Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [P*]=1.2×10-46). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P*=7.0×10-8), DSP (odds ratio=14.9, P*=1.0×10-8), and BAG3 (odds ratio=53.1, P*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P=2.5×10-4), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

HomeCirculationVol. 134, No. 7Response by Arany and Elkayam to Letter Regarding Article, “Peripartum Cardiomyopathy” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Arany and Elkayam to Letter Regarding Article, “Peripartum Cardiomyopathy” Zolt Arany, MD, PhD and Uri Elkayam, MD Zolt AranyZolt Arany From Perelman School of Medicine. University of Pennsylvania, Philadelphia (Z.A.); and Department of Medicine, Division of Cardiovascular Medicine, and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles (U.E.). Search for more papers by this author and Uri ElkayamUri Elkayam From Perelman School of Medicine. University of Pennsylvania, Philadelphia (Z.A.); and Department of Medicine, Division of Cardiovascular Medicine, and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles (U.E.). Search for more papers by this author Originally published16 Aug 2016https://doi.org/10.1161/CIRCULATIONAHA.116.023729Circulation. 2016;134:e83–e84In Response:Dr Dalzell and colleagues raise an important issue regarding our article.1 Recent findings indicate that 15% of women diagnosed with peripartum cardiomyopathy (PPCM) carry mutations similar to ones associated with idiopathic dilated cardiomyopathy (DCM).2 In light of these findings, should these women be excluded from a diagnosis of PPCM? We favor that they not be excluded, and that the definition of PPCM remain strictly clinical at this juncture, for the following reasons:Our knowledge of the genetic landscape remains incomplete in both PPCM and DCM. Fifteen percent of women with PPCM carry identifiable mutations, but many more unidentified mutations likely exist among the other 85% of women. The same is true with DCM, where no mutations were identified in 75% of subjects, including ones with clear family history.3 Thus, labeling a case of PPCM nongenetic because a mutation has not yet been identified would likely often be wrong. Stated another way, we do not yet know the extent of overlap between PPCM and DCM.As suggested by Dalzell et al, key decisions related to prognosis, such as counseling about the risk of future pregnancies, could be affected by knowledge of genotype. Indeed, preliminary observations suggest that the presence of truncating variants in TTN may portend worse outcome.2 However, these post hoc observations are preliminary and need validation before modifying how we counsel patients.Most importantly, there is yet no indication for different clinical management between patients with and without mutations. Any differences in response to medical management or transplantation, for example, are unknown.Finally, excluding patients who carry mutations from registries or clinical trials would be a disservice to them. A better approach is to include these patients in the studies and evaluate the effect of genetic background on clinical course.In sum, at this point, knowledge of a patient’s genetic profile does not (yet) affect the advice or treatment that can be offered to her. Of note, for these same reasons, the definition of DCM has also not been refined to reflect genetic findings. As we learn more about the effects of genetic context on prognosis and response to therapy, the question of whether, and how, to subdivide the definition of PPCM (and DCM) should continue to be revisited.DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.

BackgroundThe clinical course of dilated cardiomyopathy (DCM) is variable: while 20% of patients die within 5 years of diagnosis, up to 15% recover fully. DNA variants that truncate the sarcomeric...

To the Editor: Ware et al. (Jan. 21 issue)1 describe a very similar distribution of presumably causative genetic variants in TTN and other genes in women with peripartum cardiomyopathy and in persons with idiopathic dilated cardiomyopathy. The clinical outcome of peripartum cardiomyopathy is highly variable, ranging from full recovery to rapid progression to end-stage heart failure,2 and the appropriate duration of therapy is controversial. I therefore wonder whether analysis of the data of Ware et al. can shed light on whether TTN-truncating variants are associated with late recovery or persistent left ventricular dysfunction in patients with peripartum cardiomyopathy.To . . .

Background. Sarcomere protein genes such as MYBPC3, FLNC, TTN, RBM20 are associated with cardiomyopathies (CMP). A large number of rare genetic variants complicates the interpretation genetic studies and assessing the pathogenicity. Moreover, there is a lack of an information about rare variants frequency in a healthy Russian population. Polymorphisms in these genes often act as modifiers, aggravating the clinical course of CMP caused by mutations in other genes.Objective. To compare the frequency of rare (less than 0.1 %) missense and truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the patients with CMP and in the general population.Design and methods. The CMP group included 251 patients. The control group included 192 men (from the ESSE-RF study). A molecular genetic examination was performed using high-processive sequencing technology, followed by verification by Sanger sequencing.Results. The frequency of truncating variants in the genes TTN, FLNC, MYBPC3, RBM20 in the group with CMP was 7.17 %, and missense variants — 56.6 %: 11.5 % were pathogenic/likely pathogenic, 39.5 % — variants of uncertain significance, 49 % — probably benign/benign. The frequency of truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the control group was 0.52 %, and the frequency of missense variants was 15.1 %: 38 % were variants of uncertain significance, 62 % — probably benign/benign.Conclusion. Frequency of missense and truncating variants with a frequency of less than 0.1 % in the TTN, FLNC, MYBPC3, RBM20 genes was increased in the group of patients with CMP.

Peripartum cardiomyopathy and pre-eclampsia: two tips of the same iceberg.

Objective To characterize the cardiac magnetic resonance (CMR) features of peripartum cardiomyopathy(PPCM) and idiopathic dilated cardiomyopathy (IDCM) , and to explore the value of MRI in the diagnosis of PPCM. Methods Ten cases of PPCM and 10 cases of Idiopathic dilated cardiomyopathy (IDCM) were included in this study. With 1.5 T MRI scanner, the heart shape (atrioventricular size, hypertrabeculation, thickness of the thinnest ventricular wall), function (ventricular wall movement and the overall function), cardiomyopathy perfusion were comprehensively evaluated. Paired samplest-test andFisher exact probability method were used for statistical analysis. Results Between PPCM and IDCM group, there was no statistical significant difference in the atrioventricular size, cardiac output(CO), end diastolic volume(EDV), ejection fraction (EF), end systolic volume (ESV) and stroke volume (SV) (P> 0.05). IDCM and PPCM group both showed ventricular wall thinning on MRI, with 4 cases of PPCM and 3 cases of IDCM presenting hypertrabeculation in the left ventricular apex. Seven cases of PPCM and 4 cases of IDCM depicted left ventricular local dysfunction, while 3 cases of PPCM and 6 cases of IDCM had abnormal integral movement. Two cases of PPCM appeared local delayed enhancement, while 4 cases of IDCM showed intramural delayed enhancement. After one year of follow-up, heart function recovered in 10 cases of PPCM and 4 cases of IDCM. Conclusions MRI diagnosis using multiple sequences is an ideal method in the evaluation of PPCM. Although there were no differences in cardiac morphology and function between PPCM and IDCM, the prognosis of PPCM is better than IDCM. Key words: Magnetic resonance imaging; Cardiomyopathies; Diagnosis

We have previously described 19 pedigrees with apparent lamin (LMNA)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families. Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants. In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant. Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

Background: Cardiomyopathies represent a heterogeneous group of diseases that often lead to progressive heart failure with significant morbidity and mortality. The improved recognition or of other factor, the incidence and prevalence of heart failure due to cardiomyopathy appears to be increasing. Aims & Objectives: To study the prevalence, clinical profile and outcome of patients with cardiomyopathies and to study the echocardiographic profile. Material & methods: It is retrospective observational study of 65 patients, with age >15 years and admitted in medical ICU and ward of KIMSU, karad. This study was conducted over period of one year. All eligible subjects underwent relevant investigations including echocardiogram, Doppler study, electrocardiogram, chest radiogram and coronary angiogram. Proforma included age gender presenting complaints, past history, history of medications, clinical examination and laboratory investigations. Trans-thoracic 2-dimensional echocardiogram and Doppler study was done according to the standard protocol. Statistical analysis: Results were given as mean ± SD. Means are compared by unpaired Students t-test. Chi-square was used as appropriate. The observations and data were analyzed in the statistical package social sciences (SPSS) trial version 11. The level of significance was set at P<0.05. Results: A total of 65 patients were admitted from Jan 2010 to Dec 2012 who were diagnosed with cardiomyopathy with mean age of 58.76 years (SD±15.98). Out of the total 65 cardiomyopathy patients admitted 27 (41.53%) had Dilated cardiomyopathy (idiopathic), 15 (23.07%) patients were diagnosed with Ischemic cardiomyopathy. Total 42 (64.61%) patients had Dilated cardiomyopathy (i.e. idiopathic and ischemic dilated cardiomyopathy). A total 11 (16.92%) had Hypertrophic cardiomyopathy (HCM), 2 (3.07%) patients had Hypertrophic obstructive cardiomyopathy (HOCM) with LVOT significant gradient, 5 (7.69%) patients had Restrictive cardiomyopathy (RCMP), 4 (6.15%) had Peripartum cardiomyopathy (PPCM) and 1 (1.53%) patient had miscellaneous (alcohol induced) Cardiomyopathy. Out of 27 patients diagnosed with Dilated Cardiomyopathy (DCM), 15 (55.55%) were male patients and 12 (44.45%) were females. Out of 15 patients diagnosed with Ischemic cardiomyopathy, 7(46.66%) were males and 8(53.33%) were females. Out of 11 patients diagnosed with HCM, 9(81.81%) were males and 2(18.18%) were females. Out of 2 patients diagnosed with HOCM 1(50%) was a male patient and 1(50%) was a female patient. There were 4 female patients who were diagnosed with PPCM. A total of 5 patients were diagnosed with RCMP, out of which 1(20%) was a male patient 4(80%) patients were females. There was 1 male patient diagnosed with cardiomyopathy secondary to chronic alcohol consumption. In present study breathlessness 89.23% was most common presenting symptom and palpitations (81.53%) and cough (58.46%) were next to it with ‘p’ <0.001. Overall VPC’s (36%) were the most common ECG abnormality in patients with cardiomyopathy in present study with ‘p’ value <0.01. The LBBB (35.71%) was more frequently seen in patients with dilated cardiomyopathy with ‘p’ <0.02. The atrial flutter/ fibrillation found more commonly in patients with restrictive cardiomyopathy (80%) with ‘p’ value < 0.02. Total 74.07% of DCM, 86.67% of ischemic cardiomyopathy, 50% of PPCM, 81.82% of HCM, 100% of HOCM, RCMP and alcoholic cardiomyopathy patients had diastolic dysfunction. Idiopathic Dilated cardiomyopathy had 22% (±7.7) of lowest left ventricular ejection fraction (LVEF). Out of total 65 patients two patients with dilated cardiomyopathy succumbed with overall mortality 3.08% and case fatality rate for DCM was 4.76%. Total 96.92% patient were discharged after treatment from the hospital. Conclusion: Present study highlights significant burden of Idiopathic dilated cardiomyopathy and next to it was ischemic cardiomyopathy. A total 6 (9.23%) patients had potentially reversible cardiomyopathy like peripartum, alcoholic and myocarditis. The cardiomyopathy is asymptomatic in the early stages hence early diagnosis and management is of vital importance in the form of judicious use of anticoagulant, digoxin, diuretics, ACE inhibitors and betablocker is mandatory to reduce complications, morbidity and mortality associated cardiomyopathies. Trans-thoracic echocardiogram is an important, simple and noninvasive modality of investigation which can be reproducible for the diagnosis and fallow upof most of the cardiomyopathies. Key words: Echocardiogram, Dilated cardiomyopathy, Hypertrophic obstructivecardiomyopathy, Peripartum cardiomyopathy, Restrictive cardiomypathy.

Introduction Some studies reported familial clustering of Peripartum Cardiomyopathy (PPCM), and also co-occurrence with Dilated Cardiomyopathy (DCM), a phenotypically similar disease. PPCM and DCM share a genetic predisposition, with truncating variants in the TTN gene accounting for 10% to 20% of cases in both conditions. Multifactorial etiopathogenesis is also described in both, and immunology may be part of it. History of the family A 65 year-old woman (index patient, fig.1A - III3) was admitted in 2022 with de novo severe heart failure (HF) and reduced LVEF-25% (fig.1B). She was previously healthy but due to a family history of PPCM in her two oldest sisters (who have died both with DCM and HF at 52 and 55 years (y)), she was regularly followed during the last 40 years. Eight months before admission, her ECG and echocardiogram were normal. Genetic testing identified a pathogenic heterozygous variant c.78009G&amp;gt;A, p.(Trp26003*) in the TTN gene. After 11 months of optimised therapy, LVEF was 50% (fig.1C) and remained stable thereafter. Her 42-year-old daughter (fig.1A, IV3), who had PPCM immediately after a normal pregnancy and delivery at 38y, developed acute HF (LVEF-32%) with cardiogenic shock, and the LVEF recovered slowly to 56% after 1 year (fig.1E). She is a carrier of the same TTNtvs identified in her mother. Going back 40 years, the oldest sister of the index patient (fig.1A, III1) developed severe HF at 32 years, 20 days after a normal pregnancy and delivery. She had severe LV dilation and diffuse hypocontractility (fig.1D). Without any benefit from symptomatic therapy, immunosuppression (prednisolone and azathioprine) was decided, and a rapid clinical improvement occurred, returning to everyday life. However, severely reduced LV function persisted (fig.1F, G). Her daughter, 39 years old (fig.1A, IV1), has a normal heart and had three uneventful pregnancies. She refused a genetic test. A similar clinical history had the second sister (fig.1A, II-2) who developed PPCM when she was 30y. She was also treated with immunosuppressive therapy with a good clinical response, but the reduced LV function also persisted throughout life. Her only daughter chose not to be a mother. She has a normal heart and also refused a genetic test. Conclusion PPCM and DCM may occur as individual entities, or pregnancy can act as a modifier to unmask the latent phenotype of familial TTNtvs DCM. This family illustrates the concept that the genetic predisposition to PPCM and DCM may be the same. However, different evolutive profiles can be observed throughout life in affected patients within the same family, making genotype-phenotype correlations particularly difficult in DCM and PPCM.

TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Phenotypic differences between peripartum cardiomyopathy and idiopathic or familial cardiomyopathy in young women

Peripartum Cardiomyopathy

Introduction: Peripartum cardiomyopathy (PPCM) presents as left ventricular systolic dysfunction (LVSD) during pregnancy or the post-partum interval. The underlying cause of PPCM remains incompletely defined, with hypotheses suggesting either pregnancy-related environmental (e.g., hormonal, hemodynamic) cause or genetic cause similar to dilated cardiomyopathy (DCM). Hypothesis: If PPCM results principally from pregnancy-related environmental cause, then first-degree relatives (FDRs) of women with PPCM will have lower risk of DCM than FDRs of women with DCM because they cannot share this risk. Conversely, if DCM genetics underlies both PPCM and DCM, then FDRs of women with PPCM or DCM are equally likely to share these genetic factors and will have comparable risks. Aims: In female probands with PPCM or DCM from the DCM Precision Medicine Study, evaluate proband DCM-relevant rare variant genetics; in their FDRs, compare the age-specific cumulative risk of DCM, LVSD, or LV enlargement [LVE]. Methods: Of 452 female probands with DCM, 72 met criteria for PPCM; all underwent exome sequencing and analysis of rare variants in 36 DCM genes. Their 665 FDRs were assessed for DCM, LVSD, or LVE. Hierarchical logit models were used to describe the distribution of the most deleterious variant identified (none, variant of uncertain significance, or pathogenic/likely pathogenic) in probands. For FDRs, binary data on the presence or absence of DCM, LVSD, or LVE at enrollment were used to model age-specific cumulative risk in a Weibull proportional hazards model. Models accounted for site heterogeneity and, in FDRs, intrafamilial correlation. Results: The odds of finding a DCM-relevant rare variant were comparable between female probands with PPCM and DCM (OR=1.07, 95% CI: 0.37-3.11, p=0.90) adjusting for ancestry, ethnicity, and diagnosis age. DCM-relevant rare variants of PPCM probands were similar to those of DCM probands for ClinGen gene evidence category (p=0.55) and variant predicted impact (loss-of-function, missense, or other; p=0.90). Age-specific cumulative risk of DCM, LVSD, or LVE was not different among FDRs of women with PPCM or DCM (HR=0.96, 95% CI: 0.59-1.57, p=0.87) adjusting for proband ancestry and diagnosis age and FDR sex. Conclusion: Data from female probands indicate that PPCM and DCM have a similar rare variant genetic basis. FDRs of both PPCM and DCM probands show similar risks of DCM, LVSD, or LVE, further supporting an underlying genetic cause for PPCM.