Cardiomyopathies: Still Paradigm of Idiopathic Diseases?
CMPs are myocardial disorders characterized by structurally and functionally abnormal heart muscle and absence of other diseases sufficient to cause the observed myocardial abnormality.48 The morphofunctional phenotypes DCM, HCM, RCM, arrhythmogenic right, left and biventricular cardiomyopathy (ARC), and left ventricular noncompaction cardiomyopathy (LVNC) drive the currently used clinical classifications. In this context, LVNC is still a debated entity that is considered a genetic CMP in the American Heart Association, or AHA, classification49 and a nonclassified entity in the European Society of Cardiology (ESC) classification.48 More recently, the novel MOGE(S) nosology endorsed by the WHF proposed a simple description of the trait in individuals with either normal left ventricular size and wall thickness and preserved systolic and diastolic function, or in combination with HCM, RCM or DCM or ARVC19,34 (for classification of CMPs, see Chap. 57). Each subtype of CMP is described in detail in Chaps. 58, 59 60. Here, we aim to highlight concepts and workup shared by all CMPs.
CMPs have been considered for decades as being the paradigm of “idiopathic myocardial diseases.” This concept will be progressively abandoned as their causes are identified. Most of them in fact have a precise and detectable genetic cause. CMPs now represent one of the fields of development of precision cardiology, with progression from the past phenotype-based classification to an integrated morphofunctional, etiology-based classification.19,34
Epidemiology and Familial Cardiomyopathies
The burden of CMP is currently estimated on phenotype-based data: HCM in 1:500 young adults. A revised estimate of the combined prevalence of clinically expressed HCM and gene carriers (at risk for developing the disease phenotype) is placed at about 1 in 200.50 The prevalence of nonamyloid primary RCM in adults is unknown; in children, the estimated annual incidence in the United States and Australia is 0.04 and 0.03 per 100,000 children, respectively,51 and that of DCM and ARVC 1:5000. These values are expected to increase as far as data on patients with early diagnoses in familial CMPs enter scientific literature. In fact, most CMPs have a genetic origin. Familial clustering and gene mutations segregating with the phenotype in families occur in more than 70% of HCM and nonamyloid RCM, and in 50% to 70% of DCM and ARVC.38 The integration of clinical and genetic diagnoses will provide the basis for the molecular epidemiology of CMP. The overall burden of CMP will include patients with clinically overt, symptomatic CMP; asymptomatic patients diagnosed by family screening; and patients with “early” instrumental manifestation of CMP identified by family screening or incidentally in screening programs for sports, driving licensure, and professional suitability.52 Several systematic family screening studies demonstrate familial aggregation.53,54,55,56,57,58,59,60,61,62,63,64,65,66 For each subtype of CMP, several phenocopies exist, and they should be precisely recognized because each of them may be crucial for risk stratification or be associated with prevention strategies and/or disease-specific treatments.37,38
Cardiomyopathies as Clinically Heterogeneous, Chronic Diseases
CMPs are clinically heterogeneous diseases, and inheritance pattern (AD in up to 80% of cases; AR, XLR, and maternal in the remaining 20% of familial CMPs), age of onset, and disease progression and severity may differ, even within affected members of the same family.19,34,37,38 Beyond diagnostic criteria for each type of CMP,48 cardiac and extracardiac markers may recur in CMPs caused by defects of different genes. Imaging markers such as LVNC or increased trabeculation recur more commonly in rare CMPs affecting children, such as Barth syndrome. Extracardiac traits can be associated with CMP. Such markers may be ocular (early cataract, retinopathy, palpebral ptosis), auditory (sensorineural hearing loss, dysmorphology of the ears), gastrointestinal (heritable autoinflammatory diseases), renal (spectrum from proteinuria to renal failure), hepatic (liver involvement in systemic storage diseases), musculoskeletal (syndactyly to severe skeletal deformations), or cutaneous/integumental (striae distensae to skin malignancies), or involve the central nervous system (transient ischemic attacks with white matter lesions to cryptogenic stroke), peripheral nervous system (acroparesthesias to overt peripheral neuropathies), or skeletal muscle (mildly increased serum creatine phosphokinase to myopathies/dystrophies).37 Cognitive impairment may also recur in patients with phenocopies of more typical CMPs, such as in Danon disease, lysosomal disorders, or mitochondrial diseases. When integrated in a family cardiomyopathy “mindset,” the pattern of inheritance and both cardiac and extracardiac traits may contribute to phenotype characterization, independently of the number of genes explored in NGS analysis, thus further contributing to the interpretation of genetic results. Each patient diagnosed with CMP introduces a family case study.
Although the clinical onset may coincide with acute heart failure or cardiogenic shock, and past classification included syndromes such as left ventricular apical ballooning syndrome among CMPs,48,49 typical CMPs are chronic disorders that require lifelong cardiovascular care. Once the diagnosis is consolidated, spontaneous restoration of normal left ventricular size and function in untreated patients does not occur. Current protocols with personalized optimal medical treatments may modify disease progression, extent of left ventricular remodeling, and risk and occurrence of arrhythmias, but cannot not cure affected hearts.
Heritable CMPs are a paradigmatic example of genetically heterogeneous diseases. More than 100 disease or candidate genes have been reported to date as associated with the different subtypes of CMP; several disease genes are not specifically associated with HCM or DCM or ARC, but show genetic overlap.67 Accordingly, mutations in genes coding sarcomeric proteins that typically cause HCM may also cause RCM or DCM; similarly, mutations causing DCM (ie, LMNA) may also cause ARC and vice versa. The complex heterogeneity of CMPs and related disease genes is shown in Fig. 9–5A and B.
A. One gene → more diseases and vice versa: MYH7. The left side shows the most common disease genes for hypertrophic cardiomyopathy; MYH7 is one of the most common disease genes in HCM (up to 30% of cases). The echocardiographic figure refers to a patient with hypertrophic cardiomyopathy, carrier of a mutation in MYH7. The right side of the figure shows the list of diseases formally included in the MIM catalog and associated with mutations in MYH7 gene. B. One gene → more diseases and vice versa: LMNA. The left side figure shows the most common disease genes for dilated cardiomyopathy; LMNA is one of the most common disease genes in dilated cardiomyopathy (up to 7% of cases). The echocardiographic figure refers to a patient with dilated cardiomyopathy, carrier of a mutation in LMNA. The right side of the figure shows the list of diseases formally included in the MIM catalog and associated with mutations in the LMNA gene.
Modern clinical workup in CMPs now includes deep phenotyping of the proband, clinical family screening, clinically oriented genetic testing when possible, or genetic screening of large panels of disease and candidate genes. The present challenge is accurate interpretation of the results of genetic testing, which includes both correct assignment of the causative role of the precise mutation to a disease and interpretation of mutations with possible modifier affects. Gene expression studies,68 pathology studies of affected hearts testing the expression of a mutated protein,69,70,71 computational tools, and bioinformatic pipelines contribute to the final interpretation of mutations as being pathologic and disease-causing; this means that, in the absence of the given mutations, the disease does not manifest.45 However, no tool can substitute for segregation studies in families or pathologic demonstration of the effects of the mutation in the affected myocardium.47 In vitro studies investigating gene expression, protein expression, and structural changes in mutated cells (induced pluripotent stem cell–derived cardiomyocytes) isolated from skin fibroblasts or peripheral mononuclear cells can provide a surrogate alternative to pathologic studies of affected myocardium. Future clustering of CMPs by phenotype, inheritance, and specific cause of disease can (1) generate data for precise clinical-genetic epidemiology and on the natural history of disease, and (2) highlight the need for development of therapies that can specifically target the cause.
Heritable Aneurysmal Diseases
Heritable Thoracic Aortic Aneurysm and Dissection
Heritable thoracic aortic aneurysm and dissection (TAAD) includes more than 40 genetically different disorders (Table 9–1). Syndromic diseases such as MFS, vascular EDSIV, and LDS are characterized by phenotypic traits that usually allow clinical diagnosis,6 with genetic testing playing a confirmatory role. TAAD can further occur as an isolated trait or in the context of less-known syndromes.
TABLE 9–1.Disease Genes and Phenotypes in Which Aortic Aneurysm Recura ||Download (.pdf) TABLE 9–1. Disease Genes and Phenotypes in Which Aortic Aneurysm Recura
|MIM* Gene ||Gene ||Protein ||Phenotypes/Diseases Allelic at the sSme Locus ||Inheritance ||Aortic Aneurysm ||Extra-aortic Aneurysm ||CHD/Valve Disease ||Stroke, CAD ||Tromboembolic Events ||Arterial Tortuosity ||Skeletal System ||Facies ||Ocular System ||Nervous System ||Integumantal System ||Respiratory System ||Craniosynostosis ||Learning Disability ||Hearing Loss |
|102620 ||ACTA2 ||Actin, alpha-2, smooth muscle, ||Aortic aneurysm, familial thoracic 6 ||AD ||x ||x ||x ||x || || || || ||x IF || || || || || || |
|604539 ||ADAMTS2 ||A disintegrin-like & metallo-proteinase with thrombo-spondin type 1 motif, 2 ||Ehlers-Danlos syndrome, type VIIC ||AR ||x ||x || || || || ||x ||x || || ||x ||x || || || |
|300011 ||ATP7A ||ATPase, Cu (2+)-transporting, a polypeptide ||Menkes syndrome ||XLR ||x ||x || || || || ||x ||x || ||x ||x || || ||x || |
|613381 ||CBS ||Cystathionine beta-synthase ||Homocystinuria, B6-responsive and nonresponsive ||AR ||x ||x || || ||x ||x ||x || ||x EL ||x ||x || || ||x || |
|608429 ||CHST14 ||Carbohydrate sulfotransferase 14 ||Ehlers-Danlos syndrome, musculocontractural, 1 ||AR || ||x ||x || || ||x ||x ||x ||x ||x ||x ||x ||x ||x || |
|120150 ||COL1A1 ||Collagen, type 1, alpha-1 ||Ehlers-Danlos syndrome, classic, VIIA ||AD ||x ||x || || || || ||x ||x || || ||x ||x || || || |
| || || ||Osteogenesis imperfecta I, II, III, IV || ||x || ||x || || || ||x || ||x BS || ||x ||x || || ||x |
|120160 ||COL1A2 ||Collagen, type 1, alpha-2 ||Ehlers-Danlos syndrome II, III, IV, VIIB, cardiac valvular form ||AR ||x ||x ||x || || || ||x || ||x BS ||x ||x || || || || |
|120180 ||COL3A1 ||Collagen, type 3, alpha-1 ||Ehlers-Danlos syndrome, type IV ||AD ||x ||x ||x || || || ||x ||x ||x BS || ||x ||x || || || |
|120130 ||COL4A1 ||Collagen, type 4, alpha-1 ||Tortuosity of retinal arteries, angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, brain small vessel disease with or without ocular anomalies, porencephaly 1, susceptibility to hemorrhage, intracerebral. ||AD || || || || || ||x ||x ||x ||x ||x ||x || || ||x || |
|120070 ||COL4A3 ||Collagen, type 4, alpha-3 ||Alport syndrome, autosomal dominant ||AD ||x || || || || ||x ||x || ||x || || || || || ||x |
| || || ||Alport syndrome, autosomal recessive ||AR ||x || || || || || || || ||x || || || || || ||x |
|120131 ||COL4A4 ||Collagen, type 4, alpha-4 ||Alport syndrome, autosomal recessive ||AR ||x || || || || || || || ||x || || || || || ||x |
|303630 ||COL4A5 ||Collagen, type 4, alpha-5 ||Alport syndrome, X-linked ||XLD ||x || || || || || || || ||x || ||x || || || ||x |
|120215 ||COL5A1 ||Collagen, type 5, alpha-1 ||Ehlers-Danlos syndrome, classic type ||AD ||x || ||x || || || ||x || ||x ||x ||x || || || || |
|120190 ||COL5A2 ||Collagen, type 5, alpha-2 ||Ehlers-Danlos syndrome, classic type ||AD ||x || ||x || || || || || ||x ||x ||x || || || || |
|120110 ||COL10A1 ||Collagen, type 10, alpha-1 ||Metaphyseal chondrodysplasia, Schmid type ||AD || || || || || || ||x || || || || || || || || |
|604633 ||EFEMP2 ||EGF-containing fibulin-like extracellular matrix protein 2 ||Cutis laxa, autosomal recessive, type IB ||AR ||x ||x || || || ||x ||x ||x ||x ||x ||x || || || || |
|130160 ||ELN ||Elastin ||Cutis laxa; supravalvar aortic stenosis ||AD ||x ||x ||x || || || ||x || || ||x ||x ||x || || || |
|134797 ||FBN1 ||Fibrillin1 ||Ectopia lentis, familial; Marfan syndrome; acromicric dysplasia; aortic aneurysm, ascending, and dissection; geleophysic dysplasia 2; Stiff skin syndrome; MASS syndrome; Weill-Marchesani syndrome 2, dominant ||AD ||x || || || || ||x ||x || ||x ||x ||x ||x ||x || || |
|612570 ||FBN2 ||Fibrillin 2 ||Contractural arachnodactyly, congenital; macular degeneration, early onset ||AD ||x || || || || || ||x || ||x ||x ||x || ||x || || |
|614505 ||FKBP14 ||FK-506 binding protein 14 ||Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss ||AR || || || || || || ||x || || ||x ||x || || || ||x |
|300017 ||FLNA ||Filamin A ||Cardiac valvular dysplasia, X-linked; heterotopia, periventricular; congenital short bowel syndrome; frontometaphyseal dysplasia; intestinal neuronal pseudoobstruction, ||XLR/XLD ||x ||x || ||x || || ||x || ||x ||x ||x || || ||x || |
|609367 ||KIAA1279 ||Kinesis-binding protein 1279 ||Goldberg-Shprintzen megacolon syndrome ||AR || || || || || || ||x ||x ||x ||x || || || ||x || |
|601468 ||MAT2A ||Methionine adenosyltransferase II, Alpha || ||AD ||x || || || || || || || || || || || || || || |
|601103 ||MFAP5 ||Microfibrillar-associated protein 5 ||Aortic aneurysm, familial thoracic 9 ||AD ||x || || || || || ||x || || || || || || || || |
|160745 ||MYH11 ||Myosin, heavy chain 11, smooth muscle ||Aortic aneurysm, familial thoracic 4 ||AD ||x ||x ||x ||x || || || || || || || || || || || |
|600922 ||MYLK ||Myosin light chain kinase ||Aortic aneurysm, familial thoracic 7 ||AD ||x || || || || || || || || || || || || || || |
|190198 ||NOTCH1 ||NOTCH, Drosophila, homolog of ||Aortic valve disease; Adams-Oliver syndrome 5 ||AD ||x || ||x || || || || || ||x || ||x || || || || |
|153454 ||PLOD1 ||Procollagen-lysine, 2-oxoglutarate 5-dioxigenase ||Ehlers-Danlos syndrome, type VI ||AR || || || || || || ||x || ||x ||x ||x ||x || || || |
|176894 ||PRKG1 ||Protein kinase, cGMP-dependent, regulatory, type 1 ||Aortic aneurysm, familial thoracic 8 ||AD ||x || || ||x || || ||x || || ||x || || || || || |
|164780 ||SKI ||V-ski avian sarcoma viral oncogene homolog ||Shprintzen-Goldberg syndrome ||AD ||x || ||x || || ||x ||x ||x ||x ||x ||x || ||x ||x || |
|606145 ||SLC2A10 ||Solute carrier family 2 ||Arterial tortuosity syndrome ||AR ||x ||x || ||x ||x ||x ||x ||x ||x ||x ||x || ||x ||x || |
|608735 ||SLC39A13 ||Solute carrier family 39 (zinc transporter), member 13 ||Spondylocheirodysplasia, Ehlers-Danlos syndrome-like ||AR || || || || || || ||x || ||x BS || || || || ||x || |
|603109 ||SMAD3 ||Mothers against Decapentaplegic, Drosophila, homolog Of, 3 ||Loeys-Dietz syndrome, 3 ||AD ||x ||x || || || ||x ||x ||x || || ||x || ||x || || |
|600993 ||SMAD4 ||Mothers against Decapentaplegic, Drosophila, homolog of, 4 ||Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Myhre syndrome, polyposis, juvenile intestinal ||AD ||x || || || || || ||x || || || ||x || || || || |
|190180 ||TGFB1 ||Transforming growth factor, beta-1 ||Camurati-Engelmann disease, cystic fibrosis lung disease ||AD, AR ||x || || || || || ||x || || || ||x || || || || |
|190220 ||TGFB2 ||Transforming growth factor, beta-2 ||Loeys-Dietz syndrome, 4 ||AD ||x ||x || || || ||x ||x ||x ||x ||x ||x || || || || |
|190230 ||TGFB3 ||Transforming growth factor, beta-3 ||Loeys-Dietz syndrome 5, arrhythmogenic right ventricular dysplasia 1 ||AD ||x ||x || || || ||x ||x ||x ||x ||x ||x || || || || |
|190181 ||TGFBR1 ||Transforming growth factor-beta receptor, type I ||Loeys-Dietz syndrome, 1; multiple self-healing squamous epithelioma ||AD ||x || || || || ||x ||x ||x ||x BS || ||x || ||x || || |
|190182 ||TGFBR2 ||Transforming growth factor-beta receptor, type II ||Colorectal cancer, hereditary nonpolyposis,6; esophageal cancer, Loeys-Dietz syndrome 2 ||AD ||x ||x || || || ||x ||x ||x ||x BS ||x ||x || || || || |
|600742 ||TGFBR3 ||Transforming growth factor-beta receptor, type III ||Thoracic aortic aneurysm ||AD || ||x || || || || || || || || || || || || || |
|600985 ||TNXB ||Tenascin Xb ||Ehlers-Danlos syndrome caused by tenascin X deficiency; vesicoureteral reflux 8 ||AR, AD || || ||x || || || ||x || || || ||x || || || || |
Genetic, familial TAAD (FTAAD) can be grouped according to the molecular pathway/structure in which disease genes are involved.6,72 Genes encoding components of the extracellular matrix are associated with MFS (FBN1 gene) and other diseases allelic at the same locus (isolated FTAAD, MAAS, Weill-Marchesani syndrome, familial ectopia lentis syndrome, and geleophysic and acromicric dysplasia)1,72,73 as well as vascular EDSIV74 caused by mutations in the COL3A1 gene. Genes encoding components of the transforming growth factor-beta (TGF-beta) signaling pathway include TGFBR1 and TGBFR2 that cause LDS1 and LDS2 and FTAAD in patients who do not show common traits recurring in LDS1.72,75 Mutations in the SMAD3 gene (playing its role in the TGF-beta signaling pathway) cause the osteoarthritis-aneurysm syndrome.76 Mutations in genes encoding structural components of vascular smooth muscle cells cause FTAAD either as an isolated trait or in association with recurrence of CHD, such as patent ductus arteriosus, bicuspid aortic valve, premature stroke, CAD, and moyamoya disease.77,78,79 Precise description of the phenotype (TAAD) and of the corresponding disease genes (eg, FTAAD-SMAD3, FTAAD-TGFBR1) incorporates the essential diagnostic information, providing a system to precisely communicate diagnoses.6
Bicuspid aortic valve (BAV) is common in the general population (1%). In 25% of cases, it is associated with dilation of the ascending aorta.80 BAV-associated aortopathy constitutes a further independent subgroup of aortic diseases, which should be distinguished from that recurring in CHD (such as hypoplastic left heart syndrome, coarctation of aorta, septal defects) and in syndromes such as Andersen-Tawil, DiGeorge, Noonan, LEOPARD, and Turner syndromes.80,81 Nonsyndromic familial BAV has been associated with mutations in NOTCH182 that encode a single-pass transmembrane receptor with signaling functions, and in GATA5,83 which encodes a cardiac transcription factor. BAV associated with aortic dilatation has also been reported in isolated FTAAD-TGFBR1, FTAAD-TGFBR2, FTAAD-SMAD3, FTAAD-TGFB2, and FTAAD-ACTA2.6
In clinical practice, the phenotype-based approach to the diagnosis is distinctly useful for syndromes: most clinicians now recognize MFS patients by their typical skeletal traits, LDS1 patients by their typical craniofacial traits, or EDSIV patients from their skin and face morphology. This diagnostic impact is uniquely beneficial in emergency situations when aortic dissection coincides with the clinical onset of the disease. Additional clinically useful information for patients presenting with emergency aortic dissection is family history, exploring prior similar events or “unexplained” sudden death in relatives.
Genetic workup can be either thoracic aortic aneurysm (TAA)–oriented in patients presenting for genetic evaluation after an established diagnosis of arterial aneurysm (aorta or other arteries), or phenotype-based in patients referred for genetic evaluation of skeletal, craniofacial, or ocular traits or syndromes in which TAA may recur. The latter group of patients should undergo 2D echocardiography, wherein the morphology and dimensions of the aortic valve annulus, root, sinotubular junction, ascending aorta, arch, thoracic descending aorta, and abdominal aorta should be systematically annotated. Geneticists involved in TAAD multidisciplinary evaluation should be familiar with normal measures and calculation of corresponding z-scores.84 Genetic workup starts with counseling and physical examination of probands; multidisciplinary evaluation can add value to the genetic visit via characterization of multiple phenotypic traits. The pedigree construction may (1) highlight a positive family history for the given syndrome or for isolated TAAD or (2) describe fatal events in relatives.
Diagnosis of Thoracic Aortic Aneurysm
Current guidelines provide detailed information on cardiovascular workup.85,86 TAA is routinely diagnosed by cardiac/angioimaging, with 2D echocardiography playing a key role. Further imaging investigation includes magnetic resonance or angio-CT scan, either limited to the thorax or extended to the total arterial tree, exploring the entire aorta as well as nonaortic arteries. In syndromes such as EDSIV, aortic dilation is not the rule, whereas aneurysms of muscular arteries are common. Arterial tortuosity is a nonspecific marker but is far more common in LDS than in MFS,87 with extreme manifestation in ATS.88 Information on nonaortic arteries is essential both as marker of disease and as detection of potentially harmful extra-aortic aneurysms.
Thoracic Aortic Aneurysm in Children
Clinical genetic evaluation should carefully distinguish diseases in which the aortic aneurysm may affect children from those in which the aneurysm develop in young-adult age. Pediatric aortic aneurysms are uncommon in MFS but common in LDS. Other diseases, such as Takayasu arteritis, should be considered, especially when an aortic aneurysm is present as isolated, nonsyndromic trait.89 Pediatric nonaortic arterial aneurysms may affect different vascular territories and may contribute to the diagnosis of malignant diseases such as vascular EDSIV.90
Most heritable isolated or syndromic TAADs are autosomal dominant diseases (Fig. 9–6). AR and XL TAAD are rare and, in small families, they may appear as sporadic diseases when a unique family member is affected. Typical examples of AR TAAD are ATS, homocystinuria, and cutis laxa type IB. Typical AR syndromes with aortic aneurysm include Alport syndrome and rare lysosomal diseases. Examples of X-linked TAADs include Menkes syndrome and diseases caused by defects of filamin A, which can be both XLR or XL dominant. Aortopathies can occur in patients with CHD, either as monogenic diseases or chromosomal disorders. TAA occurring in children or young and adult patients who do not carry known risk factors for aortic aneurysms should be suspected to have a genetic origin regardless of family history. De novo disease is common in syndromic TAAD, and possible in rare storage diseases such as AFD, in which GB3 accumulates in vascular smooth muscle cells (Fig. 9–7). Two-dimensional echocardiography-based screening of relatives may demonstrate a familial TAAD. In fact, aortic dilation is asymptomatic, unless exerting some compressive effects on closer structures or manifesting with dissection.
The figure shows the pedigree of a family with autosomal dominant Marfan syndrome; the proband is the father whose first diagnosis coincided with aortic dissection. Two of four are children affected. The affected son also has autosomal recessive epidemolysis bullosa and demonstrates a severe aortic aneurysm involving the root, with loss of sinotubular junction and dilation of the ascending aorta.
Electron micrograph of arteriolar smooth muscle cells (SMCs) in a male patient diagnosed with Anderson Fabry disease. The cells show diffuse cytoplasmic accumulation of GB3.
The decision to proceed to genetic testing relies in part on the family pedigree. If there is no clear phenotype in other family members (all family members appear nonaffected), then the utility of genetic testing is reduced and less commonly pursued. However, isolated TAA can be present in asymptomatic family members who are not aware of their disease. Therefore, a negative family pedigree obtained on the narrative of the proband is not sufficient to exclude a familial TAA. The pedigree can be considered informative after clinical family screening including echocardiographic evaluation of first-degree relatives of the proband.
Genetic testing can be performed by sequencing a unique gene in the instance of a strong clinical diagnostic hypothesis. Alternatively, large panels of disease genes and exome sequencing are used to identify mutations in known disease genes or novel candidate/disease genes.91,92,93,94 Depending on the disease gene, the interpretation of results may confirm the clinical diagnosis or play a diagnostic role in isolated, nonsyndromic TAAD. This highlights the need of deep phenotyping in isolated TAAD in order to identify traits specifically recurring in apparently nonsyndromic TAAD associated with mutations in different genes, so that physicians are able to ascertain markers of disease or traits predicting the occurrence of the aortic aneurysm. A representative example is iris focculi, which may recur in families with ACTA2-TAAD.35,95 Prenatal diagnosis is now offered on a regular basis to couples in which one parent is affected by MFS.96 Noninvasive prenatal and preimplantation diagnosis can be an alternative to a conventional prenatal diagnosis for couples that do not accept the risk of pregnancy loss.97
Genotype-phenotype correlation studies have been performed in several syndromic TAADs with the major aim of distinguishing highly malignant diseases from milder phenotypes. MFS is the most widely investigated disease; nosology has changed over time, from the pre-genomic era, to the last 2010 revision,98 in which genetic testing entered as a major diagnostic criterion. Genetic testing is recommended in newly suspected MFS, especially when two systems are involved, with at least one major system affected.99 Patients who carry FBN1 mutations and demonstrate only one major clinical criterion or only minor clinical criteria in one or more organ system represent 5% of the adult series.100 The majority of clinical manifestations of MFS increase with age.101 Infant carriers of mutations in the neonatal exons demonstrate severe phenotypes102; in children less than 1 year of age, a shorter survival was associated with presence of valve insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.103 A higher risk of aortic dissection is reported in male patients.104
The Impact of Precise Genetic Diagnosis
In the past 10 years, it has been demonstrated that risk stratification for aortic dissection may vary based on the different subtypes of FTAAD and that preventive surgery should be planned considering both the individual patient and the disease-specific risk.85 In addition, the proposed role of TGF-beta in aneurysmal diseases, and FBN1 mouse models treated with anti-TGF-beta antibodies or drugs acting on TGF-beta opened up the possibility of exploring the effects of angiotensin receptor blockers (ARBs) in patients with MFS. Many clinical trials comparing the role of ARBs with beta-blockers105 have recently been concluded and others will conclude in the near future (Table 9–2).106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127 Based on results achieved to date, patients with MFS and aortic root dilation should receive medical therapy, with either beta-blockers or ARBs or both. Medications seem to be more effective at reduction of aortic root z-score in younger subjects, which suggests that medical therapy should be prescribed even in the youngest children with early/mild aortic dilation. For patients without aortic dilation, indications for medical treatment are less clear. In patients with severe and/or progressive aortic dilation the combination of a beta-blocker and ARB should be considered, although current trial results are mixed with respect to the efficacy of combination therapy versus monotherapy.
TABLE 9–2.Clinical Trials in Patients with Marfan Syndromea ||Download (.pdf) TABLE 9–2. Clinical Trials in Patients with Marfan Syndromea
|Study ||Nation ||Single Center/Multicenter ||Medications ||Study Type ||Sample Size ||Primary End Point ||Imaging ||Age ||Result ||Follow-up (years) |
|Nonrandomized Studies |
|Shores et al.106 ||US ||Single center ||No treatment vs propranolol ||Prospective, randomized, nonblinded || |
Control: 38 vs treated: 32
|Aortic root dimensions ||Echo ||12-50 years; < 18 years at entry: control: 68% vs treated: 60% ||BB was effective in slowing the rate of aortic dilatation and reducing the development of aortic complications ||Control: 9.3 years vs treated: 10.7 years |
|Salim et al.107 ||US ||Multicenter ||Propranolol or atenolol vs no therapy ||Prospective, nonrandomized, nonblinded ||113 ||Aortic root growth rate || |
|< 21 years at time of first visit ||Treatment at a younger age blunted the aortic root growth rate to a greater extent || |
Control: 5.7 ± 1.8 years
Group A: 5.5 ± 2.7 years; Group B: 4.2 ± 2.1 years
|Rossi-Foulkes et al.108 ||US ||Single center ||Verapamil or BB vs no therapy ||Prospective, nonrandomized, nonblinded ||44 ||Aortic root growth rate ||Echo || |
Female: < 17 years
Male: < 19 years
|BB and CCB decreased aortic root growth rate ||3.67 ± 2 years |
|Selamet Tierney et al.109 ||US ||Multicenter ||BB vs no BB ||Retrospective, nonrandomized, nonblinded || |
Control: 34 vs treated: 29
|Rates of change in the aortic root measurements and their correspondingz scores over time ||Echo ||≤ 18 years ||Rates of change of aortic root measurements and the corresponding z scores were not statistically different between the two groups ||Control: 6.75 ± 4.49 years; treated: 6.36 ± 2.58 years |
|Ladouceur et al.110 ||France ||Multicenter || |
No treatment vs BB
Atenolol: > 70%
|Retrospective, nonrandomized, nonblinded ||155 ||Aortic root growth rate ||Echo ||< 12 years ||BB significantly decreased the rate of aortic-root dilatation by a mean of 0.16 mm/year compared to no treatment. ||4.5 ± 3.7 years |
|Brooke et al.111 ||US ||Single center ||Losartan or irbesartan ||Nonrandomized, retrospective, observational ||18 ||Rate of change in aortic root diameter ||Echo ||1-16 years ||ARB therapy significantly slowed the rate of progressive aortic root dilation ||Median, 2.175 years; range, 1-3.92 years |
|Pees et al.112 ||Austria ||Single center ||Losartan monotherapy vs matched healthy cohort ||Prospective, unselected cohort compared with matched healthy cohort ||20 ||Aortic dimensions and elasticity indexes ||Echo ||1.7-21.6 years ||Significant improvement with losartan only; therapy was proven in all affected proximal aortic segments with a better response to therapy when started at an earlier age and with a longer duration of therapy ||2.75 ± 0.92 years |
|Mueller et al.113 ||DE ||Single center ||Valsartan v. metoprolol ||Nonrandomized, retrospective, observational ||40 ||Aortic root growth rate ||Echo ||9.01 ± 5.7 years ||Both ARBs and BBs led to a significant reduction in aortic root dilation ||ARB: 1.4 ± 0.24 years vs BB: 5.51 ± 3.3 years |
|Yetman et al.114 ||US ||Multicenter ||Enalapril vs propranolol or atenolol ||Prospective, nonrandomized, open label ||58 ||Aortic elastic properties and aortic root growth rate ||Echo ||- ||Treatment with enalapril improved aortic distensibility, reduced aortic stiffness index, decreased aortic root growth rate, and resulted in fewer clinical end points during follow-up compared with BBs ||3 ± 0.2 years |
|Phomakay et al.115 ||US ||Single center ||Atenolol (46%), metoprolol (48%), and propranolol (6%). Lisinopril (13%), enalapril (85%), and captopril (2%) ||Retrospective, nonrandomized ||67 ||Aortic root growth rate ||Echo ||13±10 years ||Angiotensin-converting enzyme inhibitor did not significantly decrease aortic root growth rate ||7.6 ± 5.8 years |
|Randomized Clinical Trials |
|Chiu et al.116 ||Taiwan ||Single center ||Atenolol or propranolol vs losartan with atenolol or propranolol ||Randomized, open-label ||28 || |
Aortic root growth rate
Efficacy and safety of losartan with BB treatment
|Echo ||6.8-19.4 years ||Losartan combined with BB therapy was safe and provided more effective protection to slow the progression of aortic root dilation than BB alone ||2.93 years |
|Ahimastos et al.117 ||Australia ||Single center ||BB with placebo vsBB with perindopril ||Prospective, randomized, double-blind, placebo-controlled || |
|Arterial stiffness and aortic root diameter || |
|27-40 years ||Perindopril reduced aortic stiffness and aortic root diameter in patients who received standard BB therapy ||0.46 Year |
|Williams et al.118 ||UK ||Multicenter ||Atenolol vs perindopril vs verapamil ||Prospective, randomized, double-blind, crossover trial ||18 ||Large artery function: central aortic pressure, augmentation of central pressure, conduit arterial stiffness || |
Pulse wave analysis
|16-60 years ||Perindopril, verapamil, and atenolol all reduced peripheral and central pressure ||0.35 Year |
|Nonrandomized Studies |
|Groenink et al.119 ||Netherlands ||Multicenter ||Losartan with baseline therapy vs no additional therapy (control) ||Randomized, open-label, blinded assessments of end points ||223 ||Aortic dilatation rate at 6 predefined aortic levels assessed with MRI or CT || |
|≥ 18 years ||Losartan reduced aortic root dilatation rate. After aortic root replacement, losartan reduced dilatation rate of the aortic arch ||3.1 ± 0.4 years |
|Milleron et al.120 ||France ||Multicenter ||Losartan with baseline therapy vs placebo with baseline therapy (BB 86%) ||Prospective, randomized, double-blind, placebo-controlled, parallel group, add-on trial ||303 ||Aortic root growth rate, normalized to its theoretical value and expressed as mean change in z-score per year ||Echo ||≥ 10 years ||Losartan did not reduce aortic dilatation during a 3-year period ||3.5 years (median) |
|Lacro et al.121 ||US ||Multicenter ||Atenolol vs losartan ||Prospective, randomized, participants and echo core laboratory blinded to treatment assignment ||608 ||Rate of change in aortic root z-score (slope) ||Echo ||0.5-25 years ||No significant difference in the rate of aortic root dilatation between the two treatment groups ||3 years |
|Sandor et al.122 ||Canada ||Multicenter ||Atenolol (25-50 mg) vs losartan (25 mg) ||Prospective, randomized, double-blind ||17 ||Vascular function; pulse wave velocity || |
|10.6-27.8 years ||Atenolol and losartan might have different mechanisms of action on vascular function ||1 Year |
|Bhatt et al.123 ||US ||Multicenter ||Losartan (100 mg) vs atenolol (50 mg) ||Prospective, randomized, double-blind ||34 ||Arterial stiffness values; carotid-femoral pulse wave velocity, central augmentation index; aortic diameter; left ventricular function || |
|> 25 years ||Atenolol improved pulse wave velocity; Losartan reduces central augmentation index ||0.5 Year |
|Forteza et al.124 ||Spain ||Multicenter ||Atenolol vs losartan ||Prospective, randomized, double-blind ||150 ||Aortic growth and distensibility; prevention of adverse event ||MRI ||5-60 years ||Aortic root diameter increased significantly in both groups: 1.1 mm (95% CI, 0.6-1.6) in the losartan and 1.4 mm (95% CI, 0.9-1.9) in the atenolol group, with aortic dilatation progression being similar in both groups: absolute difference between losartan and atenolol -0.3 mm (95% CI, -1.1 to 0.4, P = 0.382) and indexed by BSA -0.5 mm/m (2) (95% CI -1.2 to 0.1, P = .092). Similarly, no significant differences were found in indexed ascending aorta diameter changes between the losartan and atenolol groups: -0.3 mm/m (2) (95% CI -0.8 to 0.3, P = .326). ||3 years |
|Randomized Clinical Trials Still Open |
|Gambarin et al.125 ||Italy ||Single center ||Nebivolol vs losartan vs nebivolol with losartan ||Randomized, open label, phase III study ||291 ||Aortic root growth rate ||Echo ||1-55 years ||Pending ||4 years |
|Moberg et al.126 ||Belgium ||Single center ||Losartan vs placebo with BB ||Prospective, randomized, double-blind, placebo-controlled ||174 ||Aortic root growth rate || |
|≥ 10 years ||Pending ||3 years |
|Mullen et al.127 ||UK ||Multicenter ||Irbesartan vs placebo ||Prospective, randomized, double-blind, placebo-controlled ||490 ||Absolute change in aortic root growth rate ||Echo ||6-40 years ||Pending ||4 years |
Independent of the results, the message from these studies is the novel impact of precise diagnosis on the potential development of personalized, disease-oriented treatment of heritable aneurysmal diseases.
Definition and Classification
Pulmonary arterial hypertension (PAH) is a rare, life-threatening disease, affecting between 1 to 2 per 100,000 and 1 per 1 million people128 (see Chap. 74). In the 2016 ESC guidelines, pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure—at least 25 mm Hg at rest as assessed by right heart catheterization.129 Current clinical classification is based on the principles of similarities in pathobiology, clinical features, and therapeutic options.130 More than 40 different diseases are divided into 5 groups (updated classification, Nice, 2013):
Group 1: idiopathic, heritable, drug-induced PAH, CHD with pulmonary hypertension, pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. This includes chromosomal deletion syndromes such as Williams-Beuren syndrome (deletion 7q11.23) and Alagille syndrome (deletion 20p11-2) as well as monogenic diseases such as Keutal syndrome and cutis laxa, in which peripheral pulmonary artery stenosis may occur either as isolated defects or in association with other congenital heart defects.
Group 2: pulmonary venous hypertension or PAH caused by left heart disease
Group 3: PAH caused by lung diseases and/or hypoxia
Group 4: chronic thromboembolic PAH (CTEPH)
Group 5: miscellaneous disorders that can affect the pulmonary vasculature with unclear and/or multifactorial mechanisms.
The causes can be genetic in primary PAH, group 1, and group 5.
Genetic Workup and Assessment of Disease-Specific Risk Factors
Genetic causes are well recognized in several forms of PAH. Accordingly, the diagnostic workup should systematically include counseling and, in case of monogenic diseases, clinical family screening, and cascade genetic testing. Genetic counseling explores personal and family medical history as well as exposure to known toxic agents and drugs, followed by genetic testing as recommended by scientific societies.131 Disease-specific risk factors are classified as definite, likely, or possible on the basis of the strength of their association with PH and their probable causal role130,132 (Table 9–3). A definite association is acknowledged in the case of appetite suppressants, or for drugs demonstrated as being associated with PAH in multicenter epidemiological studies. A likely association is considered when demonstrated in a single-center case-control study or multiple case series, or when clinical and hemodynamic recovery occurs after cessation of exposure (ie, dasatinib-induced PAH). The association is defined as possible for drugs with similar mechanisms of action as those in the two aforementioned categories, but have not yet been systematically studied, such as those used to treat attention deficit disorders. Genetic counseling should also explore autoimmune diseases, infections such as human immunodeficiency virus (HIV), possible parasitic diseases, exposure to radiation, living environment (high altitude), chronic renal diseases, sarcoidosis, and prior splenectomy. In patients with CTEPH, the investigation should include history of venous thromboembolic events (when known) and thrombophilic disorders.133,134 The pattern of inheritance is autosomal dominant in most patients with familial pulmonary hypertension; however, rare pulmonary veno-occlusive forms are inherited as recessive traits and may appear as sporadic, especially in small or noninformative families. Accordingly, genetic counseling, and eventually genetic testing, should be offered to all patients diagnosed with PAH (group 1) and pulmonary hypertension of unclear origin (group 5).
TABLE 9–3.Pulmonary Hypertension: Disease-Specific Risk Factors To Be Systematically Investigated in Genetic Counseling ||Download (.pdf) TABLE 9–3. Pulmonary Hypertension: Disease-Specific Risk Factors To Be Systematically Investigated in Genetic Counseling
|Definite ||Likely ||Possible |
Toxic rapeseed oil
Selective serotonin reuptake inhibitors (> risk of persistent pulmonary hypertension in newborns of treated mothers)
St John’s wort
Interferon α and β
Chemotherapeutic (ie, alkylating agents such as mytomycin C, cyclophosphamide [in particular for pulmonary veno-occlusive disease])
More than one disease gene has been identified in primary pulmonary hypertension (PPH)128,135 (Table 9–4). Genetic testing in probands can be clinically guided or performed through the screening of multigene panels by NGS. A clinically oriented approach is feasible for familial autosomal dominant PPH, in which mutations of bone morphogenetic protein receptor 2 (BMPR2) recur in up to 80% of patients and families. BMPR2 plays a role in the pathway of BMP and is a member of the TGF-beta superfamily that regulates cell growth, differentiation, apoptosis, and development. Less common disease genes, such as SMAD9, play a role in the same BMP pathway as downstream modulators of the BMP signaling pathway and cause a phenotypically similar, autosomal dominant PPH. Other disease genes, such as ALK-1 and endoglin (ENG), play a role in the TGF pathway; these genes account for a minority of familial PPH, which is a major trait of Osler–Weber–Rendu disease. Defects in other rare disease genes, such as CAVEOLIN 3 (CAV3), or genes coding ion channels, such as KCNH3, result in a similar phenotype, but via different mechanisms. Novel candidate genes include TOPBP1136 and CYP1B1.137 Pulmonary veno-occlusive hypertension is allelic at the PPH1 locus (BMPR2), whereas the recessive form is caused by mutations in EIF2AK4.138 Finally, group 5 PAH includes a variety of acquired and heritable diseases such as the AD lymphangioleiomyomatos139 and lysosomal storage diseases such as glycogen storage disease types 1 and 3140,141 and Gaucher disease type 1.142,143
TABLE 9–4.Disease Genes, Gene loci (*), Phenotypes and Inheritance Pattern of Primary Pulmonary Hypertension, as well as Genes Associated with the Veno-Occlusive Form of Pulmonary Hypertension and with Hereditary Hemorrhagic Telangiectasia ||Download (.pdf) TABLE 9–4. Disease Genes, Gene loci (*), Phenotypes and Inheritance Pattern of Primary Pulmonary Hypertension, as well as Genes Associated with the Veno-Occlusive Form of Pulmonary Hypertension and with Hereditary Hemorrhagic Telangiectasia
|WHO Group ||Type ||Gene ||*Gene Locus ||Protein ||Inheritance |
|Primary Pulmonary Hypertension (PPH) |
|1 ||PPH1 ||BMPR2a ||600799 ||Bone morphogenetic protein receptor 2 ||AD |
|1 ||PPH2 ||SMAD9 ||603295 ||Mothers against decapentaplegic Drosophila, homolog of, 9 ||AD |
|1 ||PPH3 ||CAV1 ||601047 b ||Caveolin1 ||AD |
|1 ||PPH4 ||KCNK3 ||603220 ||Potassium channel, subfamily K, member 3 ||AD |
|1 ||Dexfenfluramine-associated pulmonary hypertension ||CYP1B1 ||601771 ||Cytochrome P450; subfamily 1; polypeptide 1 ||AD(?) |
|- ||Phenotype not yet included in the OMIM catalog ||TOPBP1 ||607760 ||Topoisomerase DNA binding II binding protein 1 ||AD |
|Pulmonary Venoocclusive Disease (PVOD) |
|1 ||PVOD1 ||BMPR2 ||600799 ||Bone morphogenetic protein receptor 2 ||AD |
|1 ||PVOD2 ||EIF2AK4 ||609280 ||Eukaryotic translation initiation factor-2, alpha kinase 4 ||AR |
|Hereditary Hemorrhagic Telangiectasia (HHT) |
|1 ||HHT1 (Rendu-Osler-Weber) ||ENG ||131195 ||Endoglein (CD105) ||AD |
|1 ||HHT2 ||ACVRL1 ||601284 ||Activin A receptor, type II-like 1 ||AD |
|Lymphangioleiomyomatosis (LAM) |
|5 ||Tuberous sclerosis-1; LAM ||TSC1 ||605284 ||Amartin ||AD |
|5 ||Tuberous sclerosis-2 and LAM somatic mutations ||TSC2 ||191092 ||Tuberin ||AD |
|Lysosomal Storage Diseases |
|5 ||Glycogen storage disease type1 || |
|Glucose-6-phosphatase and glucose-6-phosphate translocase ||AR |
|5 ||Glycogen storage disease types 3a and b ||AGL ||610860 ||Glycogen debrancher enzyme ||AR |
|5 ||Gaucher disease type 1 (with or without splenectomy) ||GBA ||606463 ||Acid beta-glucosidase ||AR |
Interpretation of the Results of Genetic Tests
The type of mutation facilitates the interpretation of BMPR2 testing results. Most mutations are truncation-predicting defects (frameshift, nonsense, splice site) ending in haploinsufficiency.135 In carriers of missense mutations, family segregation studies, in silico analysis, and eventually pathologic studies (when lung samples are available) may contribute to clarify their role. Genetic tests should be expanded to all probands presenting with “idiopathic” PPH; up to 20% of patients with apparently sporadic PPH carry BMPR2 mutations.
The segregation analysis of the genotype with phenotype can be complicated by incomplete penetrance because affected members of the same family may not show the phenotype at time of screening; regular clinical monitoring should be scheduled for clinically unaffected but genetically affected family members. Phenotype expression may be age-dependent or may be influenced by exposure to environmental factors. A double-hit hypothesis has been proposed to explain the variable clinical manifestations of the disease. The hypothesis of anticipation of the phenotype in younger members of the same family does not have corresponding molecular mechanisms. Current knowledge regarding the molecular basis of PPH1 does not include evidence of triplet expansion, and recent longitudinal studies do not seem to confirm this hypothesis.144 Finally, incomplete penetrance can be a result of incomplete genotyping; the spectrum of disease and modifier genes potentially involved in PPH are far from being fully elucidated.
Clinical genetics with counseling and pedigree construction, search for known risk factors and annotation of novel potential risk factors, family investigation, and genetic testing are currently translated in the clinical setting. Clinical attention to PAH is encouraged by the availability of new medical treatments (endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, soluble guanylate cyclase stimulators, and prostanoids) that continue to be tried in patients with idiopathic, heritable, drug-induced, and connective tissue disease-associated PAH. Genetic workup significantly contributes to precise diagnosis.
Inherited Atrial Diseases
Genetic Atrial Diseases: Beyond Atrial Fibrillation
Heritable atrial diseases include rare atrial CMPs, AR or AD sick sinus syndrome, rare novel syndromes with extracardiac involvement, and a certain proportion of lone atrial fibrillation (AF). The aim of this section is to highlight the genetic workup of rare heritable atrial diseases and familial lone AF (see AF in Chap. 83).
Atrial Dilated Cardiomyopathy
ADCM is a rare AR disease characterized by clinical onset in adulthood, biatrial dilatation up to giant size, early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill, thromboembolic complications, stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease, and severely decreased levels of atrial natriuretic peptide. The disease is caused homozygous mutations in the natriuretic peptide precursor A (NPPA) gene; heterozygous carriers are healthy and demonstrate normal levels of atrial natriuretic peptides.11 Phenotypically similar, adult-onset phenotypes have been reported in one Indian case,145 two Australian patients,146 and, more recently, children with isolated right atrial dilation.147 Similar atrial disease and isolated atrial amyloidosis in three Japanese siblings148 suggest a recessive inheritance, and the possible contribution of atrial amyloid deposits to the pathological substrates of atrial CMPs. In the past, these diseases were described as idiopathic atrial dilation or congenital atrial malformations.149,150 A precise diagnosis influences decision on treatments such as ablation for arrhythmias and early anticoagulation that should be initiated in patients with atrial dilation regardless of the arrhythmias. When the disease is unrecognized, stroke can coincide with disease onset.
Sick sinus syndrome (SSS) is clinically characterized by sinus bradycardia, sinus arrest, chronotropic incompetence and susceptibility to atrial arrhythmias.151 SSS can be sporadic, such as the common SSS observed in older persons,152 or familial, typically manifesting in young patients. Familial SSS are clinically and genetically heterogeneous diseases, either AD or AR. The onset of AR SSS (SSS1, MIM #608567) may occur in childhood and adolescence.153,154,155,156,157 It is caused by mutations in SCN5A gene, which encodes the α-subunit of the cardiac Na+ channel. In small families, the disease may appear as sporadic; however, the young age of patients and the absence of other cardiac diseases that may explain the phenotype are by themselves sufficient to refer probands and families for genetic counseling. Clinical family screening demonstrates the absence of manifestations in parents. Parental consanguinity or origin of parents from geographic isolates may contribute to suspect AR inheritance. Genetic testing demonstrating homozygous mutations or compound mutations in the SCN5A gene is uniquely useful to conclude the diagnostic workup.158 The AD SSS (SSS2, MIM #163800) is caused by mutations in the HCN4 gene that codes for hyperpolarization activated cyclic nucleotide-gated potassium channel.159 Heterozygous mutations have been identified in patients with SSS complicated by life-threatening arrhythmias160 and in familial asymptomatic sinus bradycardia.161 The genetic diagnosis of SSS contributes to identify at-risk family members, to schedule monitoring for prevention of arrhythmias, and to support decisions for ablation of atrial arrhythmias or PM implantation.
Rare Novel and Known Syndromes: Cohesinopathies
Cohesinopathies are disorders caused by mutations in subunits or regulators of cohesin.162 They may commonly affect the heart and manifest with arrhythmias and/or CHD. Atrial arrhythmias recur in chronic atrial and intestinal dysrhythmia (CAID) syndrome, a recently described AR disorder. CAID is clinically characterized by deregulation of the cardiac sinus node leading to SSS and of gastrointestinal motility resulting in chronic intestinal pseudo-obstruction (CIPO).163 Both traits can represent distinct disorders associated with mutations in genes known to cause either SSS or CIPO. However, when SSS and CIPO coexist, the disease-causing gene is Shugosin-like 1 (SGOL1, MIM *609168), which has been recently identified in 16 French Canadians and 1 Swede; the gene encodes a component of the cohesin complex (made up of SGO1 and SGO2) that protects centromeric integrity.163 Atrial arrhythmias do not seem to be common in other cohesinopathies, such as Cornelia de Lange syndrome (CDLS) in which CHD recur in up to 30% of cases164; left ventricular dilation and hypertrophy, right ventricular CMP, and sudden death in CDLS have been reported in autopsy series165 or in patients demonstrating HCM.166 CDLS is a genetically heterogeneous disease entity, with five associated genes, all of which are active in the cohesin complex.167
The precise diagnosis of CAID has clinical implications for affected children and young adults, not only for atrial arrhythmias but also for treatments of CIPO, including both prokinetic agents used to relieve symptoms caused by gut dysmotility (ie, arrhythmogenic effect of cisapride)168,169 and nonopioid drugs used to control abdominal pain.170
AF is the most common arrhythmia (1.5% of the general population), affecting health and quality of life. Lone AF accounts for about 5% to 10% of all AF. AF can be sporadic or familial171,172; about 30% of patients with AF have a positive family history,173,174 and individuals with at least one parent with AF have a relative risk of AF of 85%.173 Genetic studies are rapidly progressing, and numerous disease genes and chromosomal loci have been identified to date in familial AF175 (Table 9–5).
TABLE 9–5.The Table Shows the List of Genes that have been Reported as Associated with Familial Af. The Red and Blue Dots Indicate Genes that have been Assigned to the Atrial Fibrillation (Atfb) Phenotype (#) in the Mim Catalogue; Red Dots () Indicate Autosomal Dominant And Blue Dots () Autosomal Recessive Inheritance. Dark Gray Dots (•) Indicate Genes in Which Mutations have been Reported in One or a Few Cases and are Not Yet Validated. The Table also Lists All Disorders that are Recognised to be Allelic at the Same Locus. Up To January 2016, Af Has Not Been Associated With Mutations In ANK2 (Lqt4), CACNA1C (Lqt8, Thimoty Syndrome, Brugada Syndrome 3), CAV3 (Lqt9), AKAP9 (Lqt11), SNTA1 (Lqt12), CALM1 (Lqt14), CALM2 (Lqt15), GPD1L (Brugada Syndrome 3), CACNB2 (Brugada Syndrome 4), and HCN4 (Brugada Syndrome 8). This Latter Gene However is Involved in Sss Type 2, Autosomal Dominant. ||Download (.pdf) TABLE 9–5. The Table Shows the List of Genes that have been Reported as Associated with Familial Af. The Red and Blue Dots Indicate Genes that have been Assigned to the Atrial Fibrillation (Atfb) Phenotype (#) in the Mim Catalogue; Red Dots () Indicate Autosomal Dominant And Blue Dots () Autosomal Recessive Inheritance. Dark Gray Dots (•) Indicate Genes in Which Mutations have been Reported in One or a Few Cases and are Not Yet Validated. The Table also Lists All Disorders that are Recognised to be Allelic at the Same Locus. Up To January 2016, Af Has Not Been Associated With Mutations In ANK2 (Lqt4), CACNA1C (Lqt8, Thimoty Syndrome, Brugada Syndrome 3), CAV3 (Lqt9), AKAP9 (Lqt11), SNTA1 (Lqt12), CALM1 (Lqt14), CALM2 (Lqt15), GPD1L (Brugada Syndrome 3), CACNB2 (Brugada Syndrome 4), and HCN4 (Brugada Syndrome 8). This Latter Gene However is Involved in Sss Type 2, Autosomal Dominant.
The role of clinical genetics involves deep phenotyping patients presenting with lone AF to exclude presence of other traits or diseases that can explain the arrhythmia. In fact, some of the genes that have been linked to AF may also cause different cardiac and noncardiac diseases. In other words, AF can represent one of the early manifestations of genetic CMPs. Family studies should demonstrate that other affected members do not exhibit CMPs or other cardiac diseases; the distinction between lone familial AF versus AF complicating other genetic heart diseases prevents incorrect assignment of a causative role for AF to genes that cause CMPs in which AF may recur as part of the evolving phenotype.176 A typical example is AF in patients with cardiolaminopathies. A systematic screening of LMNA in a cohort of 268 unrelated patients with idiopathic forms of familial and sporadic AF identified a unique, possible but nonconfirmed mutation, thus excluding this gene as a candidate for lone AF.177 Disease genes identified by linkage analysis in well-phenotyped families have been confirmed both as cause of familial AF178,179,180 and of different heritable atrial diseases (NPPA).11 Genes such as SCN5A that cause long QT syndrome (LQTS), short QT syndrome (SQTS), or Brugada syndrome may also cause AF, and long-term follow-up of mutation carriers is necessary to exclude other arrhythmogenic phenotypes or explore why the same mutations may manifest different arrhythmogenic phenotypes.
Precision Diagnosis of Atrial Diseases
Genetic AF is an expanding area of precision cardiology but requires family screening and monitoring to confirm a disease gene for AF. Segregation studies are complicated by the need for long-term follow-up or recording systems to clinically identify family members at risk of developing AF. Paroxysms of AF can be clinically silent and, unless an ECG recording system is implanted, clinically silent episodes of AF can be missed. Clinical surveillance can reveal silent AF episodes, thus contributing to genotype-phenotype correlation studies, preventive treatments, and elucidation of the role of genetic mutations in AF. Electroanatomic mapping in patients with AF is now contributing to the characterization of structural fibrotic changes observed in patients with heritable atrial diseases.180 Recently, the term fibrotic atrial cardiomyopathy has been introduced to describe the fibrotic substrate observed in patients with AF.181 Unraveling whether fibrosis is the cause or effect in heritable AF may contribute to treatment decisions.
Inherited Channelopathies and Life-Threatening Ventricular Arrhythmias
Cardiochannelopathies encompass a large, genetically heterogeneous group of electrical abnormalities that can be associated with unexpected sudden death.182,183 The majority of disease genes encode cardiac ion channels or proteins interacting with ion channels or involved in ion flux and metabolism (Table 9–6).182,183 Genetic workup includes clinical evaluation, genetic testing, and post-test counseling. Genetic teams, including clinicians, geneticists, genetic counselors, basic scientists, and pharmacologists, should evaluate the phenotype, age, gender, family and drug history, comorbidities, patient preferences, and therapeutic alternatives before proceeding to genetic testing.184,185 Patients and families are addressed to genetic counseling for (1) incidental observation of prolonged or short QT interval or Brugada pattern or early repolarization in ECG screening studies (eg, sport, professionals, army), (2) unexplained syncope, (3) resuscitated cardiac arrest (aborted sudden death), or (4) sudden death in a family member. The last condition represents the most complex diagnostic challenge when the DNA of the victim has not been preserved and medical records are not available. In this case, clinical family screening (ECG, 2D-echocardiography, 24-hour Holter monitoring) is the first step to establish whether relatives of the victim demonstrate ECG abnormalities or unperceived arrhythmias. The major groups of channelopathies associated with risk of sudden death include diseases that lengthen the QT interval—Brugada syndromes and catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are extensively reviewed in Chapters 79, 80, and 91. In this section, we briefly summarize major arrhythmogenic cardiochannelopathies, inheritance, disease genes, and phenotypes to provide further information for genetic counseling and testing.
TABLE 9–6.Complex and Heterogeneous Spectrum of Genes That Have Been Reported in Association with Arrhythmogenic Syndromesa ||Download (.pdf) TABLE 9–6. Complex and Heterogeneous Spectrum of Genes That Have Been Reported in Association with Arrhythmogenic Syndromesa
|Gene ||MIM* Gene ||Long QT Syndrome ||Short QT Syndrome ||Brugada Syndrome ||Catecholaminergic Polymorphic Ventricular Tachycardia |
|ABCC9 ||*601439 || || ||x || |
|ANK2 ||*106410 ||x || || ||x |
|AKAP9 ||*604001 ||x || || || |
|CACNA1C ||*114205 ||xb ||x ||x || |
|CACNA2D1 ||*114204 || ||x || || |
|CACNB2 ||*600003 || ||x || || |
|CALM1 ||*114180 ||x || || ||x |
|CALM2 ||*114182 ||x || || || |
|CASQ2 ||*114251 || || || ||x |
|CAV3 ||*601253 ||x || || || |
|GPD1L ||*611788 || || ||x || |
|HCN4 ||*605206 || || ||x || |
|MOG1 ||*607954 || ||x ||x || |
|NOS1AP ||*605551 || || ||x || |
|KCND3 ||*605411 || || ||x || |
|KCNE1 ||*176261 ||xc || || || |
|KCNE2 ||*603796 ||x || || || |
|KCNE3 ||*604433 || || ||x || |
|KCNE5 ||*300328 ||x || ||x || |
|KCNH2 ||*152427 ||x ||x ||x || |
|KCNQ1 ||*607542 ||x ||x || || |
|KCNQ2 ||*602235 ||x ||x || || |
|KCNJ2 ||*600681d ||x ||x ||x ||x |
|KCNJ5 ||*600734e ||x || || || |
|KCNJ8 ||*600935 || || ||x ||x |
|PKP2 ||*602861 || || ||x || |
|RYR2 ||*180902 || || || ||x |
|SCN1B ||*600235 ||x || ||x || |
|SCN2B ||*601327 || || ||x || |
|SCN3B ||*608214 || || ||x || |
|SCN4B ||*608256 ||x || || || |
|SCN5A ||*600163 ||x || ||x || |
|SCN10A ||*604427 || || ||x || |
|SLMAP ||*602701 || || ||x || |
|SNTA1 ||*601017 ||x || ||x || |
|TRDN ||*603283 || || ||x ||x |
|TRPM4 ||*606936 || || |
LQTS is an autosomal dominant arrhythmic disease characterized by a prolonged QT interval on resting 12-lead surface ECG in the absence of structural heart disease. Inheritance is AR in the rare Jervell and Lange-Nielsen syndrome. Patients with LQTS may remain asymptomatic during their entire life or manifest symptoms caused by ventricular arrhythmias; syncope, aborted cardiac arrest, or sudden cardiac death can be the first manifestation of the disease.186 Although many genetically different types of LQTS are known, 90% of cases are associated with mutations in KCNQ1 encoding Kv7.1 (LQT1), KCNH2 encoding Kv11.1 (LQT2), and SCN5A encoding Nav 1.5 (LQT3).187 In LQT1, T waves are broad-based and symptoms recur during exercise; in LQT2, T waves are low-amplitude, notched or biphasic, and symptoms are induced by acoustic triggers; and in LQT3, narrow-based T waves are preceded by long isoelectric segment and symptoms occur during rest.187,188 The remaining 10% of pathogenic mutations occur in genes encoding other ion channels or in genes encoding proteins interacting with ion channels (see Table 9–6).
The diagnosis of LQTS is based on consensus criteria.189 A scoring system allows for the summation of points assigned to ECG findings at baseline and after exercise stress, evidence of torsade de pointes, history of syncope, congenital deafness, family history and members with LQTS, and unexplained sudden cardiac death (SCD) below age 30 years among immediate family members.190,191 A score equal to or greater than 3.5 points is the diagnostic cutoff, with a greater than 70% probability of identifying pathogenic mutations when the score is equal to or greater than 4. Genotype is not included in the score. The risk of life-threatening arrhythmias and events is high in (1) patients with QTc interval equal to or greater than 500 ms and a history of syncope, (2) LQT1 associated with missense mutations in residues of the cytoplasmic loop of the protein, and (3) females with LQTS2 and males with pore-loop missense mutations.192,193,194
Treatment includes beta-blockers (propranolol and nadolol) whose effectiveness may vary in the different subtypes of LQTS: highest for LQT1, less effective in LQT2 and LQT3.195 Mexiletine and ranolazine can be used adjunct to beta-blockers in LQT3.196,197 Implantable cardioverter defibrillator (ICD) therapy is indicated in patients who suffered syncope while treated with beta-blockers and in those with very long QTc (0.550-ms) intervals. Left cardiac sympathetic denervation is a possible added therapy for severely affected patients who are refractory to beta-blocker therapy.189 For drugs to be avoided by patients with long QT syndrome, see https://crediblemeds.org/pdftemp/pdf/DrugsToAvoidList.pdf.
SQTS is an inherited arrhythmic disease associated with increased risk of AF, ventricular tachycardia/ventricular fibrillation (VT/VF), and SCD.198 Current estimates indicate a prevalence of 0.02% to 0.1% in the adult population and 0.05% in children and adolescents.199 The diagnosis is made when the QT interval is equal to or less than 330 ms in the absence of tachycardia or bradycardia. Gain-of-function mutations in three genes encoding potassium channels, KCNQ1, KCNH2, and KCNJ2, have been associated with SQTS. Given the high risk of SCD, prophylactic ICD therapy is appropriate; adjunctive pharmacological therapy such as quinidine that prolongs QT interval is beneficial in a subset of these patients.189,200
Brugada syndrome is an AD arrhythmogenic disease characterized by ST-segment elevation with negative T wave in the right precordial leads in the absence of structural cardiac abnormalities.201,202 Although clinical manifestations include syncope or cardiac arrest caused by VF, the majority of patients remain asymptomatic lifelong. The disease burden is estimated to range from 5 to 20 individuals in 10,000, with higher prevalence in Asian populations. Although the mean age of patients manifesting life-threatening arrhythmias is around 40 years, arrhythmic events can occur at any age; arrhythmias typically occur while sleeping or at rest, after heavy meals, or during episodes of fever.202,203 To date, numerous genes have been associated with Brugada syndrome, but pathogenic mutations are identified in about 30% of patients, with SCN5A gene accounting for the majority of cases and other genes accounting for about 5% of genotyped cases.204 Overlap phenotypes (LQTS, SQTS and Brugada syndrome) are possible in affected members of the same families, given that the disease gene can be the same (eg, SCN5A).205 A recent “oligogenetic inheritance” hypothesis postulates that mutations in more than one disease gene are needed to induce a clinical phenotype.206 In patients with equivocal baseline ECG pattern as unique evidence of possible disease, ajmaline provocation tests can be performed.189 Other diseases/factors potentially manifesting a Brugada-like ECG patterns (IHD, hyperkalemia, hypercalcemia, arrhythmogenic right ventricular dysplasia, myocarditis, mechanical compression of the right ventricular outflow tract, or pulmonary embolism) should be excluded. In symptomatic patients, risk stratification includes history of VT/VF, syncope and spontaneous coved-type ST-segment elevation. In asymptomatic patients, risk stratification includes male gender and fragmented QRS, which is a marker of conduction abnormality and a predictor of prognosis.207 The first-line therapy is ICD in patients with a history of VT/VF or syncope.189 Administration of drugs that can trigger type 1 ECG changes and arrhythmias (www.brugadadrugs.org) should be avoided. For phenocopies, see www.brugadaphenocopy.com.
Catecholaminergic Polymorphic Ventricular Tachycardia
CPVT is a rare disease (1:10,000) that typically presents with syncope or cardiac arrest triggered by exercise or emotion in children/adolescents.27,208 Mortality is high in affected, unrecognized, and untreated patients. The baseline ECG is normal but exercise induces the polymorphic ventricular arrhythmias; a few patients may demonstrate bidirectional ventricular tachycardia.208,209 The disease is genetically heterogeneous. CPVT1 (60%–70%) is AD and caused by mutations in the gene RYR2 gene, and CPVT2 is AR and is associated with mutations in the cardiac calsequestrin gene (CASQ2).210 Both RYR2 and CASQ2 are involved in myocyte calcium homeostasis.209 Less common disease genes include KCNJ2 (CPVT3), calmodulin (CALM1), and triadin (TRDN).211,212 Risk factors for arrhythmic events include young age, male gender, history of cardiac arrest, occurrence of arrhythmias while taking beta-blockers, and mutation in the c-terminus of the RYR2 gene.213 All genotyped patients should be treated with beta-blockers at the highest tolerable dose, adding flecainide when beta-blockers do not control arrhythmias. In severely affected patients, ICD discharge can induce catecholamine release, causing ventricular storms.214,215
Overall, geneticists actively involved in counseling and testing patients with suspected cardiochannelopathies and potential risk of life-threatening ventricular arrhythmias should be part of multidisciplinary specialized teams and be cautious in the interpretation of the role of genetic variants identified by genetic testing. In fact, family segregation studies, which usually strongly contribute to support causality of mutations, may be limited by the difficult phenotype characterization of asymptomatic and “ECG-negative” relatives who may or may not manifest traits typically recurring in these diseases.
Tumors of the Heart and Genetics
Rare and Genetic Tumors of the Heart
Tumors of the heart are rare (see Chap. 101), with autopsy incidence ranging from 0.001% to 0.03%, including all primary benign and malignant neoplasms. In the revised World Health Organization 2015 classification, they are grouped as benign tumors, tumors of uncertain biologic behavior, germ cell tumors, and malignant tumors.216 Among all, myxoma, rhabdomyoma, fibroma, and some tumor-like histiocytoid diseases of the heart may be present in the context of syndromes suspected based on their clinical presentation and confirmed by genetic testing.
Cardiac myxoma occurs in Carney complex and accounts for up to 10% of all cardiac myxomas,217 but it may also occur as isolated neoplasm. Carney complex is clinically characterized by pigmented lesions of the skin and mucosa, recurrent cardiac, cutaneous and other myxomas, and multiple endocrine tumors.218 Patients are usually younger than those with sporadic myxoma, and there is no female predominance. Carney complex type 1 is caused by mutations in the cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A gene), whereas Carney complex type 2 has been mapped at 2p16 locus, but the gene is still unknown. A variant of Carney complex with distal arthrogryposis is associated with defects in the MYH8 gene. The diagnosis is made in the presence of (1) two of the major criteria confirmed by histology, imaging, or biochemical testing or (2) one major criterion in addition to the presence of one supplemental criterion.219,220 Pancreatic acinar cell carcinoma, adenocarcinoma, and intraductal pancreatic mucinous tumors have been reported in as many as 2.5% of patients.221 Genetic counseling and testing are part of the diagnostic workup.
Rhabdomyoma typically occurs in patients with tuberous sclerosis, an AD disorder that is clinically characterized by the triad of neurofibromatous lesions, mental slowing, and cutaneous lesions.222 Multiple rhabdomyomas are found in about half of children affected by tuberous sclerosis. The disease is caused by mutations in tumor suppressor genes [TSC1 coding amartin (9q34) and TSC2 coding tuberin (16p 13.3)] that also cause lymphangioleiomyomatosis and pulmonary hypertension. The inactivation of the tuberous sclerosis complex genes, TSC1 and TSC2, and the activation of the mammalian target of the rapamycin (mTOR) pathway enhance cell proliferation and migration, lymphangiogenesis, metastatic spread, sex steroid sensitivity and deregulated autophagy.223 The mTOR activation provides the basis for target therapy with mTOR inhibitors.224
Cardiac fibroma recurs in the AD basal nevus syndrome or Gorlin syndrome, causally linked with mutations in the tumor suppressor protein encoding patched Drosophila homolog 1 (PTCH1) gene.225,226 The PTCH1 transmembrane protein represses transcription in specific cells of genes encoding members of the TGF-beta and Wnt families of signaling proteins. The penetrance of the PTCH1 mutations is complete, but the clinical phenotype may vary, including skeletal abnormalities and increased risk of tumors—in particular, desmoplastic medulloblastoma. The diagnosis and management requires multidisciplinary collaboration because the disease is multisystemic. Genetic counseling for parents of affected children reveals the complex association of phenotypic traits, the relevance of early diagnosis, and the need for scheduled multidisciplinary monitoring of and decision making about the multiple lesions.227
Purkinje cell hamartoma, or cardiac hamartoma, also termed histiocytoid cardiomyopathy (or oncocytic cardiomyopathy), is an XL dominant disease. Endocardial or myocardial nodules that may involve the sinoatrial and atrioventricular nodes characterize the macroscopic view. Histologically, myocytes appear round and vacuolated and demonstrate conspicuous numbers of mitochondria. The disease has recently been associated with the de novo nonsense mutations in the NADH ubiquinone oxidoreductase subunit B11 gene (NDUFB11) in two unrelated female patients and with two de novo missense mutations in NDUFAF2 and NDUFB9 in a third female patient.228 Although rare, diseases associated with mutations in NDUFB11 are of special interest because they represent one of the very few examples of XL dominant diseases (ie, linear skin defects with multiple congenital abnormalities 3, MIM #300952), and because of the possible synergy with additional mtDNA variants.
Somatic mutations in cardiovascular tumors are emerging as novel potential contributors to identify therapeutic targets. Target next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes in primary cardiac angiosarcomas have demonstrated that the p.R707Q mutation in phospholipase C gamma 1 (PLCG1) constitutively activates the protein PLCγ1 and provides an alternative way of activation of kinase insert domain receptor (KDR)-PLCγ1 signaling in angiosarcomas. This evidence opens novel avenues for VEGF/KDR targeted therapies.229 Intimal sarcomas of the heart have demonstrated mouse double minute 2 homolog (MDM2) gene amplification and overexpression of the MDM2 protein, again raising the possibility of targeted therapies.229
Identification of the Genetic Basis Facilitates Novel Treatment Strategies
Genetic tumors of the heart, both isolated or, more commonly, part of complex syndromes, can be clinically recognized by family screening and precisely diagnosed by testing corresponding disease genes. The precise diagnosis, including the pathology and the constitutive and somatic genetic defects, provide novel basis for targeted treatments. Clinical implications include scheduling of surgery for excising potentially recurring tumors (ie, atrial myxoma in Carney complex) especially in children, introducing mTOR inhibitors such as rapamycin for control of lymphangiogenesis, and tailored monitoring and interventions in syndromes with multiple tumors such as Gorlin syndrome. Somatic mutations in sarcoma cells can drive novel anticancer therapies in primary cardiac malignancies.
Heritable Autoinflammatory Diseases
Diseases That Should Be Included in the Differential Diagnosis of Inflammatory Heart Diseases
The heart can be involved in heritable autoinflammatory disorders (HAIDs). HAIDs are a group of monogenic diseases characterized by exaggerated inflammatory response through uncontrolled production of cytokines, which cause recurrent episodes of inflammation, followed by symptom-free periods of variable length.174,230 HAIDs usually manifest with periodic fever syndromes. Cardiac involvement may occur as direct effect of the systemic inflammatory process. The onset may mimic infective pericarditis, myocarditis, or myocardial inflammation with fibrosis; in clinical practice, these conditions often remain labeled as idiopathic. Vascular involvement is rare.231 Myocardial infection is usually the first diagnostic hypothesis in patients presenting with fever and either chest pain and normal coronary arteries, arrhythmias, or heart failure. Differential diagnosis now includes possible genetic origin of inflammatory heart disease.
Heritable Autoinflammatory Disorders: An Expanding Clinical Field
The number of clinically and genetically characterized autoinflammatory diseases is expanding. The feasibility of precise diagnoses and the increasing number of drugs specifically targeting key molecules that mediate tissue inflammation and damage are becoming vastly important in this field. HAIDs demonstrate the nonobligate relationship between cardiac inflammation and infections, and possible targeted treatment once patients have a precise diagnosis. Table 9–7 lists major diseases, genes, and organ involvement; for some of them, the type of cardiac involvement is known, whereas for others, cardiac involvement is not yet reported. Detailed description of all of these diseases goes beyond the scope of this section. We shortly discuss familial Mediterranean fever (FMF), which is the paradigmatic example of HAID demonstrating cardiac involvement (see also Chap. 61).
TABLE 9–7.Genes and Organs Involved in the Hereditary Autosomal Dominant or Autosomal Recessive Autoinflammatory Disorders ||Download (.pdf) TABLE 9–7. Genes and Organs Involved in the Hereditary Autosomal Dominant or Autosomal Recessive Autoinflammatory Disorders
Familial Mediterranean Fever
FMF is the most common familial autoinflammatory monogenic disease. It was first described as an autosomal recessive disease recurring in Eastern Mediterranean populations (Fig. 9–8).232 The disease is caused by mutations in the MEFV gene that encodes pyrin, a component of the cellular inflammasome. After the identification of the MEFV gene, the genetic-driven name pyrin-associated periodic fever syndrome (PAPS) was proposed. Analogous to CMPs that have been recently reclassified integrating the phenotype-based, descriptive diagnosis with the specific cause of each subtype of CMP,19 a precise nosology of HAIDs will be especially beneficial in the incoming era of precision cardiology, especially when target treatments are available and effective. PAPS is inherited as an AR disease233,234 (see Fig. 9–1). Milder disease course, later onset, and less frequent and less severe inflammatory attacks may recur in patients who carry genetic variations that are not associated with the classical phenotype. Systematic sequencing of the whole MEFV exons showed that homozygous mutations recurred in 20% to 30% of patients with FMF.235 Heterozygous carriers of MEFV mutations can develop a different inflammatory AD disease236,237 or manifest the phenotype in the setting of exogenous triggers (ie, infections),238 suggesting a double-hit hypothesis.239,240,241
Pedigree of a family with autosomal recessive familial Mediterranean fever. Note parental consanguinity and minor involvement in heterozygous carriers of the MEFV mutation.
Genetic Diagnosis and Recommendations
Although the first recommendation for genetic diagnosis of FMF states that, “FMF is a clinical diagnosis, which can be supported but not excluded by genetic testing” (level of evidence B), genetic testing and genotype-phenotype correlations are part of the modern diagnostic workup of PAPS. Of the eight recommendations provided by experts, level A evidence is for asymptomatic individuals homozygous for p.(Met694Val) mutations; these individuals should be evaluated and followed closely so that appropriate therapy is considered.242
Multifactorial Cardiovascular Diseases
Genetics in Multifactorial Diseases
Most cardiovascular diseases have a multifactorial origin. Common examples include atherosclerosis, CAD, heart failure syndrome, hypertension, dyslipidemia, and diabetes. Each of them results from a complex interplay between environmental and genetic factors. The baseline risk in individuals with positive family history of MI, diabetes, hypertension, or dyslipidemia includes nonmodifiable factors (family history, gender, age).243 Traditional risk factors and combinations thereof, age of onset and duration and treatments, are largely modifiable, even in heritable diseases such as AD familial hypercholesterolemia.244 The risk of events (ie, acute MI) includes the global risk of the underlying disease (atherosclerosis) and the event-related risk that incorporates factors involved in local and systemic inflammation and arterial thrombosis.243 The impact of positive family history varies in different multifactorial diseases. It is higher for CAD245 and lower for “heart failure syndrome,”246 in which risk stratification includes the primary cause of heart disease, the remodeling pathway, and the responsiveness to therapy.
Coronary Artery Disease as a Paradigm of Multifactorial Disease
Scientific and clinical achievements over the past 50 years (the post-Framingham era of cardiology) are tremendous. Identification of risk factors; prevention programs; drugs such as aspirin, statins, RAS inhibitors, and beta-blockers; and interventional procedures have modified the epidemiology and outcome of many multifactorial cardiovascular diseases.247 Primary and secondary prevention programs as well as better diagnosis and treatments have resulted in increased survival, better quality of life, and increased life expectancy. In developed countries, the disease is decreasing,248 whereas in developing countries, the disease is increasing.249 Future contribution of genetics is expected to implement personalized precision medicine, which aims at tailoring risk, prevention, and treatments on individual clinical profiles and needs.249
The completion of the Human Genome Project,250 the sustainable sequencing of large panels of genes or whole exome/genome sequencing, promises progressing individual genotyping and genetic characterization of individuals at risk (eg, association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate). Together, these variants explain approximately 10.6% of CAD heritability.251 The study confirms that the four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. A recent GWAS meta-analysis, including about 185,000 CAD cases and controls and interrogating 6.7 million common (minor allele frequency [MAF] > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants, confirmed most known CAD-associated loci and further identified ten new loci (eight additive and two recessive) that contain candidate causal genes, newly implicating biological processes in vessel walls. The analysis shows that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.252 Because loci identified by GWAS explain less than 10% of the genetic variance in CAD (90% of CAD heritability remains to be explained), systems genetics-building network models of relevant molecular processes can also capture environmental and modifiable influences on CAD. This combination is likely to be a lot more powerful for characterization of individuals with CAD than just DNA alone.253
Paradoxically, as far as new genetic information enters the scientific world, the translation calls for clinical skill, deep phenotyping, and family studies. New endovascular imaging and imaging markers (coronary artery calcium score, carotid intima-media thickness, and ankle-branchial index),254 as well as new biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, secretory phospholipase A2)255 will contribute to personalized diagnosis, risk stratification, and disease phenotyping.
Monogenic Coronary Artery Disease
AD CAD (#608320, ADCAD1) associated with mutations in MEF2A gene (*600660; first reported AD MI256 but later not confirmed257) and ADCAD2 (#610947) associated with mutations in the LRP6 gene (*603507) are not confirmed. Susceptibility genes and loci to MI (LRP8, GCLM, TNFSF4, LTA, GCLC, ESR1, OLR1, F7, PSMA6, ITGB3, MIAT, LGALS2) should be considered provisional. The expansion of investigation for individual whole risk can beneficially start from comprehensive phenotype investigation, including evaluation of comorbidities, exposures to high risk environment, disease mapping clinical monitoring, and family studies exploring both events and risk factors.
Family History of Coronary Artery Disease
A positive family history, a nonmodifiable risk factor, is the sum of the low effect of multiple genetic variants and familial environmental risk factors. Gender-related imprinting contributes to family-related risk: the paternal history of MI may simply reflect the higher prevalence of MI in males, whereas the less common maternal history of MI carries a higher risk.258 A gender-related parental effect also includes risk factors such as type 1 diabetes,259 suggesting the involvement of imprinted genes. The relative risk of MI is higher in individuals with one or more affected first-degree relatives and further increases when relatives are affected at earlier ages260 (Figs. 9–9 and 9–10). Studies in twins demonstrated a higher risk of coronary death after one twin died of premature CAD.261 Twin studies also contributed to highlighting genetic factors262,263 and dissecting genetic and environmental-related risk. Nonetheless, precise estimation of family-related risk remains difficult in clinical practice because its contribution is subject to classification errors and bias, as well as descriptive ability and recall of participants. For risk factors such as cigarette smoking, metabolites associated with smoking behaviors could provide more precise data than those obtained by counting the number of cigarettes per day or packs per year,264 facilitating accurate partition of components of positive family history, family-related environment, and entirely exogenous factors.
Routine genetic counseling and educational impact. 1999, the consultant (→ III:1), with hypertension, dyslipidemia, and tobacco use, asks about his risk of acute myocardial infarction (AMI) after the second and fatal AMI of his brother (III:2), who had hypertension and dyslipidemia but who was younger and a nonsmoker. His risk stratification included the three risk factors plus the nonmodifiable family history and gender. In 2010, he came again asking about his risk after the AMI of the cousin (III:6), who was regularly treated for both hypertension and type 2 diabetes mellitus (DM). He had stopped smoking after counseling and was treated for hypertension and hypercholesterolemia; the overall risk was lower but his age was greater (67 years). Of the six smoking members of the family, five stopped smoking. One with obesity and hypercholesterolemia (III:11) developed type 2 DM and one (IV:1) developed hypertension. COPD, chronic obstructive pulmonary disease; IHD, ischemic heart disease; PCI, percutaneous coronary intervention.
The two pedigrees show two family members (family A, III:5 and family B III:5), both males but with different family risk—lower in the former and higher in the latter. ACS, acute coronary syndrome; AMI, acute myocardial infarction; CABG, coronary artery bypass graft; DM, diabetes mellitus; N-STEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, sudden death.
Familial environment can contribute to the risk. Dietary styles are influenced by familial lifestyles. The first quarter of an individual’s life is spent within family; thereafter, each individual may either maintain the familial lifestyle or modify his or her habits. Well-balanced diets (plant- vs meat-based diets, intake of polyunsaturated fatty acids, low salt consumption) are protective; even factors such as salt taste, which is partially under genetic control,265 can be regenerated266 and therefore be modifiable. Regular, moderate exercise is protective against acute MI. Early childhood attitude to sport influences exercise levels throughout life: monozygotic twins demonstrated long-term familial aggregation of adherence to exercise.267 Parental use of tobacco and reduced family cohesiveness are essential components of positive preteen attitudes toward smoking; family-based interventions can prevent children and adolescents from starting to smoke.268 Common infections cluster in families and institutions, and the relationship between MI and chronic infections caused by Helicobacter pylori, cytomegalovirus, Chlamydia pneumoniae, hepatitis viruses, or oral pathogens is still a matter of debate.269,270,271 Certain infections may influence systemic inflammation and therefore contribute to atherothrombosis.272
Factors that may influence the risk of, or protect from, CAD include (1) low-dose input of different genes playing roles in known pathways with biological plausibility with respect to current knowledge on risk and events and (2) pathways without immediate biological plausibility (ie, transcription factors and increased risk of MI).272 The occurrence of MI in individuals without traditional risk factors highlights the existence of powerful, still unknown mediators that play their role independently of, or in addition to, the underlying coronary ATS. Genetic risk of CAD as a whole may not coincide with the genetic risk of MI. Studies distinguishing MI series from coronary atherosclerosis series demonstrated risk loci in patients with angiographic CAD (eg, the 15q25.1 ADAMTS7 locus) but not MI, as well as risk loci shared by both CAD and MI (9q34.2 ABO locus).273,274 Replicated studies support the role of genes partaking in coagulation or inflammatory pathways, or of chromosomal loci in which still unknown candidate genes map. In a recent meta-analysis, patients with coronary atherosclerosis who carry the high-risk genotype of the 9p21-3 allele may be more likely to have multivessel CAD275; at present, SNP markers in the 9p21 chromosomal locus seem to be robust GWAS signals for CAD risk.276 These data are not translated into current clinical practice.
Individuals who are genetically predisposed to MI (positive family history) but not exposed to acute or chronic environmental risk factors may not develop MI, and vice versa. Genetic predictors of minor risk in the overall population may predict a high risk in specific subsets of individuals as a result of gene-environment interactions, including cigarette smoking, infections, meals, and drugs. For example, the CYP2B6 allele seems to increase the risk of tobacco dependence throughout adolescence.277 The rs1051730 (C/T) SNP, which is a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 gene cluster, is associated with an increased risk of death in smokers278 and variants in Rho-GTPase pathway genes seem to exert their effects in early-onset CAD.279 Recent epigenome-wide methylation studies demonstrated that DNA hypomethylation in certain genes is associated with tobacco exposure.219,280 Specific methylation markers may show gradual reversal of methylation levels from those typical of current smokers to those have never smoked.281 DNA methylation may also be associated with modulation of the risk related to diabetes mellitus, with TXNIP gene methylation being associated with sustained hyperglycemia levels (HbA1c ≥ 7%).282
The awareness of clinical and molecular genetics in multifactorial diseases is modifying models of care and introducing novel outpatient models for genetic investigation,283 including systematic genetic testing in phenotypically characterized high-risk patients (such as children with hypercholesterolemia),284 and is expanding information on genetic risk of CAD and conventional risk estimates to patients.285 Family history and deep phenotyping of patients and relatives may contribute to characterize correlations between genetic risk and overall risk, events, and outcome. New, targeted treatments are becoming available for subgroups of patients with well-characterized phenotype and genotype. These include gene-based agents, eg, mipomersen, approved in the United States for homozygous familial hypercholesterolemia; and Glybera, AAV1-LPLS447X gene therapy, conditionally approved in Europe for lipoprotein lipase deficiency286 in carriers of null LDLR mutations who are at increased risk, even in the setting of early diagnosis and regular lipid-lowering treatments.