Dilated cardiomyopathy: genetic determinants and mechanisms

Abstract

Nonischemic dilated cardiomyopathy often has a genetic etiology. Because of the large number of genes and alleles attributed to dilated cardiomyopathy, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at-risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of dilated cardiomyopathy, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to dilated cardiomyopathy and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of dilated cardiomyopathy, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

Prevalence and etiology of dilated cardiomyopathy

Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal. Morphologically defined subtypes include hypertrophic (HCM), dilated (DCM), arrhythmogenic (AC) and left ventricular noncompaction (LVNC) cardiomyopathies^{1, 2}, and each of these subtypes can be genetically mediated (Figure 1). DCM is characterized by an enlarged and poorly contractile left ventricle (LV). DCM can be attributed to genetic and nongenetic causes including hypertension, valve disease, inflammatory/infectious causes and toxins³. Even these “nongenetic” forms of cardiomyopathy, can be influenced by an individual’s genetic profile and, furthermore, mixed etiologies may be present. In DCM, the degree of LV systolic dysfunction is variable, and LV systolic dysfunction is often progressive. DCM is a major risk factor for developing heart failure (HF) as the presence of reduced systolic function does not imply symptoms. Notably, DCM is often associated with an increased risk of severe arrhythmia indicating the pathological involvement of the cardiac conduction system.

Figure 1. Echocardiography demonstrates forms of cardiomyopathy.

Left ventricular noncompaction cardiomyopathy (LVNC) is shown in the upper right (arrows indicate deep trabeculations in the left ventricle (LV). Dilated cardiomyopathy (DCM) is defined by enlarged LV diameters (dashed double sided arrow). Hypertrophic cardiomyopathy (HCM) is defined with a thickened LV, including the septum (marked with double sided arrow).

Randomized clinical heart failure trials typically report 30–40% of subjects with a nonischemic DCM compared to ischemic DCM³. Clinical trials are evaluating interventions to reduce CHF symptoms, these studies may focus on the later stages of disease. Similarly, a recent survey of hospitalized patients in the United States in which the mean age was 75 years (n=156,013) found that ischemic cardiomyopathy was more common than nonischemic (59% compared to 41%)⁴. Of nonischemic DCM, hypertension accounted for 48% and idiopathic was the next most common at 31%. In this study, individuals with nonischemic DCM were more likely to be female, nonwhite, and younger that those with ischemic cardiomyopathy.

The true prevalence of DCM, and of genetically mediated DCM, is not fully known. An early estimate of DCM prevalence derived from a study carried out from 1975 to 1984 in Olmstead County, MN, USA⁵. This epidemiological study relied on echocardiography, angiography or autopsy evaluation of DCM cases and resulted in a prevalence of 36.5/100,000 individuals, or 1 in 2,700 with a male to female ratio of 3.4 in a European-American population⁵. The prevalence of DCM varies likely reflecting geographic and ethnic differences, as well as the methodologies used^6–10. Studies from England (8.3/100,000)¹¹, Italy (7.0/100,000)¹², and Japan (14/100,000)⁹, each report similar DCM prevalence. However, the prevalence of DCM is likely underestimated. The prior studies relied on older less sensitive imaging modalities¹³. More recently, Hershberger and colleagues used a different approach to estimate DCM prevalence, based on the known ratio of idiopathic DCM to HCM of approximately 2:1, prevalence estimates of heart failure and prevalence estimates of left ventricular dysfunction as a surrogate for DCM¹⁴. With this approach, a much higher prevalence of DCM is estimated, in the range of 1:250. Similarly, estimates of familial DCM prevalence varies: a meta-analysis of 23 studies found a prevalence estimate of 23% with a range of 2% to 65% indicating a significant heterogeneity in diagnostic criteria, and a frequency progressively increasing over time due to more systematic clinical screening¹⁵. In the clinical practice and in the current guidelines, the prevalence of familial DCM is assumed to be around 30 – 50%^{1, 3, 13, 16–18}. In patients with familial DCM, approximately 40% has an identifiable genetic cause¹⁷. Also in sporadic DCM pathogenic genetic variants can be identified, although the frequency of genetic causes in this population is not well defined¹⁷.

Clinical diagnosis of DCM

DCM has been defined by the presence of: a) fractional shortening (FS) less than 25% (> 2SD) and/or ejection fraction less than 45% (> 2SD); and b) left ventricular end diastolic diameter (LVEDD) greater than 117% (>2SD of the predicted value of 112% corrected for age and body surface area, BSA), excluding any known cause of myocardial disease¹⁹. In the context of a familial DCM, these criteria are used to diagnose the proband in a family¹⁹ and the strategy for evaluation is shown in Figure 2. Familial DCM is defined by the presence of: a) two or more affected relatives with DCM meeting the above criteria; or b) a relative of a DCM patient with unexplained sudden death before the age of 35 years¹⁹. Family members may be classified as affected, unaffected, or unknown when subtle cardiac abnormalities are present but not sufficient for a definitive diagnosis. Less common forms of primary cardiomyopathies are peripartum, tachycardia-induced, stress-provoked Takotsubo cardiomyopathy and myocarditis, according to the 2006 AHA definition and classification². Interestingly, myocarditis and peripartum cardiomyopathy can occur in a familial setting and are believed to have a genetic component^20–22. Secondary forms of cardiomyopathies, in which cardiomyopathy arises from systemic disorders such as amyloidosis, hemochromatosis, and due to toxicity from agents like doxorubicin are also under genetic influence or may arise due to primary genetic mutations^{23, 24}. Neuromuscular disease is also commonly associated with cardiomyopathy, and cardiomyopathy typically arises from the primary responsible genetic mutation exerting pathological effects directly in the myocardium (see below). With the increase in using genetic testing, especially testing in family members, it is now possible to use cardiac imaging modalities to ascertain early features of disease in gene mutation positive individual who do not fully manifest disease. Since many of these studies examine gene positive individuals at one point in time, a full view of DCM is progression has not been delineated. Definitive studies on DCM in progression in genetically at-risk individuals must span many years. Imaging studies have identified chamber size dimensions, strain abnormalities and contrast enhancement each as features of early DCM²³.

Figure 2. Algorithm for the management of a patient with nonischemic DCM.

CMR: cardiac magnetic resonance, CK: creatine kinase. DCM patients should undergo an accurate family history examination. A comprehensive exam should include serum CK to evaluate skeletal muscle involvement. Genetic testing and genetic counseling should be offered to DCM patients, regardless of family history; 1^st degree relatives should be examined (physical exam, ECG, echocardiogram). A positive genetic testing in the proband offers the possibility of a confirmatory genetic testing in relatives, which may guide follow up and need of further testing. Adapted from^{14, 19, 140, 164}

Imaging - Echocardiography

To diagnose DCM, LV measurements can be determined using multiple imaging modalities. M-mode and 2-dimensional echocardiography are frequently used to determine LV internal dimensions in systole and diastole (LVIDd, LVIDs, respectively) (Figure 1). It was originally thought that LV dilation occurs in response to reduced function. However, in genetic DCM, where genetic markers make it feasible to monitor LV dimensions over many years, increased LV dimensions typically precede detectable reduction in function^25–27. This state of LV enlargement is recognized as a prodome to DCM. Enlarged LV dimensions contrast with what is seen in hypertrophic cardiomyopathy (HCM), where the earliest findings in genetically mediated, sarcomere-positive HCM are reduced LV dimensions²⁸. Strain and strain rate differences can be detected by echocardiography in first degree relatives of those with newly diagnosed nonischemic DCM, indicating that LV dimensions are not the earliest detectable differences in familial DCM^{29, 30}.

Imaging - Cardiac Magnetic Resonance (CMR)

LV chamber dimensions and function, including strain measurements, are also accurately determined by CMR imaging. Contrast agents, mainly gadolinium, are used to evaluate fibrosis and therefore provide additional information on myocardial tissue quality. In DCM, the degree of fibrosis, marked by delayed gadolinium enhancement, is a predictor of all-cause mortality and need for future hospitalization³¹. Specifically, delayed enhancement is associated with increased risk for ventricular arrhythmias^32–34. Delayed enhancement may also reflect features beyond fibrosis including edema and inflammatory infiltrate³⁵.

DCM can also be associated with LV noncompaction seen using either echocardiography or CMR. A ratio of greater than 2.3:1 for the noncompacted to compacted layer of LV myocardium is considered abnormal, but notably can be detected in normal hearts³⁶. Recent studies have suggested that hypertrabeculation is seen in a high fraction (36%) of adult DCM, although this was not associated with adverse outcomes compared to DCM without these noncompaction features³⁷.

Endomyocardial Biopsy (EMB)

EMB has been used to confirm etiology in some forms of DCM, although with improved cardiac imaging, EMB is less frequently used. In some settings, for example, iron overload, amyloid, and other infiltrative processes myocardial biopsy may still be highly useful³⁸. The complication rates with EMB range from 1–3%, and serious complications including perforation and tamponade occur at 0.5%³⁸. EMB has been used to evaluate myocarditis and in the setting of unexplained HF^{39, 40}. The nonuniform nature of infiltrative disease limits the sensitivity of myocardial biopsy, as the RV septum is targeted for sampling⁴¹. For the majority of genetic cardiomyopathies, genetic testing is favored over EMB. Of the genetic cardiomyopathies, ARVC may be evaluated by EMB, although more recent work suggests that alternative and more easily accessible cell types can be used to diagnose ARVC and avoid EMB^{42, 43}.

Non-invasive arrhythmia monitoring

DCM is associated with an increased risk for cardiac arrhythmias and sudden cardiac death (SCD)⁴⁴, and specific genetic DCM subtypes are especially prone to arrhythmias. CMR, especially the identification of delayed enhancement, can help risk stratify for sudden death³⁴. Because of increased risk for SCD, there is need for arrhythmia surveillance in order to more appropriately deploy device management, including pacemakers and/or internal cardioverter defibrillators (ICDs). Symptomatic and even life-threatening bradycardia and tachycardia may occur in genetic DCM. Personal history of syncope or near syncope should be ascertained, and patient education to increase awareness of symptoms is needed. Holter monitoring, for its ease, remains a mainstay using 24–48 hour sampling. Other external event recorders are similarly transcutaneous and provide real-time, transmitted data as well as triggered monitoring. External loop recorders and now implantable loop recorders offer longer-term information. Those with familial DCM are likely to have more findings of ventricular ectopy and ventricular tachycardia (VT) on monitoring⁴⁵. For primary prevention of SCD in DCM, risk stratification often relies on evaluating the specific genetic etiology (see below), family history, delayed enhancement and presence of VT on monitoring.

Clinical manifestations including neuromuscular findings

The range of clinical manifestations in DCM ranges from none to overt heart failure. With the increase in familial and genetic screening, it is now more common to identify the minimally to mildly affected stage of DCM in younger individuals. Using genetic markers, strain defects can be detected by echo or CMR. LGE may be present even when the heart appears still normal, suggesting that disease is ongoing. There is an emerging view that this represents an early stage of disease and one in which early institution of treatment should benefit. Although it is generally thought that arrhythmia risk scales with degree of LV dysfunction, for several subtypes of genetic cardiomyopathy, arrhythmias may be the earliest manifestation^46–49. Specifically, in LMNA and SCN5A-mediated cardiomyopathies, arrhythmias including atrial fibrillation with slow ventricular response or ventricular arrhythmias may be the presenting finding. There is little in the clinical evaluation that makes it possible to distinguish one genetic subtype of DCM from another. This “phenocopying” is what has driven gene panel testing since with this approach multiple genes are screened at the same time. A DCM gene panel is shown in Figure 3, and a comprehensive list of DCM genes in Table 1.

Figure 3. DCM gene panels are used for genetic testing.

Shown is a list of 111 genes offered from multiple commercial testing laboratories for the evaluation of DCM. Those shown in black are commonly found on DCM panels from multiple sources, while those shown in gray are found on only some panels reflecting their role in syndromic cardiomyopathy such as Noonan syndrome, neuromuscular disease and/or mitochondrial myopathies.

Table 1.

Frequency and phenotype correlates of definitive and putative DCM genes

Gene	Protein	Frequency and overlapping phenotypes
Sarcomere	Force generation/transmission
MYH6	Alpha-myosin heavy chain	HCM, CHD, Sick Sinus Syndrome
MYH7*	Beta-myosin heavy chain	3–4% of DCM; HCM, LVNC
TPM1	Alpha-tropomyosin	1–2% of DCM; HCM, LVNC
ACTC1	Alpha cardiac actin	HCM, LVNC
TNNT2*	Cardiac troponin T	3% of DCM; HCM, LVNC
TNNC1	Cardiac troponin C	HCM, LVNC
TNNI3	Cardiac troponin I	HCM
MYBPC3	Myosin-binding protein C	HCM, LVNC
TTN*	Titin	12–25% of DCM; HCM, tibial muscle dystrophy
TNNI3K	Troponin I interacting kinase	Conduction defect, atrial fibrillation
MYL2	myosin light chain2, regulatory	HCM
MYL3	myosin light chain 3	HCM
MYLK2	Myosin Light Chain Kinase 2	HCM; in panels, not reported as DCM gene
MYOM1	myomesin 1	Myofibrillar myopathy; in panels, not reported as DCM gene
MYOZ2	myozenin 2	HCM
Z-disk	Mechanosensing/mechanosignaling
ACTN2	Alpha-actinin 2	LVNC
BAG3	BCL2 Associated Athanogene 3	Myofibrillar myopathy
CRYAB	Alpha-B-crystallin	Protein aggregation myopathy
TCAP	Titin-cap/telethonin	LGMD2G
MYPN	Myopalladin	HCM, RCM
CSRP3	Muscle LIM protein	HCM
NEXN	Nexilin	HCM
FHL1	Four-and-a-half LIM protein1	EDMD, HCM
FHL2	Four-and-a-half LIM protein 2	HCM
ANKRD1	Cardiac ankyrin repeat protein	Congenital heart disease
MURC	Muscle Related Coiled-Coil Protein
LDB3	Cypher/ZASP	LVNC
NEBL	nebulette	LVNC, HCM
Dystrophin complex	Sarcolemma, structural integrity
DMD	Dystrophin	Duchenne/Becker muscular dystrophy
DTNA	Alpha-dystrobrevin	LVNC
SGCA	Alpha-sarcoglycan	LGMD2D
SGCB	Beta-sarcoglycan	LGMD2E
SGCD	Delta-sarcoglycan	LGMD2F
SGCG	Gamma-sarcoglycan	LGMD2C
CAV3	Caveolin	HCM, LGMD1C, distal myopathy
ILK	Integrin-linked kinase
FKTN	Fukutin	dystroglycanopathy, congenital muscular dystrophy
FKRP	Fukutin-related protein	dystroglycanopathy, LGMD
Cytoskeleton	Mechanotransduction/mechanosignaling/structural integrity
DES	Desmin	<1% of DCM; Desminopathies, myofibrillar myopathy
VCL	Metavinculin	1% of DCM
FLNC	Filamin C	1% of DCM, AR-DCM; Myofibrillar myopathy, HCM, RCM
SYNM	Desmulin
PDLIM3	PDZ LIM domain protein 3
PLEC1	Plectin-1	LGMD2Q, epidermolysis bullosa
Desmosomes	Cell–cell adhesion/mechanotransmission/mechanosignaling
DSC2	Desmocollin 2	ARVC, mild palmoplantar keratoderma
DSG2	Desmoglein 2	ARVC
DSP*	Desmoplakin	2% of DCM; ARVC
PKP2	Plakophilin 2	ARVC
CTNNA3	Catenin Alpha 3	ARVC; in panels, not reported as DCM gene
Sarcoplasmic reticulum and cytoplasm	Ca homeostasis, contractility modulation, signaling
PLN	Phospholamban	ARVC, HCM
RYR2	Ryanodine receptor 2, Ca channel	ARVC, CPVT
CALR3	Calreticulin-3	ARVC, HCM; in panels, not reported as DCM gene
JPH2	Junctophilin 2	HCM
DOLK	Dolichol KINASE	Congenital disorder of glycosylation
MAP2K1	Mitogen-Activated Protein Kinase Kinase 1	Noonan Syndrome; in panels, not reported as DCM gene
MAP2K2	Mitogen-Activated Protein Kinase Kinase 2	HCM, Noonan Syndrome; in panels, not reported as DCM gene
NRAS	Neuroblastoma RAS Viral Oncogene Homolog	HCM, Noonan Syndrome
PRKAG2	Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2	HCM, WPW
PTPN11	Protein Tyrosine Phosphatase, Non-Receptor Type 11	HCM, Noonan and Leopard Syndromes
RAF1	Proto-Oncogene	HCM, Noonan and Leopard Syndromes
RIT1	Ras Like Protein	Noonan Syndrome; in panels, not reported as DCM gene
SOS1	SOS Ras/Rac Guanine Nucleotide Exchange Factor 1	HCM, Noonan Syndrome; in panels, not reported as DCM gene
TRDN	Triadin	CVPT; in panels, not reported as DCM gene
Nuclear envelope	Nuclear structural integrity, mechanotransduction, mechanosignaling
LMNA*	Lamin A/C	4–8% of DCM; multiple phenotypes, LGMD1B, EDMD, progeria
EMD	Emerin	EDMD
LAP2/TMPO	Lamin-associated polypeptide 2
SYNE1/2	Nesprin 1/2	EDMD, ataxia
Nucleus	Transcription cofactors, gene expression
EYA4	Eyes absent 4	Deafness
FOXD4	Forkhead box D4
HOPX	Homeobox only protein
NFKB1	NF-kappa B1
PRDM16	PR domain containing 16	LVNC
TBX20	T-box 20	Atrial septal defect
ZBTB17	Zinc finger and BTB domain containing protein 17
RBM20*	RNA-binding protein 20	2% of DCM; RNA-binding protein of spliceosome of TTN and other proteins
GATA4	GATA binding protein 4	Atrial, ventricular septal defects, Fallot
GATA5	GATA binding protein 6	Atrial, ventricular septal defects, Fallot
GATAD1	GATA zinc finger domain-protein 1
NKX2–5	Cardiac specific homeobox 1	Atrial, ventricular septal defects, Fallot, hypoplastic left heart
ALSM1	Centrosome And Basal Body Associated Protein	Alstrom Syndrome (phenocopy)
ALPK3	Alpha kinase 3	Pediatric cardiomyopathy
LRRC10	Leucine Rich Repeat Containing 10
NPPA	Natriuretic paptide A	Atrial fibrillation
PLEKHM2	Pleckstrin Homology Domain	LVNC
TGFB3	Transforming Growth Factor Beta 3	ARVC; in panels, not reported as DCM gene
TMEM43	Transmembrane Protein 43	ARVC, EDMD; in panels, not reported as DCM gene
Ion channels
SCN5A*	Type V Voltage-gated cardiac Na channel	2–3% of DCM; LQT, Brugada, atrial fibrillation, conduction defects
ABCC9	Sulfonylurea receptor 2A, component of ATP-sensitive potassium channel	Atrial fibrillation, osteochondrodysplasia
KCNQ1	Potassium channel	Atrial fibrillation, LQT1, Short QT1, Jervell and Lange-Nielsen syndrome
CACNA1C	Calcium Voltage-Gated Channel Subunit Alpha1 C	Brugada Syndrome, Timothy Sindrome
HCN4	Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4	Brugada, Sick Sinus Syndrome
Mitochondria	Supply and/or regulation of energy metabolism
CPT2	Carnitine palmitoyltransferase 2	carnitine deficiency, myopathy, lethal neonatal
FRDA/FXN	Frataxin	Fredreich ataxia
DNAJC19	HSP40 homolog, C19	3-methylglutaconic aciduria, type V
SDHA	Succinate dehydrogenase	Leigh syndrome
SOD2	Superoxide dismutase
TAZ/G4.5	Tafazzin	LVNC, Barth syndrome, endocardial fibroelastosis 2
CTF1	Cardiotrophin 1 cytokine
mtDNA	Mitochondrially Encoded TRNA genes	Typically syndromic, mitochondial myopathy; in panels, not always reported as DCM genes
TXNRD2	Thioredoxin Reductase 2
Extracellular matrix	Cell adhesion and mechanosignaling
LAMA2	Laminin 2, merosin	Congenital muscular dystrophy
LAMA4	Laminin 4
Lysosome
LAMP2	Lysosome-associated membrane protein 2	Danon Disease
AGL	Amylo-Alpha-1, 6-Glucosidase, 4-Alpha-Glucanotransferase	Glycogen storage disease
BRAF	B-Raf Proto-Oncogene, Serine/Threonine Kinase	Cardiofaciocutaneous, Leopard, Noonan Syndromes
GAA	Glucosidase Alpha, Acid	Glycogen storage disease
GLA	Alpha galactosidase	Fabry Disease
Other
PSEN1	Presenillin 1, Gamma secretase intramembrane protease complex	Alzheimer disease
PSEN2	Presenillin 2, Gamma secretase intramembrane protease complex	Alzheimer disease
CHRM2	Cholinergic Receptor Muscarinic 2
HFE	Hemochromatosis	Phenocopy
HRAS	HRas Proto-Oncogene, GTPase	HCM, Costello Syndrome; in panels, not reported as DCM gene
KRAS	KRAS Proto-Oncogene, GTPase	HCM, Costello Syndrome; in panels, not reported as DCM gene
MIB1	Mitogen-Activated Protein Kinase Kinase 2	LVNC; in panels, not reported as DCM gene
SLC22A5	Cation/Carnitine Transporter	Skeletal myopathy
TTR	Transthyretin	Amyloidosis (phenocopy)

Legend: frequent (asterisk), definitive (bold) and putative DCM genes,^{14, 23, 58, 164, 165} OMIM (www.omim.org, accessed 01/19/2017); GeneCards (www.genecards.org, accessed 01/19/2017). AR-DCM: arrhythmogenic DCM; ARVC: arrhythmogenic right ventricular cardiomyopathy; CPVT: cathecolaminergic polymorphic ventricular tachycardia; DCM: dilated cardiomyopathy, EDMD: Emery-Dreyfuss muscular dystrophy, HCM: hypertrophic cardiomyopathy, LGMD: limb-girdle muscular dystrophy, LVNC: left ventricular noncompaction, RCM: restrictive cardiomyopathy.

Neuromuscular disease may accompany cardiomyopathy, and in some forms of neuromuscular disease, the presenting feature may be irregular heart rhythms. LMNA mutations can present with or without muscle disease, and the muscle disease ranges from limb girdle muscular dystrophy to Emery Dreifuss Muscular Dystrophy, which is typically associated with contractures of the elbows and Achilles tendons⁵⁰. LMNA mutations are inherited in an autosomal manner, seen as multiple affected family members in each generation. Both X-linked and autosomal neuromuscular diseases can also associate with cardiomyopathy, and this includes Duchenne Muscular Dystrophy as well as the autosomal recessive forms of sarcoglycanopathies⁵¹. In these disorders, skeletal muscle disease usually appears in childhood with a typical dilated cardiomyopathy arising in the teenage years or early twenties. DCM in neuromuscular disease is highly amenable to treatment and responds well to guideline directed medical therapy. Both forms of myotonic muscular dystrophy, type 1 and type 2, can also be associated with DCM^52–55. Atrial and ventricular arrhythmias are common in these tri- and tetra-nucleotide repeat expansion disorders, and should be aggressively managed. Myotonic dystrophy type 2 usually present in older individuals and in this case, genetic testing panels usually do not include these genes and thus the diagnosis can be easily missed especially if neuromuscular symptoms are not so pronounced.

DCM Genetics

The majority of genetic DCM is inherited in an autosomal dominant pattern with variable expressivity and penetrance (Figure 4), although specific forms of autosomal recessive, X-linked recessive and mitochondrial inheritance each occur^{14, 19, 56}. De novo mutations also contribute to genetic cardiomyopathy and are defined when neither biological parent carries the offspring’s mutation. De novo mutations have been described in many different genes, and the presence of a de novo variant can be used to define the pathogenic status of genetic variants since the frequency of de novo variation in each genome is exceedingly rare. Thus, a novel mutation introducing a protein altering change in a cardiomyopathy gene is typically considered pathogenic.

Figure 4.

A typical DCM pedigree is shown highlighting variable expressivity. Most DCM is inherited in an autosomal dominant pattern. Affected individuals with DCM are shown in black. A gene panel revealed the previously reported pathogenic TPM1 E54K variant. The proband (arrow) presented in early life requiring heart transplant during early childhood. Other members of the family are in their 3^rd to 6^th decade with LVEF 45%, demonstrating variable expressivity of the primary mutation. Environmental and additional genetic factors may contribute to variable expressivity.

Interpreting whether genetic variants are pathogenic is increasing complex, owing to the vast amount of rare variation in each human genome. The emerging consensus around interpretation of genetic variation and its effect on phenotype relies on a classification system ranging from pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign⁵⁷. The availability of large control cohorts provides invaluable information of the frequency of variants, and the largest available data set is currently ExAC (Exome Aggregation Consortium) (http://exac.broadinstitute.org), which collected exome sequencing data of over 60,000 individuals from a series of studies including the 1000 Genomes Project and the Exome Sequencing Project (http://evs.gs.washington.edu/EVS). The current trend is to consider putative pathogenic variants as those that are either unique to the DCM patient or family⁵⁸, or extremely rare, (MAF <1 × 10⁻⁴)⁵⁹. The recently adopted, more stringent criteria for genetic testing have prompted the reclassification of variants and indicate the needs of a continuous reanalysis of data⁵⁸. The use of whole exome/genome sequencing in clinical laboratories warrants strong criteria to discriminate common variants. At present, genetic testing typically relies on self-reported ethnicity testing, and it is important to match ethnicity between the proband and testing databases. However, at this point, this integration of common and rare variation is not routinely being used in cardiomyopathy genetic testing, potentially contributing to false positive interpretation⁶⁰.

DCM is genetically heterogeneous, and DCM genes encode proteins of broad cellular functions. Mutations in genes encoding cytoskeletal, sarcomeric, mitochondrial, desmosomal, nuclear membrane and RNA binding proteins have all been linked to DCM. Thus, the pathological mechanisms that lead to DCM are very diverse. The genes below are listed in order of frequency for their contribution to genetic DCM with focus on the most commonly implicated genes and their mechanism of action if known.

TTN

The discovery of the role of TTN truncating variants in DCM has been major advance⁶¹. The TTN gene encodes the giant protein titin, which is the largest known protein expressed in the heart. Titin functions as a spring, providing passive force and regulating sarcomere contraction and signaling⁶². Titin is a large ~35,000 aa protein that spans half the length of the sarcomere from Z-disc to M-band, and is referred to as a “third” filament with the thin and thick filaments that comprise the sarcomere. Proposed as a molecular rule for the sarcomere, titin has domains that can accommodate passive stiffness⁶³. Titin’s I band region includes the PEVK (proline-glutamate-valine-lysine) repetitive region, which is thought to directly regulate passive tension. The I band region of the TTN gene is encoded by 220 of TTN’s 360 exons. The large size, repetitive nature, and extensive alternative splicing of TTN makes it challenging for genetic analysis. The PEVK region is just carboxyl to the N2A and N2B regions that interact with the FHL (four and half LIM protein), identified as a modifier for HCM⁶⁴. Notably, TTN is differentially spliced throughout heart development and adaptively to distinct physiological states including HF⁶⁵. The larger N2A form is associated with a more compliant ventricle (Figure 5). In contrast, the smaller N2B form lacks more of the repetitive units and is associated with stiffer heart. Deep RNA sequencing of TTN from failed hearts suggests highly variable exon usage in this region consistent with even subtler defects in cardiac elasticity that may be variable across regions of the LV⁶⁶.

Figure 5.

Shown in the top is a schematic of the sarcomere with the position of the thick myosin-containing filaments and the thin actin-containing filaments. Titin is considered a third filament of the sarcomere since its spans from Z disk to M band. The lower schematics show the major splice forms of titin (N2-BA, N2-B, N2-A). The green box represents a unique sequence domain. The PEVK region is named for the repetitive amino acid sequences (proline, glutamine, valine, lysine).

Using a TTN specific array designed to capture all TTN exons, it was shown that truncating variants of TTN contribute to 20–25% of nonischemic DCM⁶¹. Prior to this, only a few missense TTN variants had been described linked to DCM⁶⁷. Induced pluripotent stem cells (iPSC) differentiated into cardiomyocytes in culture demonstrate a paucity of sarcomeres, suggesting that force may be impaired directly through sarcomere loss in TTN truncations⁶⁸. In these studies and others it has been shown that TTN truncations are observed at a low frequency in the general population, ranging from 1–3%^{61, 66, 69}. There is a tendency for TTN truncations in DCM to distribute to the A band, rather than the I band⁶⁶, and TTN truncations can also be associated with mild DCM⁷⁰. A recent study showed that truncating variants in the general population are linked to eccentric cardiac remodeling, suggesting that TTN truncations may be “at-risk” alleles⁷¹.

Peripartum cardiomyopathy is a heterogeneous syndrome of mixed etiology. Yet a subset of peripartum cardiomyopathy is attributable to TTN truncating variants^{72, 73}. Peripartum cardiomyopathy can be associated with recovered LV function after pregnancy. Moreover, the observation that TTN truncating variants can be associated with recovery of function in DCM after LV assist device (LVAD) placement also suggests a dynamic state of TTN truncating variants⁷⁴. Additional genes with mutations beyond TTN have also been described in peripartum cardiomyopathy²¹. Overall, the presence of TTN truncating variants in the general population argues for caution in interpreting these variants and again underscores the importance of familial segregation analysis. At this point, until more is known, the presence of a TTN truncation variant should trigger at least intermittent cardiac imaging and management aimed at reducing other stressors to the heart.

TTN has a high prevalence of missense variants, both rare and common⁷⁵. TTN missense variants have been reported in ARVC and other forms of cardiomyopathy^{67, 75–78}. Additionally, TTN missense variants have also been reported in skeletal myopathy, including the common tibial myopathy^{79, 80}. The enormous number of TTN missense variants makes these variants exceedingly complex to interpret in the context of broad genetic testing on individuals with DCM.

Zebrafish have been used successfully to model myopathies due to TTN mutations, demonstrating both cardiac and skeletal muscle defects⁸¹. A mouse models with an in frame deletion in the PEVK region of TTN develops diastolic dysfunction, consistent with the complex role of titin for both systolic and diastolic dysfunction⁸². In both rats and mice with heterozygous TTN truncation mutations, additional stressors like transaortic constriction are used to promote the development of DCM^{71, 83}.

LMNA

LMNA missense and truncating mutations account for 5–8% of genetic DCM^{84, 85}. Like TTN, LMNA mutations are inherited in an autosomal dominant manner. The single LMNA gene encodes lamins A and C, and differential splicing at the 3′ end results in two proteins that are identical across their first 566 amino acids; mutations in LMNA lead to a constellation of diseases from premature aging, to myopathies and DCM⁸⁶. Mutations that alter processing of lamin A lead to accumulation of prelamin A (sometimes called progerin) and these have been associated with the premature aging syndrome Hutchinson Gilford Progeria⁸⁷. LMNA mutations linked to autosomal dominant DCM are both missense and frameshifting in nature, and these mutations may occur anywhere along the length of the coding region. DCM-associated mutations are not specifically associated with Prelamin A accumulation; thus, the basic mechanisms underlying the premature aging syndrome versus DCM appear to be distinct. The mechanisms responsible for autosomal dominant DCM LMNA mutations may be a mix of multiple defects including dominant-negative function as well as haploinsufficiency^{88, 89}. Lamins A and C are implicated in many different cellular processes from regulating gene expression, mechanosensing, DNA replication, and nuclear to cytoplasmic transport.

Loss of LMNA leads to a defect in mechanosignaling^{90, 91}. Mechanosignaling defects were observed in cell with a homozygous deletion in the mouse Lmna gene. Male mice heterozygously deleted for Lmna exhibit cardiomyopathy features in later life, suggesting that mice can be used to model laminopathy⁹². In LMNA associated adult-onset DCM, the mTOR pathway can be activated and, in animal models, inhibition mTOR by temsirolimus or rapamycin was able to rescue the DCM phenotype^{93, 94}. Mitogen activated protein kinase (MAPK) signaling is increased in these models, leading to clinical trials testing compounds aimed at reducing this signaling⁹⁵. Recently, early phase, encouraging results were reported from a Phase 2 registration trial on A797 (Array Biopharma), an oral, selective p38 mitogen-activated protein kinase inhibitor in 12 patients with LMNA–associated DCM⁹⁶.

LMNA mutations associate frequently with a signature of dysrhythmias that includes sinus node dysfunction, atrial fibrillation, AV node dysfunction, VT and ventricular fibrillation and SCD^{46, 47}. Notably, cardiac conduction system disease may precede the development of LV dilation and dysfunction, and the presence of early conduction system disease may suggest and LMNA mutation. Aspects of the arrhythmia and LV dysfunction phenotypes are not fully replicated in the mouse models; namely atrial fibrillation and ventricular arrhythmias are not frequently seen and a homozygous mutation is often needed to generate DCM. Heterozygous truncating LMNA mutations have a higher arrhythmia risk than missense variants⁴⁷, and a prolonged PR interval indicates cardiac conduction system disease in laminopathy⁹⁷. The susceptibility of the cardiac conduction system to LMNA mutations is not well understood.

PLN

The PLN gene encodes phospholamban, a 52 aa residue transmembrane protein that, when unphosphorylated, inhibits sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). Several dominant mutations in PLN have been associated with DCM, including the R14del mutation that appears to be a founder mutation in the Netherlands and Germany. Thus, in some populations the percentage of DCM due to PLN mutations is quite high. The phenotype with PLN mutations is variable. Early onset DCM with lethal ventricular arrhythmias was described^{98, 99}. Similarly, individuals from the Netherlands with the R14del founder mutation have a severe phenotype¹⁰⁰. However, other reports suggest a milder phenotype^{101, 102}. Identifying the same primary mutation(s) with a range of phenotype dependent on genetic background supports that other factors, including genetic factors, may modify the outcome of DCM due to PLN mutations.

iPSCs with the R14del PLN mutation were generated and found to display features of cellular cardiomyopathy including aberrant Ca²⁺ handling after caffeine and a higher percentage of irregular Ca²⁺ transients, and these features were reversed after gene editing to correct the primary mutation¹⁰³. These same cells were used to engineer three dimensional human heart tissues and in this setting, more clear cut cardiomyopathic features were seen including reduced developed force that was improved after genetic correction¹⁰⁴. In iPSC-derived cardiomyocytes and in hearts from PLN-mutation carriers, aggregates of phospholamban were seen in a perinuclear and cytoplasmic pattern suggesting that aggregated phospholamban contributes to the pathology possibly through aberrant autophagy¹⁰⁵.

RBM20

RNA binding motif 20 is an RNA binding protein expressed highly in both atria and ventricle. Dominant mutations in the RBM20 gene were first described in DCM, where they contribute to 1–5% of DCM^{106, 107}. RBM20 is 1227 aa in length and contains a ribonucleic acid recognition motif (RRM) domain between residues 525 to 600 aa. A second conserved domain is found between 650 and 725, and the mutations originally described in nonischemic DCM fall within or near these domains. More recently, mutations in a third conserved region were identified in a glutamate rich region¹⁰⁸. As an RNA binding protein, RBM20 is implicated in tissue specific splicing relevant to development and adaptation to disease states. In the heart, RBM20 regulates cardiac splicing including the splicing of TTN^109–111. Thus, the downstream molecular consequences of RBM20 mutations may share similarities to those occurring from TTN truncating variants.

iPSC-derived cardiomyocytes with the RBM20 R636S mutation develop a gene expression and splicing profile consistent with cardiomyopathy affecting not only TTN but also the CAMK2D and CACNA1C genes¹¹². Sarcomeres within these RBM20 mutant lines were thinner, similar to what was described for TTN mutant iPSC-cardiomyocytes⁶⁸. Recently, RBM20 was implicated in the production of circular RNAs from the TTN locus, and mice deleted for RBM20 failed to produce these Ttn-derived circular RNAs¹¹³. Although the function of circular RNAs is not known, the authors described that a subset of Ttn-derived circular RNAs were misregulated in DCM.

SCN5A

SCN5A encodes the major sodium channel expressed in the heart and heterozygous dominant mutations in SCN5A are also found in primary arrhythmia syndromes including the Long QT and Brugada syndromes. Missense mutations in SCN5A have also been described in familial DCM, and these mutations carry a higher risk for arrhythmias^{48, 49}. There is considerable genetic heterogeneity in the SCN5A gene in the general population, making it challenging to interpret rare variation in the SCN5A gene⁵⁹. Genotype-phenotype association studies may guide genotype-based therapies. For example, the SCN5A R222Q falls within the S4 voltage sensor and is thought to enhance excitability. Treatment with lidocaine was observed to suppress the bigeminy associated with cardiomyopathy¹¹⁴.

iPSCs have been used to model SCN5A mutations associated with primary human arrhythmia syndrome^115–117. Transgenic directed inducible expression of the Scn5A F1759A in mice leads to atrial fibrillation and persistent sodium currents in atria and ventricles¹¹⁸. Along with atrial fibrillation, these mice have progressive reduced LVEF consistent with a model for DCM. Thus, the distinct roles of SCN5A in the myocardium and the conduction system lead to a combination of arrhythmia and myocyte dysfunction.

Cytoskeletal genes

Genes encoding cardiac cytoskeletal proteins have been implicated in DCM (Figure 6). For example, mutations in dystrophin link to X-linked DCM and cardiomyopathy in Duchenne Muscular Dystrophy^119–121. Along with dystrophin mutations, mutations in the sarcoglycan genes produce cardiomyopathy, usually associated with muscular dystrophy^{51, 122}. In these disorders, the gene products play a normal and essential role in managing sarcolemmal stability. Thus, in the absence of these genes, the sarcolemma becomes unstable leading to cardiomyocytes loss and heart dysfunction. A number of emerging therapies for restoring dystrophin expression are being tested or have been approved recently^{123, 124}. Antisense oligonucleotides are being delivered to produce internally truncated dystrophin proteins, and stop codon suppression compounds promote read through of premature stop codons. The degree to which these drugs access the human heart is not well known and ongoing studies will be in a position to assess this in humans.

Figure 6.

Shown are major components within the cardiomyocyte with emphasis on compartments that contribute to genetically mediated DCM. The extracellular matrix is shown in gray. The dystrophin complex that includes the sarcoglycans (green) is mutated in forms of DCM with neuromuscular disease. The sarcomeres (pink) include components that are mutated in both HCM and DCM. Z band (dark red) is a mechanosensing hub that serves to transmit force from the sarcomeres. Mutations in both mitochondrially encoded (purple) and nuclear encoded mitochondria proteins lead to cardiomyopathy. The nuclear lamina include lamins A and C, and the gene LMNA is commonly mutated in DCM.

More recently FLNC mutations, in the gene encoding filamin C, have been described in DCM^125–127. Filamin C interacts with the dystrophin complex, and deletion of Flnc from the mouse leads to skeletal myopathy^{128, 129}. In humans, truncating mutations lead to cardiomyopathy that is associated with a high rate of ventricular arrhythmias and SCD suggesting that filamin C has a role in the cardiac conduction system in addition to the cardiomyocyte.

Mitochondrial mutations

Both nuclear encoded and mitochondrially encoded mitochondrial genes lead to cardiomyopathy^130–133. Mutations in the mitochondrial genomes may be difficult to identify and interpret given the role of heteroplasmy and the fact that most genetic testing relies on peripheral blood DNA, which may or may not match what occurs in the heart. Nuclear encoded mitochondrial genes follow either autosomal dominant or recessive inheritance, while mitochondrially encoded genes shows maternal inheritance.

Additional genetic mutations in DCM

The proteins encoding the sarcomere, the unit of contraction, are also implicated in DCM. Recent data from clinical genetic testing indicates that MYH7, TNNT2 and TPM1 are the most frequent mutated sarcomere genes in DCM, ranging from approximately 2 to 4%, while MYBPC3 mutations are rare⁵⁸. Recently, truncations of the gene encoding obscurin have been found in both LVNC and DCM phenotypes¹³⁴. DCM may be best considered as a cardiomyopathy of mixed origin, familial in approximately 30–50% of patients, consistent with its being a genetic disease. Non-familial or idiopathic DCM may still have a genetic origin, albeit a complex one. Since all DCM mutations have variable expressivity, this may support a model of oligogenic contribution along with environmental or other pathogenic stimuli. As it currently, stands not all DCM genes have been discovered. Thus, the etiology in nonfamilial cases could be as yet undiscovered genes, low penetrance, de novo mutations, “missing heritability” due to multiple genes with weaker effect, copy number variations, enhancer region mutations, and intronic variants, or may be the result of the interaction between modifier genes and the environment^{13, 135}.

Digenic/oligogenic etiology

Occasionally, digenic variants have been reported; while it is possible that some of these variants may in fact be VUS or benign, in other cases the digenic condition have been found to segregate in informative kindred and associate with a more severe phenotype. This is the case of a large family cosegregating a LMNA mutation, where relatives with an additional TTN truncation showed worse outcome and distinct pathological changes¹³⁶. With the growth of gene panels for cardiomyopathy genetic testing, it is not uncommon to identify more than one potential pathogenic variant. Segregation analysis may be helpful to clarify “primary” versus other variants. Compound mutations MYBPC3 lead to early onset, sometime neonatal cardiomyopathy^137–139. Thus, in families with multiple affected members with DCM, a broad gene panel on a younger, affected proband may provide a more comprehensive view of potential variation. Segregation testing for variants of interest can then help clarify those variants with greatest effect.

Genetic testing

Family screening

Genetic evaluation of DCM should begin with extensive and accurate evaluation of the patient’s family history, involving at least three generations and including history of cardiomyopathy as well as history of sudden unexpected death at young age (<35)^{3, 19, 140}. This information will guide genetic testing, provide good care to family members, and aid in the interpretation of the results and help identifying relatives at risk of disease.

Clinical cascade screening of relatives is recommended per AHA and ESC guidelines^{3, 141}. First-degree relatives of affected family members should be clinically evaluated (Figure 2). First line of screening usually relies on ECG and echocardiography to evaluate ventricular size and function. Clinical history should evaluate signs and symptoms for arrhythmias and any history of neuromuscular disease. Other cost effective tools to consider in family member screening include ascertaining arrhythmia history and Holter monitoring⁴⁵. A diagnosis of familial DCM is made where two or more family members are affected by DCM¹⁹.

Clinical Genetic testing

According to the 2016 AHA Scientific Statement on DCM³, genetic testing is recommended (with moderate level of consensus) in patients with familial (Level of Evidence A) and non-familial ‘idiopathic’ cardiomyopathy in conjunction with genetic counseling (Level of Evidence B), while there is strong level of consensus in recommending mutation-specific genetic testing for family members after the identification of a DCM-causative mutation in the proband (Level of Evidence B). Reflecting lack of full consensus in the field, the 2016 ESC Position Statement¹⁴¹ is slightly different and recommends genetic testing in all familial DCM, or non-familial with clinical clues (such as atrio-ventricular block or CK elevation). Interestingly, the ESC Position Statement recommends that genetic testing should be oriented by clinical diagnostic clues and restricted to genes known to cause DCM, while considering large panels of genes only when the family structure is large enough to permit segregation analysis.

Multiple commercial and academic vendors provide genetic testing gene panels under certification of the Clinical Laboratory Improvement Amendment (CLIA). A typical DCM gene panel includes approximately 40–50 genes (Figure 3)^{58, 142}. The probability of positive genetic testing in familial DCM is overall in the range of 40% with the current next-generation sequencing panels, and seems not different compared to sporadic cases^{13, 58}. A pancardiomyopathy panel, as opposed to a DCM panel, is chosen when the phenotype is unclear and a more comprehensive screening is preferred. The level of evidence to support testing for some genes has been questioned, and this is largely based on a high level of genetic variation in those genes in the population at large¹⁴³. Larger panels may yield greater difficulty in interpreting the results because of variant of unknown significance (VUS). Indeed, in a survey of 766 patients screened in a clinical laboratory, with the introduction of next generation sequencing technology and larger panels, while the rate of positive testing increased from 10% to 40%, the number of VUS increased 10 fold^{13, 58, 144}.

Genetic Counseling

Genetic counselors, especially those with experience in cardiovascular testing, provide both pre- and post-test counseling. With the increasing complexity of cardiomyopathy genetic testing, referral to specialized cardiovascular genetic clinics should be considered¹⁴⁰. Pre-test genetic counseling should involve discussion of potential genetic results, (pathogenic mutations, variants of uncertain significance and benign genetic variants). This counseling should also discuss the impact on insurability, reproduction and lifestyle. Post-test counseling focuses on variant interpretation/possible reinterpretation, reproductive risks to offspring and family testing.

If a genetic mutation is identified, genetic cascade screening can be conducted with family members. Cascade genetic testing evaluates the specific family mutation, rather than a gene panel. Site specific testing is of low cost and rapid turnaround so that this can be a cost-effective strategy to eliminate the need to serially follow gene mutation-negative family members. For gene mutation-positive family members, current guidelines suggest an annual clinical follow up with ECG and echocardiography^{3, 140, 141}.

In the absence of an informative genetic testing, asymptomatic first degree relatives should be examined every 3 to 5 years¹⁴⁰. This strategy may allow prompt therapeutic measures in carriers showing sign of myocardial dysfunction. Even in the absence of a positive genetic testing, longitudinal studies have shown the benefit of family screening and monitoring. In approximately 10% of cases, mild myocardial dysfunction may progress into overt DCM within 5 years^{27, 145}. Furthermore, clinical family screening in DCM helps to identify affected relatives at earlier stages of disease, and this associates with improved survival as compared to sporadic DCM¹⁴⁶.

Management of DCM

Established medical therapies

Management of DCM is focused on 1) LV dimension and function, 2) arrhythmia surveillance and treatment, and 3) reducing congestive symptoms if present. Symptomatic DCM and heart failure with reduced LVEF (HFrEF) is managed following current AHA/ACC and ESC guidelines. Guideline directed therapy includes angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), in association with beta-blockers, aldosterone antagonists, and in selected cases, vasodilators^147–149. Medications should be titrated to the dose used in clinical trials unless limited by side effects¹⁵⁰. DCM patients on optimal therapy with complete left bundle branch block (LBBB) may benefit from cardiac resynchronization^{147, 148, 151, 152}. The improvement of survival with ICDs in patients with LVEF less than 35% is also well established^{147, 148}. Patients with refractory heart failure may require advanced therapies including left ventricular assist devices or cardiac transplant^{147, 148}.

Two newer medications for those not responding to optimal medical therapy include the angiotensin receptor-neprylisin inhibitor (ARNI, valsartan/sacubitril) and the sinoatrial modulator, ivabradine^{3, 148, 151}. Updated guidelines recommend switching from ACEi/ARB to ARNI in class II-III patients who are not responding to optimal medical therapy (ESC guidelines¹⁴⁸) or even in those responding to optimal therapy, considering the evidence of superior benefit of ARNI over ACEi/ARBS in terms of mortality and morbidity (AHA/ACC/HFSA guidelines¹⁵³). Ivabradine instead can be added to optimal medical therapy to reduce morbidity in patients with sinus rhythm and a heart rate over 70 bmp^{3, 148}. The treatment of patients with a LVEF between 40% and 50%, defined in the ESC guidelines HF with midrange ejection fraction (HFmrEF) and in the ACC/AHA/HFSA guidelines HF with improved ejection fraction remain less clear¹⁵¹.

Arrhythmia management

Arrhythmia management in genetic DCM patients follows the general recommendations for prevention of SCD and ICD implantation based on the reduced LVEF (<35%). However, there are notable exceptions. First, a subset of patients with DCM present early in the disease course with life-threatening ventricular arrhythmias (2%)¹⁵⁴ or with frequent ventricular arrhythmias (30%), which are unrelated to the severity of left ventricular dysfunction⁴⁵. These patients mirror the arrhythmogenic presentation of ARVC and are described as arrhythmogenic DCM (AR-DCM)⁴⁵. AR-DCM patients who present with syncope, NSVT and frequent premature ventricular contractions, show a higher incidence of life-threatening arrhythmic events (SCD, sustained ventricular tachycardia, cardiac arrest) compared with the other DCM patients, while they show no difference in outcome of heart failure. The coexistence of a family history of SCD and the AR-DCM phenotype predicts a high risk of SCD events (Figure 7). These recent data suggest that ventricular arrhythmias should be systematically and carefully evaluated with monitoring, and that family history of ventricular arrhythmias predicts a poor prognosis and increased risk of SCD.

Figure 7. Sudden cardiac death and life-threatening ventricular arrhythmias in DCM.

Cox-estimated event-free survival stratified by 2 risk factors, family history of SCD or ventricular arrhythmias (SVT or VF) and AR-DCM diagnosis, in a cohort of 285 DCM patients. The AR-DCM phenotype (p=0.02) and family history of SCD or ventricular arrhythmias (SCD/SVT/VF) (p=0.038) showed an additive prognostic effect on mortality for arrhythmic events. AR-DCM: Arrhythmogenic Dilated Cardiomyopathy; SCD/SVT/VF: sudden cardiac death, sustained ventricular tachycardia and ventricular fibrillation. From Spezzacatene et al.,⁴⁵ with permission.

AR-DCM can be genetically determined, and a clear association between risk of SCD and gene has been established with the LMNA gene. Indeed, the 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of SCD¹⁵⁵, recommend an ICD in patients with DCM and a confirmed disease-causing LMNA mutation and clinical risk factors (NSVT during ambulatory electrocardiogram monitoring, LVEF 45%, male sex and truncating mutations (class IIa, level B). Likewise, the HRS/ACC/AHA Expert Consensus Statement on the use of ICD therapy inpatients highlighted the increased risk for SCD in LMNA carriers¹⁵⁶. Risk factors for SCD identified in two large LMNA carrier cohorts in Europe⁴⁷ and in the U.S.¹⁵⁷ include NSVT during ambulatory electrocardiogram monitoring⁴⁷, LVEF < 45⁴⁷ to 50%¹⁵⁷, male sex and truncating mutations^{47, 157}. Kumar et al. reported life-threatening ventricular arrhythmia rates of 3% to 7%/year, which is higher or comparable to other known groups of high-risk patients including those with LVEF < 25%, ARVC, HCM and high-risk ischemic cardiomyopathy.

DCM also carries an increased stroke risk, although less is known about the specific risk in genetic cardiomyopathy. As such, anticoagulation should be considered to reduce the risk of stroke in DCM with atrial fibrillation in particular in the presence of additional risk factor for cardioembolic events such as history of hypertension, diabetes mellitus, previous stroke or transient ischemic attack, or ≥75 years of age¹⁴⁷.

Management of genotype-positive/ phenotype-negative patients

Genetic testing identifies genotype-positive/ phenotype-negative family members, and this information is useful for prevention strategies, lifestyle recommendations including participation in competitive sports, and possible arrhythmia management. The current guidelines recommend observation in asymptomatic at-risk relatives with yearly clinical assessment¹⁴⁰. There is less consensus concerning the medical management, timing and the type of intervention in these patients. Current guidelines recommend control of risk factors in this stage, such as hypertension¹⁴⁷. ESC and AHA suggest restriction from competitive sports in DCM genotype-positive/ phenotype-negative, although evidence is lacking to support these recommendations¹⁵⁸. When initial signs of ventricular dysfunction present during follow-up, earlier institution of medical therapy can begin, although the exact timing of this is not known¹⁴⁰.

Cardiac Regeneration for DCM?

DCM is usually associated with cardiomyocytes loss, and the human heart has limited regenerative capacity. Strategies for regeneration and repair include the application of a cell suspension, growth factors, miRNAs and the implantation of an engineered tissue^159–161. Various studies and clinical trials have tested cardiac progenitor cells (CPCs), bone marrow-derived stem cells, and pluripotent stem cells¹⁶². Frustratingly, these clinical interventions demonstrated safety but often failed to prove functional improvement. The mechanism underlying the potential effects of bone marrow derived stem cells (BMSCs) is unclear; the injected cells do not appear to remain in the cardiac tissue, but may release paracrine factors and recruit CPCs¹⁵⁹.

Stem cells are now being used to provide cellular models of DCM. The absence of human cardiomyocyte cell lines has been a problem for advancing research in human cardiomyopathy. iPSCs can be more readily generated from human patients with DCM, and these cells can be differentiated into cardiomyocytes for study. A major limitation of iPSC derived cardiomyocytes is their relative immaturity and variability from culture to culture, but nonetheless these cells can be used to study cellular properties reflective of DCM features. As yet, these stem cells are not yet sufficiently mature for treating cardiomyopathy¹⁵⁹, although they are yielding an important platform for understanding mechanisms and testing therapies¹⁶³.

Conclusions and future directions

Better understanding of the DCM phenome and recent improvements in sequencing technology to define DCM genome will eventually improve the diagnosis, prevention and therapy of this disease. Next generation sequencing technology provides a cost-effective and accurate diagnostic method to yield biomarkers that indicate disease risk, especially within families. With this progress, criteria for pathogenic mutations are evolving and becoming more and more stringent, and may require re-evaluation of the molecular diagnosis over time. Several questions still remain in DCM management that prompt future investigations, such as the interpretation of genetic testing, the correct treatment of pre-clinical asymptomatic DCM gene carriers, and the development of gene- and mechanism-specific therapies.

Nonstandard Abbreviations

AC

arrhythmogenic cardiomyopathy

ACEi

angiotensin converting enzyme inhibitor

ARB

angiotensin receptor blocker

ARNI

angiotensin receptor-neprylisin inhibitor

BMSC

bone marrow derived stem cell

CLIA

Clinical Laboratory Improvement Amendment

CMR

cardiac magnetic resonance

CPC

cardiac progenitor cell

DCM

dilated cardiomyopathy

EMB

endomyocardial biopsy

ExAC

exome aggregation consortium

FHL

four and half LIM

FS

fractional shortening

HCM

hypertrophic cardiomyopathy

HFrEF

heart failure with reduced ejection fraction

HFmrEF

heart failure with midrange ejection fraction

ICD

implantable cardioverter-defibrillator

iPSC

induced pluripotent stem cell

LVAD

left ventricular assist device

LVEDD

left ventricular end diastolic dimension

LVIDd

left ventricular internal dimension in diastole

LVIDs

left ventricular internal dimension in systole

LVNC

left ventricular noncompaction

LV

left ventricle

MAF

minor allele frequency

NSVT

nonsustained ventricular tachycardia

PEVK

proline-glutamate-valine-lysine

RRM

ribonucleic acid recognition motif

SCD

sudden cardiac death

VUS

variant of uncertain significance

VT

ventricular tachycardia