 0.2 per 100,000 inhabitants.4
RCM can be primary/idiopathic or acquired5; recent advances in DNA sequencing demonstrated that the former are genetic diseases in both adults and children,6,7 whereas the latter are phenocopies of genetic RCM. The criterion common to primary/idiopathic or acquired RCM is the restrictive ventricular physiology, but etiology is heterogeneous. The differentiation between primary/idiopathic RCM and other diseases manifesting restrictive ventricular physiology is essential because the precise diagnosis may determine monitoring, treatment, and prognosis.
Primary and Idiopathic Restrictive Cardiomyopathies Are Genetic Diseases
RCM is morphologically characterized by normal or reduced ventricular size, bi-atrial dilation, and absence of LV hypertrophy with LV wall thickness ≤ 13 mm, and functionally defined by diastolic dysfunction with restrictive physiology and preserved systolic function.1,2,8,9 The early clinical manifestations can be subtle, and morphofunctional modifications can be latent. Most RCMs demonstrate familial clustering and genetic origin; the genetic bases are heterogeneous. More than 15 genes have been reported to date in patients and families with RCM. The clinical course is characterized by the development of HF with preserved ejection fraction, with evolution to end-stage biventricular HF where heart transplantation is the most effective treatment option.8
Probands (or index patients) are usually diagnosed because of signs and symptoms of HF with preserved ejection fraction.8,9,10 The clinical workup includes physical examination, electrocardiogram (ECG), and two-dimensional echocardiography. Physical examination reflects the elevated systemic and pulmonary venous pressures, with prominent jugular venous pulse and X and Y descents. In the advanced course of the disease, the pulse volume is low, the stroke volume declines, and the heart rate increases. A systolic murmur and filling sound reflect AV valve regurgitation and fast early diastolic filling; a fourth heart sound (S4) can be present. Hepatomegaly, ascites, and peripheral edema are common in decompensated patients. Echocardiographic criteria for diagnosing and grading diastolic dysfunction11 are listed in Table 61–2.
TABLE 61–2.Criteria in the American Society of Echocardiography Guidelines Used to Grade Diastolic Function (2013) ||Download (.pdf) TABLE 61–2. Criteria in the American Society of Echocardiography Guidelines Used to Grade Diastolic Function (2013)
|Parameter ||Normal ||Grade 1 (mild) ||Grade 2 (moderate) ||Grade 3 (severe) |
|Mitral E/A ratio ||> 0.8 ||≤ 0.8 ||0.8-2.0 ||> 2.0 |
|Deceleration time (ms) ||140-200 ||> 200 ||160-200 ||< 160 |
|e′ septal (cm/s) ||≥ 8 ||< 8 ||< 8 ||< 8 |
|e′ lateral (cm/s) ||≥ 10 ||< 10 ||< 10 ||< 10 |
|Average E/e′ (cm/s) || ||< 8 ||9-12 ||≥ 13 |
|Left atrial size (mL/m2) ||< 34 ||≥ 34 ||≥ 34 ||≥ 34 |
|Pulmonary vein systolic inflow–diastolic inflow ratio (S/D ratio) || ||> 1 ||< 1 ||< 1 |
|Ar-A (ms) || ||< 0 ||> 30 ||> 30 |
|Change in E/A ratio with Valsalva || ||Decrease < 50% ||Decrease ≥ 50% ||Decrease ≥ 50% |
In infants, RCM may present with failure to thrive, fatigue, and syncope.7 Clinical examination usually does not show traits suggesting a specific etiology. ECG may demonstrate increased voltages and signs of atrial enlargement. Two-dimensional echocardiography is the key tool for the diagnosis.11 In children, the most significant abnormalities are increased left atrial size, increased septal E′/E0, and lack of A wave and presence of mid-diastolic L0 wave; LV compliance may be decreased even with preserved early relaxation properties of the myocardium.7,11 Interpretation of diastolic dysfunction12 in children is complicated by the possible absence of key markers, such as features of delayed relaxation, and scarce contribution of mitral and pulmonary venous Doppler wave patterns.11,12
Cardiac magnetic resonance imaging (CMR) provides data for the characterization of different diseases manifesting with the RCM phenotype, for distinguishing RCM from constrictive pericarditis, and for evaluation of the extent of myocardial fibrosis.13,14,15 Certain CMR features characterize RCM with different etiologies (eg, distinguishing metabolic diseases from inflammatory diseases).16,17,18
Endomyocardial biopsy (EMB) is uniquely useful for the diagnosis of desminopathies,19 iron myocardial overload in both hemochromatosis20 and Friedreich ataxia with cardiomyopathy,21 cystinosis,22,23 pseudoxanthoma elasticum,24 lysosomal storage diseases,25,26 and cardiac amyloidosis.27 EMB may show endocardial fibrous thickening,28 endocardial thrombosis, eosinophilic infiltration,29 and granulomatous myocardial diseases.30 EMB may further help distinguish RCM from constrictive pericarditis (specific pathology features can immediately provide a precise diagnosis; eg, restrictive cardiodesminopathy) and exclude diseases with contraindication to heart transplantation (eg, amyloid light-chain [AL] cardiac amyloidosis).
Deep phenotyping in probands involves the investigation of cardiac and extracardiac traits that typically occur in RCM with different causes to generate a clinical hypothesis on precise etiologies31 by joining information on the clinical phenotype; inheritance pattern; ECG markers (conduction disease, Wolff-Parkinson-White pattern/short PR interval, QT prolongation, low or high voltages of QRS complex); echocardiographic markers, such as LV noncompaction or hypertrabeculation; CMR information, such as T2* for iron overload, as discussed later17; preferential distribution and pattern of late gadolinium enhancement on CMR18 in amyloidosis16; and values of biomarkers such as increased creatinine phosphokinase, lactic acid, and N-terminal pro-brain natriuretic peptide (NT-proBNP).31
Differential Diagnosis Between Restrictive Cardiomyopathy and Constrictive Pericarditis
It is crucial to distinguish between RCM and constrictive pericarditis (CP) because RCM typically responds only to medical management and carries a poor prognosis, whereas CP may be curable by pericardiectomy and represents a potentially reversible cause of HF (Table 61–3).32 The clinical presentation of CP can mimic that of RCM, severe tricuspid regurgitation, and noncardiac conditions, like chronic obstructive airway diseases33 (see Chap. 66).
TABLE 61–3.Major Criteria and Markers for Differential Diagnosis Between Restrictive Cardiomyopathy and Constrictive Pericarditis ||Download (.pdf) TABLE 61–3. Major Criteria and Markers for Differential Diagnosis Between Restrictive Cardiomyopathy and Constrictive Pericarditis
|Items ||RCM ||Endomyocardial Diseases ||Constrictive Pericarditis ||Amyloid Heart Disease |
|Ethnic data ||None ||Epidemics EMF, EFE ||None ||None; exceptions genetic ATTR |
|Clinical history ||Nonspecific symptoms ||Infections, fatigue ||Possible: pericarditis, cardiac surgery, autoimmune diseases, malignancy ||Nonspecific symptoms, fatigue, dyspnea |
|Family history ||Frequently positive ||Negative ||Negative ||Possibly positive |
|Physical examination |
|Jugular veins ||Large (a) or (v) waves with steep y descent || ||Short and steep y descent ||Similar to RCM |
|Paradoxus pulse ||Absent ||Absent ||Possible, 25% ||Absent |
|Murmurs/tones (systole) ||Common ||Possible ||No; friction sound ||Common |
|Murmurs/tones (diastole) ||Low-pitched S3: 0.12-0.18 s after S2, or an S4 ||Possible ||High-pitched pericardial knock: 0.06-0.12 s after S2 ||Possible |
|P wave ||High ||High ||Low ||High |
|QRS voltage ||High || ||Possible, 25% ||Low, possible ~50% |
|Q wave ||Common ||Common ||No ||Possible |
|LVH ||Possible || ||No ||No |
|Atrioventricular block ||Possible, according to the cause || ||No ||Possible, 50% |
|Arrhythmias, atrial ||Possible ||Possible ||No ||Possible, common in advanced phases |
|Chest x-ray || || || || |
|Cardiomegaly ||Present (atrial dilation) ||Possible ||No ||Possible |
|Pericardial calcification ||No ||No ||25% ||No |
|Pulmonary vascular congestion ||Possible ||Possible ||No ||Possible |
|Two-dimensional echocardiography |
|Atrial dilation ||Present ||Present ||Possible, mild ||Present |
|Ventricular septal shift ||Absent ||Absent ||Present ||Absent |
|Respiratory variation/valves ||Absent ||Absent ||Present ||Absent |
|TDI é velocity ||< 8 cm/s || ||> 8 cm/s ||< 8 cm/s |
|Doppler, color M-mode ||Slope > 100 cm/s || ||Slope < 100 cm/s ||Slope > 100 cm/s |
|CT scan |
|Pericardial calcification ||Absent ||Absent ||Possible ||Absent |
|Pericardial thickening ||Absent ||Absent ||Present ||Absent |
|Pericardial thickening ||Absent ||Absent ||Present ||Absent |
|Respiratory variation/septal ||Absent ||Absent ||Present ||Absent |
|Ventricular morphology, tubular ||Absent ||Absent ||Present ||Absent |
|Tagging: perimyocardium ||Systolic breakage || ||Absent ||Systolic breakage |
|LGE: pericardium ||Absent ||Absent ||Present ||Absent |
|LGE: myocardium ||Present ||Present ||Absent ||Present |
|LGE: endocardium ||Present ||Present ||Absent ||Present |
|Dip and plateau ||Absent ||Absent ||Present ||Absent |
|Diastolic pressure equalization ||Absent ||Absent ||Present ||Absent |
|Respiratory changes of RV and LV systolic pressures ||Concordant ||Concordant ||Discordant ||Concordant |
|RV/LV area, expiration vs inspiration ||< 1.1 ||< 1.1 ||> 1.1 ||< 1.1 |
|Inflammatory ||Normal ||Increased ||Absent ||Normal |
|BNP ||Increased ||Increased ||< Normal values ||Increased |
|Pathology: EMB |
|Features ||Can contribute to the diagnosis ||Can contribute to the diagnosis ||Do not contribute to the diagnosis ||Diagnostic |
Two-dimensional echocardiography, M-mode, and Doppler blood-flow evaluation including respiratory-related ventricular septal shift, preserved or increased medial mitral annular e′ velocity, and prominent hepatic vein expiratory diastolic flow reversal are independently associated with the diagnosis of CP.34,35,36 The assessment of early diastolic annulus velocity and annulus reversus (reversal of the relationship between lateral and medial e′ velocities) by tissue Doppler imaging (TDI) improves the differentiation of constriction from restrictive myocardial disease, and can be further facilitated by speckle tracking imaging as a complementary tool. Three-dimensional echocardiography precisely evaluates pericardial effusion or pericardial masses as it describes anatomic structures with higher accuracy than does two-dimensional echocardiography.36
Computed tomography (CT) and CMR detect global or loculated effusions and measure pericardial thickness, which, in normal conditions, is less than 4 mm and usually around 1 to 2 mm. Cardiac CT demonstrates pericardial thickening and effusions. Delayed gadolinium enhancement CMR detects pericardial and myopericardial inflammation. A multiparametric CMR approach distinguishes among active inflammation, chronic pericarditis with constriction, and effusion without inflammation.37
Cardiac catheterization is usually planned on an individual basis (eg, in patients with noncalcified or thickened pericardium especially before surgery); CP shows a more pronounced a wave and decline of rapid y descent suggesting LV filling abnormalities. However, catheterization may miss up to one-fourth of the cases of CP. Surgical exploration definitely gives an answer in unsolved cases. Finally, NT-proBNP levels are significantly higher in RCM than in CP.38
Genetic counseling, family history, and evaluation of clinical reports of family members are part of the clinical genetic workup for patients diagnosed with RCM.39 Clinical family screening includes physical examination, ECG, and two-dimensional echocardiographic evaluations of family members. Further testing, such as ambulatory Holter monitoring, treadmill testing, and CMR, are performed on an individualized basis. Familial RCM demonstrates autosomal dominant inheritance in the majority of cases; clinically sporadic cases may mask autosomal recessive inheritance or de novo genetic diseases. Accordingly, all patients with RCM should receive genetic counseling and testing; relatives should be offered clinical screening.31,39
The clinical phenotype in affected members of the same family may vary: HCM or HCM with restrictive physiology or RCM that has progressed through dilation and dysfunction may occur in different family members.40,41,42,43,44 This phenomenon is confirmed in several families and reflects phenotype heterogeneity: the genetic bases apparently coincide, but the end-phenotype may differ. The reasons are still unknown; hypotheses include complex genotypes, modifier genes, lifestyle factors (eg, athletes), or epigenetic factors (Fig. 61–1).
The figure shows the pedigrees of two families in which the probands were diagnosed with restrictive cardiomyopathy (RCM) caused by mutations in TNNI3 gene. A. Autosomal dominant RCM in a family in which different affected family members showed hypertrophic cardiomyopathy (HCM; red bordered symbols), HCM with restrictive patterns (blue bordered symbols), and early RCM with no hypertrophy, mildly dilated left atrium, and New York Heart Association (NYHA) class I. B. de novo RCM in a boy who developed early RCM characterized by severe atrial dilation, absence of left ventricular (LV) hypertrophy, and fast progression to advanced disease. Both parents were clinically and genetically healthy. C. de novo RCM in a boy who developed RCM characterized by severe atrial dilation, absence of LV hypertrophy, and clinical stability. Both parents were clinically and genetically healthy. HTx, heart transplantation.
Family screening studies identify clinically and genetically affected members who may demonstrate borderline LV hypertrophy. RCM should be distinguished from HCM with a restrictive pattern44,45; on echocardiography, a maximum LV thickness less than 13 mm, the absence of LV outflow tract obstruction, and the absence of systolic anterior motion of the mitral valve leaflet favor the diagnosis of RCM. However, long-term follow-up may show progression from RCM to HCM-RCM (Fig. 61–2). Cascade genetic testing in families is indicated after identification of the disease-causing mutation in probands.31,39,46,47,48
Two-dimensional and color Doppler echocardiography in a 14-year-old boy, who was a member of a family in which mutation in TNNI3 was associated with restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and overlapping HCM-RCM. A. Apical four-chamber view with biatrial enlargement and a small hyperkinetic left ventricle; an implantable cardioverter-defibrillator (ICD) electrode is seen extending into the right ventricle. B. Midventricular obstruction on color Doppler imaging, with evident flow acceleration and turbulent flow, in the same young patient. The young patient was first diagnosed with HCM (mild left ventricular [LV] hypertrophy) at the age of 10 years; the diastolic dysfunction was apparent since the early detection of the disease. In his family, there were three sudden deaths (SDs), one aborted SD, and three heart transplantations. The boy received an ICD at the age of 13 years. Age 9: maximal LV thickness = 8 mm; age 10: maximal LV thickness = 11 mm; age 12: maximal LV thickness = 12 mm; atrial dilation; age 13: ICD; age 14: maximal LV thickness = 14 mm; atrial dilation; age 17: maximal LV thickness = 15 mm; atrial dilation, rest gradient = 22.3 mm Hg; after Valsalva: 40 mm Hg.
Restrictive Cardiomyopathy: Genetic Bases
Genes associated with RCM encode sarcomeric structural and regulatory proteins, Z-disc proteins, and intermediate filaments. The TNNI3 gene that encodes the thin filament troponin I is the most common disease gene responsible for RCM49; several reports confirm the major role of mutations in TNNI3 in RCM.40,42,50,51,52 Mutations in the troponin T2 gene (TNNT2) are less common in RCM and may also cause HCM and DCM.53 Other sarcomeric genes involved in RCM include ACTC1, MYL3, MYH7, TTN, TPM1, MYL3, and MYL2.44,45,46,47,54 Recent reports have described mutations in Z-disc protein-encoding genes, including MYPN, FLNC, and BAG3, in patients with RCM55,56,57,58 (Table 61–4).
TABLE 61–4.Genes Associated With Restrictive Cardiomyopathy ||Download (.pdf) TABLE 61–4. Genes Associated With Restrictive Cardiomyopathy
|MIM Gene ||Nuclear Genes ||Protein ||Cardiomyopathy ||Phenotypes/Diseases Allelic at the Same Locus ||Inheritance |
|102540 ||ACTC1 ||Cardiac actin alpha ||D/H/NC ||Nemaline myopathy ||AD |
|603883 ||BAG3 ||BCL2-associated athanogene ||H/R ||BAG3-related myofibrillar myopathy; myofibrillar myopathy ||AD |
|123590 ||CRYAB ||Alpha B crystalline ||D/H ||Cataract, multiple types; myofibrillar myopathy ||AD |
|125660 ||DES ||Desmin ||D/H/A ||Des-related myofibrillar myopathy; neurogenic scapuloperoneal syndrome, Kaeser type; AVB; > sCPK ||AD, AD |
|102565 ||FLNC ||Filamin C || ||Distal myopathy, myofibrillar myopathy. ||AD |
|600958 ||MYBPC3 ||Myosin-binding protein C, cardiac ||D/H/NC || ||AD |
|160760 ||MYH7 ||Beta-myosin heavy chain 7 ||D/H/NC ||Laing distal myopathy; myosin storage myopathy; scapuloperoneal syndrome, myopathic type; possible > sCPK ||AD, AR |
|160781 ||MYL2 ||Myosin, light chain 2, regulatory, cardiac, slow ||H || ||AD |
|160790 ||MYL3 ||Myosin light chain 3 ||D/H || ||AD, AR |
|608517 ||MYPN ||Myopalladin ||D/H || ||AD |
|191040 ||TNNC1 ||Cardiac troponin C ||D/H || ||AD |
|191044 ||TNNI3 ||Cardiac troponin I3 ||D/H/NC || ||AD, AR |
|191045 ||TNNT2 ||Cardiac troponin T2 ||D/H/NC || ||AD |
|191010 ||TPM1 ||Tropomyosin 1 ||D/H/NC || ||AD |
|188840 ||TTN ||Titin ||D/H/NC ||Limb-Girdle muscular dystrophy; early-onset myopathy with fatal cardiomyopathy; proximal myopathy with early respiratory muscle involvement; tardive tibial muscular dystrophy ||AD |
The troponin complex is constituted of three subunits: cardiac troponin I, troponin C, and troponin T. It functions as sensor of the intracellular Ca2+ concentration and controls the interaction between the thick and thin filaments during cardiac contraction and relaxation. The inhibitory effect of cardiac troponin I is reversed by troponin C binding to Ca2+, resulting in conformational changes of the troponin complex and leading to muscle contraction. Mutations in any one of the components of the troponin complex may modify Ca2+ affinity and protein-protein interactions, thus potentially leading to the development of cardiomyopathy.
Founder mutations have been identified in the Netherlands in cardiac troponin I (TNNI3)43 in families presenting with both RCM and HCM phenotypes in different affected members. Similar data were confirmed in other large families in which different affected members showed different phenotypes: RCM, HCM, and HCM with a restrictive pattern.42 Intrafamily phenotype variability is not influenced by ethnicity, as it is reported in families from different continents.50 The majority of mutations in TNNI3 are missense49; rare frameshift or splice mutations have also been reported to date.51 The TNNI3-associated phenotype may manifest in children52 (Fig. 61–3). RCM hearts in patients with troponin I mutations do not show significant loss of protein expression; however, myofibrillar disarray is present even in the absence of significant LV hypertrophy (Fig. 61–4). Although TNNI3 should be considered the major candidate gene for RCM, TNNT2 mutations are less commonly responsible.53 Although the number of published cases and families is low and restrictive troponinopathies are rare, data from single cases and small series suggest that the clinical evolution is characterized by a poor prognosis.42,43,50,51,52
This figure shows the two-dimensional echocardiographic views in a boy with restrictive cardiomyopathy (RCM) associated with a de novo mutation in TNNI3. The phenotype and the genetic cause are summarized by the MOGES nosology MR OH GS EG-DN-TNNI3[p.Arg170Gln] SC-III in which M describes the morphofunctional phenotype (RCM, abbreviated as R); O describes the organs affected in the given patient (in this case, the heart was the only involved organ); G defines whether the cardiomyopathy is genetic or not and includes information on the pattern of inheritance or whether it appeared as sporadic in the family representing a possible de novo disease, which is confirmed after genetic testing; E is the precision diagnostic descriptor and specifies the cause, the disease gene(s), and the mutation(s) (in this patient, the mutation in TNNI3 was proven de novo); and S is optional and includes New York Heart Association functional class (I-IV) and American Heart Association stage (A-D). The practical use is supported by a free app at http://moges.biomeris.com/moges.html.
Anti–troponin I immunostain in myocardial samples from the heart of a patient with restrictive cardiomyopathy associated with the TNNI3 p.(Leu144Gln) mutation. A. Disarray that typically recurs in cardiomyopathies caused by defects encoding sarcomere proteins. B. Prominent interstitial fibrosis.
Nonsarcomeric Genetic Restrictive Cardiomyopathy
Recently, mutations in myopalladin (MYPN) and filamin-C (FLNC) have been reported, thus expanding the spectrum of genes potentially causing RCM.55,57,58 In a large screening study of MYPN, different types of mutations were associated with different cardiac phenotypes: The Q529X-MYPN variant was found in familial RCM, whereas the Y20C-MYPN variant was associated with HCM or DCM. The mechanism proposed for the development of RCM is disturbed myofibrillogenesis, whereas the mechanism proposed for DCM or HCM of the Y20C-MYPN variant is perturbation of the MYPN nuclear shuttling and abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.55 Mutations in FLNC segregated in two families with autosomal dominant RCM.58 FLNC is an actin cross-linking protein expressed in heart and skeletal muscle. The cardiac myocytes showed cytoplasmic inclusions suggesting protein aggregates, which were FLNC specific for p.(Ser1624Leu) by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant FLNC, providing further evidence for its pathogenicity.58 As a result of the small number of published cases and the recent association of mutations in these genes and RCM, prognostic data are still unavailable.
The desmin intermediate filament network is involved in striated muscle development and maintenance by coordinating cellular components necessary for intracellular mechanochemical signaling and trafficking processes.59 Direct or indirect deregulation of this network causes myopathies and cardiomyopathies.60,61,62,63,64,65
Restrictive desminopathies are autosomal dominant diseases in the majority of cases and recessive and de novo in a minority of cases. They are clinically characterized by restrictive physiology, mild or absent LV hypertrophy, absence of LV outflow tract obstruction, atrial dilation, and conduction system disease that may precede the clinical manifestation of RCM61,62 (Fig. 61–5). Subclinical or overt myopathy may occur in these patients.61 Conduction disease is a typical marker of the disease: it is confirmed in animal models of desminopathy.63 The course of the disease is characterized by progressive worsening of the cardiac dysfunction to end-stage HF. Heart transplantation is the only therapeutic option.64 The typical RCM desminopathy is easily diagnosed by EMB demonstrating desmin immunoreactive granulofilamentous material accumulated within myocytes61,62,65 (Fig. 61–6). Similar findings are observed in skeletal muscle biopsy independent of the presence of clinically overt myopathy. Fine-needle biopsy of the skeletal muscle provides diagnostic information when EMB cannot be performed.61
Restrictive cardiodesminopathy in a 43-year-old male patient. A. Electrocardiogram before pacemaker implantation with advanced atrioventricular block (PR interval 300 ms). B. Doppler echocardiography with restrictive pattern (E/A wave ratio > 3 and shortened deceleration time) at the transmitral flow during an episode of atrial tachycardia. C and D. Left apical four-chamber view that demonstrates the biatrial enlargement. This patient also had moderate left ventricular systolic dysfunction.
Endomyocardial biopsy (EMB), restrictive cardiodesminopathy. A. Low-magnification view of the EMB samples, with prominent endocardial and interstitial fibrosis. B. Electron micrograph demonstrates the typical intramyocyte accumulation of granulofilamentous material that corresponds to the abnormal desmin.
Multiorgan Genetic Diseases With Heart Involvement and Possible Restrictive Physiology
Lysosome storage diseases, cardiac amyloidosis, myocardial iron overload disorders, and collagen diseases may clinically manifest restrictive physiology. The cardiac phenotype is characterized by LV thickening with possible associated diastolic dysfunction and is, therefore, similar to HCM. These diseases should be separated from pure RCM to prevent confusion in the nosology of RCM. They are distinct genetic diseases, systemic in the majority of the cases, with disease-specific diagnostic workup and targeted treatments. Table 61–5 lists diseases with increased LV thickening and in which restrictive physiology is systematic (eg, amyloidosis) or recurrently present in early phases of the disease (iron storage diseases) or occasionally reported in single cases (lysosomal storage diseases such as glycogenoses, Anderson-Fabry disease, Danon disease, and Hurler disease).66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82
TABLE 61–5.Genes Causing Multiorgan/Systemic Diseases With Cardiac Involvement and Possible Restrictive Physiology ||Download (.pdf) TABLE 61–5. Genes Causing Multiorgan/Systemic Diseases With Cardiac Involvement and Possible Restrictive Physiology
|Diseases Potentially Associated With Secondary Cardiac Restriction |
|MIM Gene ||Nuclear Genes ||Protein ||Reference ||Phenotypes/Diseases Allelic at the Same Locus ||Inheritance |
|LV wall thickening (HCM phenotype) and diastolic dysfunction (restrictive pattern): frequently reported as restrictive cardiomyopathiesa |
|603234 ||ABCC6 ||ATP-binding cassette, subfamily C, member 6 ||66 ||Pseudoxanthoma elasticum ||AR |
|107680 ||APOA1 ||Apolipoprotein of high-density lipoprotein ||68 ||Amyloidosis, hereditary ||AD |
|107670 ||APOA2 ||Apolipoprotein A-II ||69 ||Amyloidosis, hereditary ||AD |
|134820 ||FGA ||Fibrinogen, A alpha polypeptide ||70 ||Amyloidosis, hereditary, familial visceral ||AD |
|137350 ||GSN ||Gelsolin ||75 ||Amyloidosis, Finnish type ||AD |
|606464 ||HAMP ||Hepcidin antimicrobial peptide ||76 ||Hemochromatosis, type 2B ||AR/AD |
|613609 ||HFE ||HFE gene ||77 ||Hemochromatosis ||AD |
|608374 ||HFE2 ||Hemojuvelin ||77 ||Hemochromatosis ||AR/AD |
|604720 ||TFR2 ||Transferrin receptor 2 ||77 ||Hemochromatosis, type 3 ||AR/AD |
|604653 ||SLC40A1 ||Solute carrier family 40 (iron-regulated transporter), member 1 ||77 ||Hemochromatosis, type 4 ||AR/AD |
|LV wall thickening (HCM phenotype): rarely described as “restrictive” cardiomyopathiesb |
|610860 ||AGL ||Amylo-1,6-glucosidase, 4-alpha-glucanotransferase ||67 ||Glycogen storage disease IIIa, glycogen storage disease IIIb ||AR |
|606800 ||GAA ||Glucosidase, alpha, acid ||71 ||Glycogen storage disease II ||AR |
|606463 ||GBA ||Glucosidase, beta, acid ||72 ||Gaucher disease, perinatal lethal, types I, II, III, IIIC ||AR |
|607839 ||GBE ||Glycogen branching enzyme ||73 ||Glycogen storage disease IV ||AR |
|610681 ||PFKM ||Phosphofructokinase, muscle type ||80 ||Glycogen storage disease VII ||AR |
|172471 ||PHKG2 ||Phosphorylase kinase, testis/liver, gamma-2 ||82 ||Glycogen storage disease IXc ||AR |
|613741 ||PYGL ||Glycogen phosphorylase, liver ||82 ||Glycogen storage disease VI ||AR |
|602671 ||SLC37A4 ||Solute carrier family 37 (glucose-6-phosphate transporter), member 4 ||83 ||Glycogen storage disease Ib, Ic ||AR |
|602743 ||PRKAG2 ||Protein kinase, Amp-activated, noncatalytic, gamma-2 ||82 ||Cardiomyopathy, hypertrophic 6, glycogen storage disease of heart, lethal congenital, Wolff-Parkinson-White syndrome ||AD |
|300644 ||GLA ||Galactosidase, alpha ||74 ||Fabry disease ||XL |
|309060 ||LAMP2 ||Lysosome-associated membrane protein 2 ||79 ||Danon disease ||XLD |
|252800 ||IDUA ||Alpha-L-iduronidase ||78 ||Hurler disease ||AR |
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive systemic disease of the connective tissue that affects the extracellular matrix of multiple organs83 with a prevalence that varies from 1 in 70,000 to 1 in 160,000. PXE involves the cutaneous, ocular, and cardiovascular systems.83,84 The cutaneous lesions typically occur in flexural areas (Figure 61–7B), and the fundi may show angioid streaks radiating out from the optic discs, subretinal neovascularization, and/or hemorrhage.
Pseudoxanthoma elasticum. A. Skin biopsy with the typical calcifications that characterize the disease; the inset shows the skin biopsy sample. B. Neck of patient with the typical cutaneous lesions in flexural areas; the patient is carrier of the homozygous p.(Arg1141X) mutation in the ABCC6 gene.
The cardiovascular manifestations are characterized by the development of arterial calcifications,85 premature coronary artery disease, peripheral vascular disease, and RCM.66,86,87,88,89 Sudden death has been occasionally reported.88,89
The histopathologic marker of the disease is the mineralization and fragmentation of elastic fibers (Fig. 61–7A). PXE is caused by homozygous or compound heterozygous mutations in the ABCC6 (ATP-binding cassette subfamily C member 6) gene that encodes a transmembrane adenosine triphosphate (ATP)-driven organic anion transporter. Carriers of heterozygous mutations may demonstrate mild and partial traits of the disorder.90,91 Drugs potentially able to modify the protein conformation, such as sodium 4-phenylbutyrate, a drug approved by the US Food and Drug Administration for clinical use in urea cycle disorders, seem to be able to restore the plasma membrane localization of mutant ABCC6, thus opening the way to target treatment.92,93 Chronic deficiency of ABCC6 is also involved in generalized arterial calcification of infancy and PXE phenocopies in thalassemias; it is a susceptibility factor and/or a modifier for myocardial infarction, stroke, cardiac fibrosis, peripheral artery disease, age-related macular degeneration, chronic kidney disease, nephrocalcinosis, and dyslipidemia. A randomized controlled trial tested the oral phosphate binder sevelamer hydrochloride and demonstrated a reduction in both calcification levels and clinical scores.94
Nephropathic cystinosis is a rare autosomal recessive disease resulting from intracellular accumulation of cystine, leading to multiple organ failure. The incidence is estimated around 0.5 to 1.0 per 100,000 live births. The disease is caused by mutations in the lysosomal cystine/proton symporter termed cystinosin (encoded by CTNS gene) and represents the most common cause of inherited renal Fanconi syndrome in the first year of life, which results in end-stage renal disease by the age of 10 years.95 The pathology of affected tissues is characterized by the tissue deposition of cystine. Early administration of cysteamine reduces intracellular levels of cysteine and can delay progression of renal damage.96 In cases that are diagnosed late, treatment options may be limited to renal transplantation.97 In the European population, mutations of CTNS include a 65-kb deletion-involving marker D17S829 and 11 other small mutations.98 Other CTNS mutations have been confirmed in African American patients with cystinosis.99 Heart involvement is rare; the pathologic hallmark is the presence of cystine rectangular colorless crystals.100
Iron Overload Heart Diseases
Iron overload cardiomyopathy can result from a primary genetic disease caused by defects in genes coding proteins active in iron metabolism, typically hereditary hemochromatosis (HH), or from secondary causes of iron overload such as acquired hematologic diseases.
HH is a heritable disorder of iron metabolism that is characterized by tissue iron overload.76,101 HF causes approximately one-third of deaths of those with HH. Historically, the average survival was less than 1 year in untreated patients with severe cardiac impairment.102,103 In classic HH, about 10% to 15% of affected adults present with cardiac symptoms at diagnosis. HF may develop suddenly in patients with juvenile forms of hemochromatosis. The HH phenotype is clinically heterogeneous and is influenced by gender and complex interactions between genotype and environmental factors (eg, alcohol, other causes of hepatitis). The cardiac phenotype is characterized by early LV diastolic dysfunction with evolution through LV systolic dysfunction and dilation, which is influenced by endocrine dysfunction, neurohormonal activation, and inflammatory cytokines.103
HH is characterized by genetic heterogeneity (Table 61–6).104,105,106,107,108,109,110 The most common HH is HFE1 (or classical HH), which is associated with recurrent mutations [p.(Cys282Tyr) homozygotes or p.(Cys282Tyr)/p.(His63Asp) compound heterozygotes] in the HFE gene (Fig. 61–8). The most frequent causes of death are complications from cirrhosis, cardiomyopathy, and diabetes, but patients who undergo successful iron depletion before development of cirrhosis or diabetes have normal survival. The diagnosis of HH is established by genetic testing in patients with elevated serum ferritin (> 300 ng/mL) and transferrin saturation values (> 55%). Timely diagnosis and treatment prevent iron overload; however, early treatment is limited by the clinically silent or minimally symptomatic manifestations of the disease. Although population screening for HH is controversial, the low cost of genetic tests and the selection of high-risk populations are cost effective.111 The current global prevalence of the different genetic causes of HH can be easily estimated using multigene panels by next-generation sequencing; this analysis also provides data on genetic epidemiology of the disease.112
TABLE 61–6.Genetic Diseases Causing Iron Overload Potentially Affecting the Heart ||Download (.pdf) TABLE 61–6. Genetic Diseases Causing Iron Overload Potentially Affecting the Heart
|MIM Gene ||Nuclear Genes ||Protein ||Disease ||Inheritance ||Heart Involvement ||Age of Onset and Disease Traits |
|613609 ||HFE ||HFE-related HH ||Hemochromatosis, type1 ||AR ||X ||Adult onset; arthropathy, skin pigmentation, liver damage, diabetes, endocrine dysfunction, hypogonadism |
|608374 ||HJV ||Hemojuvelin ||Hemochromatosis, type 2A ||AR ||XX ||Earlier onset, < 30 years old, hypogonadotropic hypogonadism, liver damage and endocrine dysfunction |
|606464 ||HAMP ||Hepcidin antimicrobial peptide ||Hemochromatosis, type 2B ||AR ||X || |
|604720 ||TFR2 ||Transferrin receptor 2 ||Hemochromatosis, type 3 ||AR ||X ||Adult onset; arthropathy, skin pigmentation, liver damage, diabetes, endocrine dysfunction, hypogonadism |
|604653 ||SLC40A1 (SLC11A3) ||Solute carrier family 40 (Iron-Regulated Transporter) Member 1 ||Hemochromatosis, type 4 ||AD ||X ||Adult onset; lower tolerance to phlebotomies, possible anemia |
|134770 ||FTH1 ||Ferritin Heavy Chain 1 ||Hemochromatosis, type 5 ||AR ||X ||Adult onset; heart involvement by magnetic resonance |
Family pedigrees of two patients with autosomal recessive hereditary hemochromatosis caused by homozygous mutation in the HFE gene. A. In this family the disease was apparently sporadic. After the diagnosis in the proband, family screening demonstrated that both parents of the proband are healthy carriers of heterozygous mutations p.(Cys282Tyr) in the HFE gene; both sons of the proband are obligate carriers. B. A family in which the genetic diagnosis in the proband led to family screening and identification of a second affected family member.
Symptomatic hemochromatosis is estimated to occur in 1 in 500 individuals.113 Common presenting symptoms, such as fatigue, malaise, and arthralgia, are nonspecific.103
In the past, the clinical diagnosis was typically late and supported by the classic triad of cirrhosis, bronze skin, and diabetes. Today, the diagnosis is established in early phases of the disease when the clinical manifestations are attenuated, but cardiac imaging may detect features suggestive of myocardial iron overload.
The ECG is nonspecific and does not significantly contribute to the diagnosis of HH cardiomyopathy; low QRS complex voltage and nonspecific repolarization abnormalities are uncommon in early phases; conduction disease may be present. Atrial fibrillation is the most common arrhythmia, whereas ventricular arrhythmias may occur when the LV dysfunction has manifested.103
Echocardiography With Tissue Doppler Imaging, Strain Imaging, and Speckle Tracking
Two-dimensional echocardiographic evaluation shows early diastolic dysfunction113 and later evolution through LV dilation and dysfunction. Restrictive physiology may persist in late disease114; in patients with asymptomatic cardiac involvement, it maintains stable after conventional phlebotomy treatment, regardless of their treatment history.115 Echocardiography contributes to early diagnosis of cardiac involvement and provides information on the extent of iron storage and severity of systolic and diastolic dysfunction. In a multivariable analysis, spectral tissue Doppler lower early (E′) diastolic velocity was independently associated with hemochromatosis.116 Mid-septal systolic and early diastolic velocities on TDI correlate with myocardial iron content predicted by magnetic resonance imaging.117 Longer isovolumetric relaxation time and lower E′ velocity indicate mildly impaired diastolic function; with aging, filling pressures increase as demonstrated by elevated transmitral early (E) filling velocity, pulmonary venous systolic peak velocity, and higher E/E′ ratio.118 Real-time three-dimensional echocardiography may contribute to earlier detection of left atrial dysfunction (eg, left atrial active emptying fraction) in asymptomatic patients with cardiac iron overload119; exercise stress TDI echocardiography may demonstrate subtle systolic abnormalities that would not have been detected by conventional echocardiography.120
Cardiac Magnetic Resonance Imaging
The T2∗ method is highly sensitive and specific and is especially useful for detecting, grading, and monitoring iron deposition.121,122,123 Patients demonstrating a T2∗ higher than 20 milliseconds are at low risk for development of HF; T2∗ between 10 and 20 ms indicates the presence of cardiac iron deposition and an intermediate risk of HF; and a T2∗ less than 10 ms indicates high risk of HF and need for immediate chelation therapy.124 The T2∗ index informs on the risk of HF and arrhythmias.125 CMR further provides a comprehensive evaluation of myocardial viability, LV ejection fraction, and cardiac volume and mass.126 The decline in LV ejection fraction correlates with the myocardial iron content measured with T2∗.127 EMB shows typical intramyocyte accumulation of iron (Fig. 61–9). However, when the diagnosis is established with clinical, imaging, and genetic data, EMB is no longer indicated.
Endomyocardial biopsy obtained from a patient presenting with restrictive cardiomyopathy phenotype; the endomyocardial biopsy shows the intramyocyte accumulation of iron (blue; Perl's stain). In this patient, genetic testing identified the homozygous p.(Cys282Tyr) mutation in the HFE gene.
Phlebotomy and iron chelators (parenteral deferoxamine or the oral iron chelators deferiprone and deferasirox) remain the standard therapy. Adequately treated patients (ie, target ferritin of 50-100 μg/L achieved) demonstrate better prognosis.128 Chelation improves ventricular function, prevents ventricular arrhythmias, and reduces mortality in patients with secondary iron overload. In patients with thalassemia major and mild-to-moderate cardiac iron loading, combination treatment with additional deferiprone reduces myocardial iron and improves ejection fraction and endothelial function.114 In patients with HF, management is based on the same basic principles as patients with DCM and systolic HF (see Chap. 70). Combined heart and liver transplantation should only be considered in severe cases refractory to standard therapies.114,129 Iron overload–induced cardiomyopathy is reversible when therapy is started before the onset of overt HF.
HH is a genetically heterogeneous disease. Common forms of HH are inherited as autosomal recessive diseases; in these families, heterozygous mutation carriers are phenotypically healthy and the illness may appear as sporadic (see Fig. 61–8). The diagnosis of HH in a proband should activate family screening including both clinical evaluation and genetic testing. However, at least one of the genetic HHs is autosomal dominant; in these families, genetic testing provides preclinical evidence of the disease. Therefore, family screening may contribute to early diagnosis and should be routinely recommended.
Non–Hereditary Hemochromatosis Iron Overload
Iron overload potentially involving the heart occurs in hemoglobinopathies (β-thalassemia major, sickle cell disease),130 sideroblastic anemia,131,132 myelodysplastic syndromes,133 aplastic anemia,134 patients with chronic kidney disease and treated with intravenous iron supplementation,135 and patients with iron toxicosis (iron poisoning).136
Iron overload may occur in β-thalassemia major, which is an inherited autosomal recessive hemoglobin disorder causing chronic hemolytic anemia that requires lifelong transfusion therapy.137 β-Thalassemia is a global health issue; the original geographic prevalence in the Mediterranean area, Southeast Asia, Middle East, and North India has been modified by population migration to northern Europe and North America.137 Cardiac involvement is caused by myocardial iron overload; it constitutes the primary cause of mortality and a major cause of morbidity for HF. The cardiac phenotypes include restrictive β-thalassemia cardiomyopathy and DCM103 that is usually preceded by diastolic dysfunction (about 80% of cases)138; in 20% of cases, right ventricular dilation and dysfunction are associated with tricuspid regurgitation, increased pulmonary artery pressure, and restrictive LV filling.130,139,140 Practice guidelines delineate recommendations for clinical monitoring and treatment (chelation therapy and cardiovascular medications).141 The precise quantification of myocardial and hepatic iron load by CMR T2* imaging provides useful information on clinical response to iron chelation therapy.124
Sideroblastic anemias (SAs) can be either acquired or inherited, and are characterized by impaired utilization of iron in the erythroblast, ineffective erythropoiesis, and variable systemic iron overload.131,142 Heritable SAs are genetically heterogeneous diseases; heart involvement is occasionally reported. They include the X-linked recessive SA with ataxia caused by mutations in the ABCB7 gene; the X-linked SA caused by mutations in the ALAS2 gene; the autosomal recessive SA with myopathy and lactic acidosis caused by mutations in the PUS1 and YARS2 genes132; the autosomal recessive SA with B-cell immunodeficiency, periodic fevers, and developmental delay caused by mutations in the TRNT1 gene; and the pyridoxine-refractory autosomal recessive SA caused by mutations in the SLC25A38 and GLRX5 genes. Mutations in TRNT1 cause the autosomal recessive congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay. In patients diagnosed with SA with myopathy and lactic acidosis, HF with preserved ejection fraction and pericardial effusion has been reported.132
Mitochondrial Iron Overload: Friedreich Ataxia
Friedreich ataxia is caused by homozygous GAA trinucleotide repeat expansion that induces a transcriptional defect of the Frataxin gene (FXN).143 Frataxin is a small mitochondrial protein whose defects are associated with mitochondrial iron overload and are responsible for all phenotypic manifestations of Friedreich ataxia. The disease affects central and peripheral nervous, cardiovascular, skeletal, and endocrine (particularly pancreatic function) systems. The cardiac involvement in Friedreich ataxia is characterized by the HCM phenotype (see Chap. 59), evolving to LV dysfunction. A restrictive filling pattern is observed in end-stage Friedreich cardiomyopathy.144 Although early studies suggested that global diastolic function was preserved when examined by TDI,145 recent studies demonstrate diastolic abnormalities in more than 25% of patients.146