Alternative titles; symbols
SNOMEDCT: 83978005; ICD10CM: I42.1; DO: 0110307;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.3 | Cardiomyopathy, familial hypertrophic | 192600 | Autosomal dominant; Digenic dominant | 3 | CAV3 | 601253 |
| 14q11.2 | Cardiomyopathy, hypertrophic, 1 | 192600 | Autosomal dominant; Digenic dominant | 3 | MYH7 | 160760 |
| 20q11.21 | Cardiomyopathy, hypertrophic, 1, digenic | 192600 | Autosomal dominant; Digenic dominant | 3 | MYLK2 | 606566 |
A number sign (#) is used with this entry because hypertrophic cardiomyopathy-1 (CMH1) is caused by heterozygous mutation in the MYH7 gene (160760) on chromosome 14q11.
Hereditary ventricular hypertrophy (CMH, HCM, ASH, or IHSS) in early stages produces a presystolic gallop due to an atrial heart sound, and EKG changes of ventricular hypertrophy. Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive heart failure, and sudden death. Seidman (2000) reviewed studies of hypertrophic cardiomyopathy in man and mouse.
Reviews
Walsh et al. (2022) reviewed hypertrophic cardiomyopathy phenotypes associated with variation in genes encoding nonsarcomeric proteins. The authors suggested that these genes likely contribute to polygenic risk scores derived from genomewide association studies that could be used to improve risk assessment in patients and family members, and noted that the diverse functions of the proteins highlight novel disease pathways and therapeutic targets for cardiomyopathies.
Genetic Heterogeneity of Hypertrophic Cardiomyopathy
Additional forms of hypertrophic cardiomyopathy include CMH2 (115195), caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; CMH3 (115196), caused by mutation in the TPM1 gene (191010) on chromosome 15q22; CMH4 (115197), caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11; CMH6 (600858), caused by mutation in the PRKAG2 gene (602743) on chromosome 7q36; CMH7 (613690), caused by mutation in the TNNI3 gene (191044) on chromosome 19q13; CMH8 (608751), caused by mutation in the MYL3 gene (160790) on chromosome 3p21; CMH9 (613765), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMH10 (608758), caused by mutation in the MYL2 gene (160781) on chromosome 12q24; CMH11 (612098), caused by mutation in the ACTC1 gene (102540) on chromosome 15q14; CMH12 (612124), caused by mutation in the CSRP3 gene (600824) on chromosome 11p15; CMH13 (613243), caused by mutation in the TNNC1 gene (191040) on chromosome 3p21; CMH14 (613251), caused by mutation in the MYH6 gene (160710) on chromosome 14q12; CMH15 (613255), caused by mutation in the VCL gene (193065) on chromosome 10q22; CMH16 (613838), caused by mutation in the MYOZ2 gene (605602) on chromosome 4q26; CMH17 (613873), caused by mutation in the JPH2 gene (605267) on chromosome 20q12; CMH18 (613874), caused by mutation in the PLN gene (172405) on chromosome 6q22; CMH20 (613876), caused by mutation in the NEXN gene (613121) on chromosome 1p31; CMH21 (614676), mapped to chromosome 7p12.1-q21; CMH22 (see 615248), caused by mutation in the MYPN gene (608517) on chromosome 10q21; CMH23 (see 612158), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMH24 (see 601493), caused by mutation in the LDB3 gene (605906) on chromosome 10q23; CMH25 (607487), caused by mutation in the TCAP gene (604488) on chromosome 17q12; CMH26 (617047), caused by mutation in the FLNC gene (102565) on chromosome 7q32; CMH27 (618052), caused by mutation in the ALPK3 gene (617608) on chromosome 15q25; CMH28 (619402), caused by mutation in the FHOD3 gene (609691) on chromosome 18q12; and CMH29 (620236), caused by mutation in the KLHL24 gene (611295) on chromosome 3q27.
The CMH5 designation was initially assigned to a CMH family showing genetic heterogeneity. Subsequently, affected individuals were found to carry mutations in the MYH7 (CMH1) and/or MYBPC3 (CMH4) genes.
Mutations in the CALR3 gene (611414), previously suggested to cause a form of CMH (Chiu et al., 2007) designated CMH19, were convincingly shown not to be a monogenic cause of cardiomyopathy by Verhagen et al. (2018); see 611414.0001.
Hypertrophic cardiomyopathy has also been associated with mutation in the gene encoding cardiac myosin light-peptide kinase (MYLK2; see 606566.0001), which resides on chromosome 20q13.3; the gene encoding caveolin-3 (CAV3; see 601253.0013), which maps to chromosome 3p25; and with mutations in genes encoding mitochondrial tRNAs: see mitochondrial tRNA-glycine (MTTG; 590035) and mitochondrial tRNA-isoleucine (MTTI; 590045).
In the first demonstration of asymmetric hypertrophy of the heart in young adults, Teare (1958) reported the autopsy findings in 9 cases of sudden death in young subjects distributed in 6 families. This condition has been called muscular subaortic stenosis but more generalized ventricular hypertrophy is often an earlier and more impressive feature, and obstruction to outflow from the right ventricle can also occur. Study of the families of probands with the full-blown condition shows that an atrial heart sound ('presystolic gallop') and EKG changes of ventricular hypertrophy are the earliest signs. Sudden death occurs in some cases. Braunwald et al. (1964) reported in detail on 64 patients; multiple cases were observed in 11 families, which contained in all at least 41 definite or probable cases. As pointed out by Nasser et al. (1967), outflow obstruction may be absent in some affected members of families in which others do have outflow obstruction. Maron et al. (1974) studied 4 infants that died with ASH in the first 5 months of life, including 1 stillborn. ASH was demonstrated in one first-degree relative of each infant. Maron et al. (1976) analyzed the clinical picture of 46 children with ASH. On the basis of a study of an outpatient population, Spirito et al. (1989) suggested that the prognosis in hypertrophic cardiomyopathy may be less grave than has usually been considered on the basis of hospital-study patients.
On morphologic grounds, 4 types of hypertrophic cardiomyopathy have been described: type 1 with hypertrophy confined to the anterior segment of the ventricular septum; type 2 with hypertrophy of both the anterior and the posterior segments of the ventricular septum; type 3 with involvement of both the ventricular septum and the free wall of the left ventricle and type 4 with involvement of the posterior segment of the septum, the anterolateral free wall, or the apical half of the septum (Maron et al., 1982; Ciro et al., 1983). Apical hypertrophic cardiomyopathy is, therefore, one form of type IV. It was first described by Yamaguchi et al. (1979) in Japan (where it appears to be more frequent than elsewhere) and later by Maron et al. (1982). The cases of apical hypertrophic cardiomyopathy described by Maron et al. (1982) belonged to families with different forms of hypertrophic cardiomyopathy. Malouf et al. (1985) reported apical hypertrophic cardiomyopathy in father and daughter of a Lebanese Christian family. The parents were not related; an only sib was normal on examination and echocardiogram as were 2 sisters of the father and their 6 children.
In a metaanalysis of sudden death from cardiac causes in children and young adults, Liberthson (1996) found that hypertrophic cardiomyopathy was the most frequent cause of sudden death in young persons in association with strenuous physical exertion or sports.
Maron et al. (1996) collected information on 158 sudden deaths that had occurred in trained athletes throughout the United States from 1985 through 1995. In 24 athletes (15%), noncardiovascular causes were found. Among the 134 athletes who had cardiovascular causes of sudden death, the median age was 17 years. The most common competitive sports involved were basketball (47 cases) and football (45 cases), together accounting for 68% of sudden deaths. The most common structural cardiovascular diseases identified at autopsy as the primary cause of death were hypertrophic cardiomyopathy (48 athletes, 36%), which was disproportionately prevalent in black athletes compared with white athletes (48% vs 26% of deaths; P = 0.01), and malformations involving anomalous coronary artery origin (17 athletes, 13%). Of 115 athletes who had a standard preparticipation medical evaluation, only 4 (3%) were suspected of having cardiovascular disease, and the cardiovascular anomaly responsible for sudden death was correctly identified in only 1 athlete (0.9%).
In a series of 387 young athletes who died suddenly, Maron (2003) found that hypertrophic cardiomyopathy was the cause in 102 (26.4%). Coronary artery anomalies had accounted for 53 (13.7%) and ruptured aortic aneurysm of Marfan syndrome for 12 (3.1%). Arrhythmogenic right ventricular cardiomyopathy was found in 11 (2.8%) and long QT syndrome in 3 (0.8%).
Cannon (2003) tabulated the features of hypertrophic cardiomyopathy that increase the risk of cardiovascular events. These included family history of sudden death, recurrent syncope, ventricular tachycardia on monitoring, extreme left ventricular hypertrophy (more than 3 cm), left ventricular outflow pressure gradient of more than 30 mm Hg, and fall in blood pressure during exercise.
In the family reported by Horlick et al. (1966), 10 persons in 4 generations were thought to have been affected. Pare et al. (1961) described this disorder in 30 out of 87 members of a French Canadian kindred. The genealogic survey was carried back to the original emigrant from France in the 1600s. The pattern of occurrence over 5 generations and 160 years since the death of the man believed to be the first instance of the heart disease indicated autosomal dominant inheritance. Elevated paternal age of sporadic (possible fresh mutation) cases was observed by Jorgensen (1968). The family study of Clark et al. (1973), using echocardiography, indicated that 28 of 30 probands (93%) had an affected parent. This agrees well with estimates of the extent to which this disorder, on the average, reduces reproductive fitness.
Greaves et al. (1987) performed echocardiographic studies of 193 first-degree relatives of 50 patients with hypertrophic cardiomyopathy. More males than females were affected. In 28 of 50 families, familial occurrence was observed. In 15 families the pattern of transmission was consistent with autosomal dominant inheritance; in the other 13 families affected members were in a single generation and the pattern of inheritance could not be determined.
The family reported by Yamaguchi et al. (1979) suggested X-linked recessive inheritance. Burn (1985) felt that the existence of a recessive form of hypertrophic cardiomyopathy (Emanuel et al., 1971; Branzi et al., 1985) could neither be established nor disproved at the time of his writing. Branzi et al. (1985) claimed the existence of an autosomal recessive form because of a family they found with 2 affected sisters and both parents normal by careful study. Formal segregation analysis supported the existence of 2 classes: one with a segregation ratio close to 50% and one with a value close to 25%.
Jarcho et al. (1989) did studies with DNA markers in the Canadian family originally reported by Pare et al. (1961). At the time of the study, hypertrophic cardiomyopathy had occurred in 20 surviving and 24 deceased family members. With a polymorphic DNA probe with the trivial name CRI-L436, which identified a DNA segment designated D14S26, they found no recombination (lod score = 9.37 at theta = 0). This probe had been assigned to chromosome 14 on the basis of somatic cell hybrid analysis (Donis-Keller et al., 1987). The gene encoding the alpha chain of the T-cell receptor (see 186880) was located approximately 20 cM from D14S26 (Mitchell et al., 1989). Solomon et al. (1990) mapped the probe CRI-L436 to 14q11-q12 by in situ hybridization. Because the cardiac myosin heavy chain genes (MYH6, 160710; MYH7) map to the same chromosomal band, they determined the genetic distance between the gene for the beta heavy chain of cardiac myosin, D14S26, and the CMH1 locus. They presented data indicating that these 3 loci are linked within 5 cM of each other. The data were consistent with the possibility that the CMH1 mutation is in either the alpha or the beta gene.
Hejtmancik et al. (1991) found that the gene for familial hypertrophic cardiomyopathy was located at 14q1 in 8 unrelated families of varied ethnic origins. Of 5 families with hypertrophic cardiomyopathy, Epstein et al. (1992) found linkage to chromosome 14 markers in one and suggestive linkage in a second. However, linkage to chromosome 14 markers was excluded in the other 3 kindreds. Ko et al. (1992) excluded linkage to D14S26 in a Chinese family, likewise indicating genetic heterogeneity.
In affected members of the large French Canadian kindred originally reported by Pare et al. (1961) and shown to have linkage to markers on the proximal portion of 14q, Geisterfer-Lowrance et al. (1990) identified heterozygosity for a missense mutation in the MYH7 gene (R403Q; 160760.0001). Ross and Knowlton (1992) reviewed this discovery beginning with the patients first seen by Pare in the 1950s.
Using a ribonuclease protection assay, Watkins et al. (1992) screened the beta cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy and identified 7 different missense mutations in 12 of the 25 families (see, e.g., 160760.0003-160760.0007).
Atiga et al. (2000) studied 36 patients with CMH1 using beat-to-beat QT variability analysis. This technique quantifies the beat-to-beat fluctuations in ventricular repolarization reflected in the QT interval. Seven mutations were found in this group: 9 patients had the 'severe' arg403-to-gln mutation (160760.0001) and 8 had the more benign leu908-to-val mutation (160760.0010). Atiga et al. (2000) found higher QT variability indices in patients with CMH1 compared with controls, and the greatest abnormality was observed in patients with the arg403-to-gln mutation. CMH1 patients therefore exhibited labile ventricular repolarization and were considered to be at higher risk of sudden death from ventricular arrhythmias, particularly those with a 'severe' mutation.
Blair et al. (2001) studied a family with familial hypertrophic cardiomyopathy in which 2 individuals suffered early sudden death and a third individual died suddenly at the age of 60 years with autopsy evidence of familial hypertrophic cardiomyopathy. A val606-to-met (V606M) mutation was observed in the MYH7 gene (160760.0005). This mutation had previously been proposed to give rise to a benign phenotype (see Abchee and Marian, 1997). A second ala728-to-val (A728V) mutation (160760.0025) was found in cis with the V606M mutation. Blair et al. (2001) suggested that this second mutation in cis explained the more severe phenotype seen in this family.
Arad et al. (2005) identified 2 different MYH7 missense mutations in 2 probands with apical hypertrophy from families in which the mutations also caused other CMH morphologies (see 160760.0038 and 160760.0039, respectively). Another MYH7 mutation (R243H; 160760.0040) was identified in a sporadic patient with apical hypertrophy; the same R243H mutation was later found by Klaassen et al. (2008) in a family segregating isolated left ventricular noncompaction (LVNC5; see 613426).
In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a missense mutation in the JPH2 gene (605267.0004); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 mutations in MYH7 (see, e.g., 160760.0016). The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband.
In a 32-year-old African American woman with severe hypertrophic cardiomyopathy (see CMH7, 613690) and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous mutation in the TNNI3 gene (P82S; 191044.0003) and a heterozygous mutation in the MYH7 gene (R453S; 160760.0043). Frazier et al. (2008) suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy.
Skeletal Muscle Involvement
Fananapazir et al. (1993) demonstrated by biopsy of the soleus muscle the presence of central core disease of skeletal muscle in association with hypertrophic cardiomyopathy due to any of 4 different mutations in the MYH7 gene. These findings were consistent with congenital myopathy-7A (CMYP7A; 608358), also caused by mutation in the MYH7 gene. However, almost all patients had no significant muscle weakness, despite the histologic changes. In 1 family with a L908V mutation (160760.0010), central cores were demonstrated on soleus muscle biopsy, although cardiac hypertrophy was absent on echocardiogram in 2 adults and 3 children. The histologic hallmark was the absence of mitochondria in the center of many type I fibers as revealed by light microscopic examination of NADH-stained fresh-frozen skeletal muscle sections. Soleus muscle samples from patients in 4 kindreds in which hypertrophic cardiomyopathy was not linked to the MYH7 locus showed no myopathy or central core disease. McKenna (1993), who stated that he had never seen clinical evidence of skeletal myopathy in CMH1, doubted the significance of the findings.
In a mother with myosin storage myopathy (CMYP7A; 608368), who later developed CMH, and in her daughter, who had early-symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7 (160760.0037). The mother presented at age 30 years with proximal muscle weakness, which progressed to the point of her being wheelchair-bound by 48 years of age. At age 51, CMH was diagnosed; echocardiography revealed no atrial or ventricular dilatation, and no abnormal appearance of the ventricular walls. Skeletal muscle biopsy at 53 years of age showed subsarcolemmal accumulation of hyaline material in type 1 fibers. Her 24-year-old daughter presented with heart failure at 3 months of age and was diagnosed with early-onset cardiomyopathy. Angiography revealed a less-contractile, irregular 'spongiotic' wall in the inferior left ventricle, and echocardiography confirmed the diagnosis of LVNC. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment and she had some difficulty with heel-walking.
In a cohort of 239 patients with hypertrophic cardiomyopathy who were negative for mutation in the 8 most common CMH-associated myofilament genes, Theis et al. (2006) analyzed 5 candidate Z-disc genes and identified 14 mutations in 13 patients. The authors observed that 11 (85%) of the 13 patients with Z-disc-associated CMH had a sigmoidal septal contour, in contrast to the reverse septal curvature seen with myofilament-associated CMH.
In affected members of an Italian family, Ferraro et al. (1990) found that 7 affected members and none of 3 unaffected members showed a fragile site on 16q (FRA16B).
Hengstenberg et al. (1993, 1994) studied a family with familial hypertrophic cardiomyopathy in which preliminary haplotype analyses excluded linkage to chromosomes 14q1, 1q3, 11p13-q13, and 15q2, suggesting the existence of another locus, designated CMH5, for this disorder. Further studies in this family by Richard et al. (1999) demonstrated that of 8 affected family members, 4 had a mutation in the MYH7 gene (160760.0033), 2 had a mutation in the MYBPC3 gene (600958.0014), and 2 were doubly heterozygous for the 2 mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than that in the other affected individuals.
Seidman and Seidman (2001) reviewed the genetic and clinical heterogeneity of hypertrophic cardiomyopathy.
Arad et al. (2002) reviewed the clinical spectrum of hypertrophic cardiomyopathy in the context of genetic heterogeneity, as well as animal models of hypertrophic cardiomyopathy.
In 108 consecutive patients with hypertrophic cardiomyopathy diagnosed by echocardiography, angiography, or findings after myectomy, Erdmann et al. (2003) screened for mutations in 6 sarcomeric genes. They identified 34 different mutations: 18 in the MYBPC3 gene in 20 patients, with 2 mutations identified twice; 13 missense mutations in the MYH7 gene in 14 patients, with 1 mutation identified twice; and 1 amino acid change each in the TPM1, TNNT2, and TNNI3 genes. No disease-causing mutation was identified in TNNC1 (191040). In only 8 of the 37 mutation carriers was the mutation sporadic. Thus, systematic mutation screening in a large sample of patients with hypertrophic cardiomyopathy led to a genetic diagnosis in approximately 30% of unrelated index patients and in approximately 57% of patients with a positive family history.
In 197 unrelated probands with familial or sporadic hypertrophic cardiomyopathy, Richard et al. (2003) screened for mutations in 9 genes and identified mutations in 124 (63%) of 197 probands. The MYBPC3 and MYH7 genes accounted for 82% of families with identified mutations (42% and 40%, respectively). A mutation was identified in 15 (60%) of 25 sporadic patients.
In 80 unrelated Australian probands with CMH, Chiu et al. (2007) screened 7 CMH genes, including MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, MYL2, and MYL3. Twenty-four different mutations were identified in 23 (29%) of 80 families, with 19 probands having a single mutation (11 in MYH7, 4 in MYBPC3, 3 in TNNI3, and 1 in TNNT2). Multiple gene mutations were identified in 4 probands: 1 was doubly heterozygous, with 1 mutation in MYH7 and 1 in MYBPC3, whereas the other 3 were compound heterozygous for mutations in MYBPC3 (see, e.g., 600958.0021 and 600958.0022). Six (43%) of 14 affected individuals from multiple mutation families experienced sudden cardiac death, compared with 10 (18%) of 55 affected members from single mutation families (p = 0.05). Septal wall thickness was increased in patients with multiple mutations (mean thickness, 30.7 mm vs 24.4 mm; p less than 0.05). Ingles et al. (2005) concluded that multiple gene mutations occurring in CMH families may result in a more severe clinical phenotype because of a 'double-dose' effect, and emphasized the importance of screening the entire panel of CMH genes even after a single mutation has been identified.
Van Driest et al. (2004) analyzed the MYBPC3 gene in a cohort of 389 CMH probands who had previously been genotyped for mutation in genes encoding the sarcomeric proteins comprising the thick filament (MYH7 and the regulatory and essential light chains, MYL2 and MYL3) and the thin filament (TNNT2, TNNI3, TPM1, and ACTC). Overall, 63 (16.2%) of the patients had a single mutation in the MYBPC3 gene, 54 (13.8%) in MYH7, 7 (1.8%) in MYL2, 6 (1.5%) in TNNT2, 4 (1.0%) in TNNI3, 2 (0.5%) in TPM1, and 1 (0.3%) in ACTC. The 10 patients with multiple mutations (2.6%) had the most severe disease presentation: they were significantly younger at diagnosis than any other subgroup, had the most hypertrophy, and had the highest incidence of myectomy and placement of implantable cardioverter-defibrillators.
From 2000 to 2012, Das et al. (2014) studied a total of 136 unrelated hypertrophic cardiomyopathy probands, of which 63 (46%) carried at least 1 pathogenic mutation. MYBPC3 (600958) accounted for 34 patients, or 47%, and MYH7 (160760) accounted for 23 patients, or 32%. Together, these gene variants accounted for 79%. In this study, 5 variants in 6 probands (10%) were reclassified: 2 variants of uncertain significance were upgraded to pathogenic, 1 variant of uncertain significance and 1 pathogenic variant were downgraded to benign, and 1 pathogenic variant (found in 2 families) was downgraded to a variant of uncertain significance. Das et al. (2014) concluded that given the rapid growth of genetic information available, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.
To screen for mutations that cause familial hypertrophic cardiomyopathy, Rosenzweig et al. (1991) capitalized on the fact that 'ectopic' or 'illegitimate' transcription of beta cardiac myosin heavy chain gene can be detected in blood lymphocytes. Preclinical or prenatal screening will make it possible to study the disorder longitudinally and to develop preventive interventions. The findings again illustrate the important application of PCR. Clarke and Harper (1992) suggested that 'the parallels between this cardiomyopathy and Huntington's disease are sufficiently striking that we would be very cautious about testing for it in childhood. The emotional consequences of being brought up under a cloud of doom may be damaging, and the lack of any uncertainty in identifying gene carriers by mutation analysis might paradoxically make this worse.' Watkins et al. (1992) countered this view, saying that children with the condition face a 4 to 6% risk of sudden death each year. Genetic diagnosis will allow evaluation of prophylactic use of antiarrhythmic agents or implantable defibrillator devices. It will also provide parents and physicians an appropriate basis on which to make decisions regarding the participation of children in competitive sports. They suggested that in their experience '...any perception of a cloud of doom comes as much from a lack of knowledge of and research into this inherited cardiomyopathy as from anything else.'
To provide a method of genetic diagnosis of cardiomyopathy, Mogensen et al. (2001) developed a method of linkage analysis using multiplex PCR of markers covering 9 loci associated with familial hypertrophic cardiomyopathy. They evaluated this method in 3 families. In all 3 families the locus showing the highest lod score was subsequently found by mutation analysis to be the locus at which the disease-causing gene was found. Mogensen et al. (2001) emphasized the importance of stringent phenotypic definitions in the diagnostic process.
Ingles et al. (2013) studied the clinical predictors of genetic testing outcomes for hypertrophic cardiomyopathy. The authors studied 265 unrelated individuals with hypertrophic cardiomyopathy over a 10-year period in specialized cardiac genetic clinics across Australia. Of the 265 individuals studied, 138 (52%) had at least 1 mutation identified. The mutation detection rate was significantly higher in probands with hypertrophic cardiomyopathy with an established family history of disease (72% vs 29%, p less than 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89% vs 59%, p less than 0.0001). Multivariate analysis identified female gender, increased left ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31% vs 7%, p = 0.012). Ingles et al. (2013) concluded that family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.
Wagner et al. (1989) investigated a possible role of adrenergic innervation or of cellular calcium regulation in pathogenesis, as suggested by the presence of hyperdynamic left ventricular function and by the clinical and symptomatic improvement seen in patients treated with beta-receptor antagonists or calcium antagonists. They found that calcium-antagonist binding sites, measured as the amount of dihydropyridine bound to atrial tissue, were increased by 33% in patients with hypertrophic cardiomyopathy. The densities of saxitoxin-binding sites on voltage-sensitive sodium channels and beta-adrenoceptors did not differ from controls. Wagner et al. (1989) interpreted the findings as suggesting that abnormal calcium fluxes through voltage-sensitive calcium channels may play a pathophysiologic role in the disease.
There is evidence that 'myocardial bridging' with compression of an epicardial coronary artery, such as the left anterior descending coronary artery, can cause myocardial ischemia and sudden death. Yetman et al. (1998) performed angiographic studies of 36 children with hypertrophic cardiomyopathy to determine whether myocardial bridging was present and, if so, to assess the characteristics of systolic narrowing of the left anterior descending coronary artery caused by myocardial bridging and the duration of residual diastolic compression. Myocardial bridging was present in 10 (28%) of the patients. As compared with patients without bridging, patients with bridging had a greater incidence of chest pain, cardiac arrest with subsequent resuscitation, and ventricular tachycardia. On average, the patients with bridging had a reduction in systolic blood pressure with exercise, as compared with an elevation in those without bridging. Patients with bridging also had greater ST segment depression with exercise and a shorter duration of exercise. Kaplan-Meier estimates of the proportions of patients who had not died or had cardiac arrest with subsequent resuscitation 5 years after the diagnosis of hypertrophic cardiomyopathy were 67% among patients with bridging and 94% among those without bridging. No statement concerning the family history or other information relevant to an etiology in these patients was provided.
Using pharmacologic models of cardiac hypertrophy in mice, Friddle et al. (2000) performed expression profiling with fragments of more than 4,000 genes to characterize and contrast expression changes during induction and regression of hypertrophy. Administration of angiotensin II and isoproterenol by osmotic minipump produced increases in cardiac weight (15% and 45%, respectively) that returned to preinduction size after drug withdrawal. From multiple expression analyses of left ventricular RNA isolated at daily time points during cardiac hypertrophy and regression, Friddle et al. (2000) identified sets of genes whose expression was altered at specific stages of this process. While confirming the participation of 25 genes or pathways previously shown to be altered by hypertrophy, a larger set of 30 genes was identified whose expression had not previously been associated with cardiac hypertrophy or regression. Of the 55 genes that showed reproducible changes during the time course of induction and regression, 32 were altered only during induction, and 8 were altered only during regression. Thus, cardiac remodeling during regression uses a set of genes that are distinct from those used during induction of hypertrophy.
Tsybouleva et al. (2004) observed that myocardial aldosterone and aldosterone synthase (CYP11B2; 124080) mRNA levels were elevated by 4- to 6-fold in patients with hypertrophic cardiomyopathy compared to controls. In studies in rat cardiomyocytes, they found that aldosterone increased expression of several hypertrophic markers via protein kinase D (PRKCM; 605435) and increased collagens and TGFB1 (190180) via PI3K-delta (PIK3CD; 602839). Inhibition of PRKCM and PIK3CD abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor antagonist spironolactone. In a mouse model of hypertrophic cardiomyopathy, spironolactone reversed interstitial fibrosis, decreased myocyte disarray, and improved diastolic function. Tsybouleva et al. (2004) concluded that aldosterone is a major link between sarcomeric mutations and cardiac phenotype in CMH.
Wilson et al. (1983) observed marked improvement in the manifestations of familial hypertrophic cardiomyopathy when affected persons with hyperthyroidism were treated for the latter condition. This prompted them to suggest that antithyroid therapy 'should be considered in this form of cardiomyopathy.'
In discussing the management of hypertrophic cardiomyopathy, Spirito et al. (1997) reviewed heterogeneity of clinical and genetic features and stated that 'the diverse clinical and genetic features of hypertrophic cardiomyopathy make it impossible to define precise guidelines for management.' The treatment of symptoms to improve quality of life and the identification of patients who are at high risk for sudden death and require aggressive therapy are 2 distinct issues that must be addressed by largely independent strategies. The stratification of risk and the prevention of sudden death were discussed.
Ventricular tachycardia or fibrillation is thought to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. Maron et al. (2000) conducted a retrospective study, the results of which indicated that in high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the prevention of sudden death. In comments on the study of Maron et al. (2000), Watkins (2000) stated that for most patients with hypertrophic cardiomyopathy, the risk is not high enough to offset the adverse effects of an implantable defibrillator. He suggested the creation of an international registry to document discharge rates after implantation for each of the indicators of risk. Ideally, the data should include molecular genetic information, since the underlying mutation will itself be predictive. He cited the cohort studies of McKenna et al. (1985) in which patients with hypertrophic cardiomyopathy who were treated with low-dose amiodarone compared with untreated historical controls suggested that long-term treatment was partially protective; and the work of Ostman-Smith et al. (1999), indicating that high doses of beta-blockers may also confer protection. Since there has been an excess rate of sudden death during or shortly after exercise, most physicians recommend that patients with hypertrophic cardiomyopathy avoid competitive sports or intensive exertion.
In a study of 480 consecutive patients with hypertrophic cardiomyopathy, Spirito et al. (2000) found that the magnitude of hypertrophy is directly related to the risk of sudden death and then is a strong and independent predictor of prognosis. Young patients with extreme hypertrophy, even those with few or no symptoms, appeared to be at substantial long-term risk and thus were considered for interventions to prevent sudden death. Most patients with mild hypertrophy were at low risk and were reassured regarding their prognosis.
Ho et al. (2002) studied confirmed MYH7 mutation heterozygotes using echocardiography, including Doppler tissue imaging. Left ventricular ejection fraction was significantly higher in mutation carriers than in normal controls. Mean early diastolic myocardial velocities were significantly lower in mutation carriers, irrespective of whether hypertrophy was already present. Overall the authors concluded that abnormalities of diastolic function were detectable before the onset of myocardial hypertrophy in mutation carriers, providing a mechanism for predicting affected individuals.
In a discussion of hypertrophic cardiomyopathy, Maron et al. (1987) stated that approximately 45% of cases are sporadic. New mutations cannot be the explanation for all of the sporadic cases; hence, there may be other etiologically distinct disorders represented in the group of hypertrophic cardiomyopathies. Systematic echocardiographic surveys of families of patients with hypertrophic cardiomyopathy have identified relatives older than 50 years of age with mild and localized left ventricular hypertrophy. Thus, the true proportion of sporadic cases may not be as high as 45%.
Darsee et al. (1979) found a lod score of 7.7 for linkage between ASH and HLA and concluded that, in addition to the hereditary form linked to HLA, a sporadic unlinked form is associated with severe systemic hypertension. This presumably strong evidence placing a gene for hypertrophic subaortic stenosis on 6p by linkage to HLA was invalidated when the infamous John R. Darsee confessed fabrication of the data. Nutter also published a retraction. Motulsky (1979) wrote a laudatory editorial to accompany the original article.
In his retraction letter, Darsee stated: 'The lod scores were calculated, in part, by one of the journal referees who felt they should be included, and partly by my own calculations. The biometrist I consulted at Emory regarding these calculations was not familiar with lod scores and unable to provide assistance.' Before Darsee confessed, Darsee and Heymsfield (1981) wrote: 'It is the pinhole through which we are forced to view this disease or these diseases that has helped confer a degree of homogeneity. The pinhole is the limited collection of tools we have to study hypertrophic cardiomyopathy--the angiogram, the echocardiogram, and the autopsy table. It is a common practice of even the most perspicacious and critical investigators to conclude that diseases that look the same on canvas were painted with the same brush.' Although these words are true in general terms and are a fine statement of the principle of genetic heterogeneity, the falsified data do not support them, of course.
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