This section provides screening, clinical cardiovascular diagnosis, counseling and treatment recommendations for patients with IDC and families with FDC. We initially published these recommendations in September, 1999 in the Journal of the American College of Cardiology (Crispell K, Wray A, Ni H, Nauman D, Hershberger R. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol 1999;34:837-847, PMID: 10483968). These recommendations were updated in 2005 (Burkett E, Hershberger RE. State of the Art: Clinical and Genetic Issues in Familial Dilated Cardiomyopathy. J Am Coll Cardiol 2005;45:969-81, PMID: 15808750). In March 2009, the Heart Failure Society of America (HFSA) published medical guidelines that reiterate these recommendations (Hershberger, RE et al. Genetic Evaluation of Cardiomyopathy: A Heart Failure Society of America Guideline. J Cardiac Failure, 2009; 15:83-97 PMID: 19254666).

a. The rationale for these recommendations rests on the following points. First and foremost, DCM is a potentially serious, life-threatening disease. Second, screening to detect DCM can be successful, as FDC is much more common than recently thought — the likelihood of FDC in a patient diagnosed with IDC is from 35-50%. Third, effective treatment is available. Extensive clinical trial data supports improved outcomes with medical treatment. Fourth, similar recommendations have been made for other genetic and familial cardiovascular diseases, such as hypertrophic cardiomyopathy, even though medical treatment may not be as effective for hypertrophic cardiomyopathy. Finally, diagnostic, therapeutic, counseling or other interventions assume the voluntary and informed consent of the subject.

b. The diagnosis of IDC most commonly rests on left ventricular enlargement accompanied by systolic dysfunction after ruling out other possible causes of dilated cardiomyopathy. Most commonly, this includes an increased left ventricular end diastolic dimension (LVEDD) at echocardiography adjusted for height or BSA in combination with evidence for systolic dysfunction (ejection fraction <50%). Other causes of dilated cardiomyopathy should be excluded, and includes most importantly ischemic heart disease, which causes ischemic dilated cardiomyopathy. Coronary heart disease should be definitively excluded in patients who appear to have IDC but who are at risk for ischemic heart disease (age > 40 years in men, age > 45 years in women, cigarette smoking, diabetes, hypertension, hypercholesterolemia and other risk factors). Other less common causes of dilated cardiomyopathy can usually be excluded by history, exam, ECG and echocardiography, and include valvular heart disease, rheumatic heart disease, hypertensive heart disease, congenital heart disease, and toxic or drug induced cardiomyopathies such as anthracycline cardiomyopathy.

c. Other non-dilated cardiomyopathies may also be familial, such as hypertrophic cardiomyopathy or arrhythmogenic right ventricular dysplasia. It is usually easy to differentiate IDC/FDC from these other non-dilated cardiomyopathies, but occasionally classification becomes difficult. In these situations comprehensive review of all cardiovascular data from all affected family members can usually lead to the correct diagnostic assignment.

A medical history, an exam, an ECG and an echocardiogram should be performed for first degree relatives (parents, siblings, children) of patients with IDC. Recommending screening for first degree family members is part of the recommendations for the genetic evaluation of DCM. Patients with IDC should be informed about the 35-50% probability of FDC. We then recommend that they inform their first degree relatives of their IDC diagnosis, of the possible familial nature of the disease, and that they should undergo IDC/FDC screening.  Some clinics use educational brochures and template letters that facilitate communication of among probands and at-risk family members.

a. Obtain a targeted family history. Guidelines also recommend obtaining a family history from patients with IDC. The family history includes an assessment for heart failure or “dropsy,” the colloquial term used in previous generations to label heart failure, sudden death not associated with known coronary disease, premature stroke or other history suggestive of heart failure. Other common historical features are sudden death and/or history of heart failure in the peripartum period. Although family history cannot detect asymptomatic DCM, it can be a helpful tool, either in a pictorial or questionnaire format.

The FDC clinical diagnosis is established most simply by diagnosing two (or more) family members with IDC in first or second degree family members. An FDC diagnosis can be established with an IDC diagnosis in more distant relatives (third degree and greater) with greater reliability when three or more family members are diagnosed with IDC. We recommend that the diagnosis of FDC is best made with a bona fide IDC diagnosis in at least two family members. This is in distinction to the assignment of affected status, once the FDC diagnosis has been established in a pedigree, with less stringent criteria (such as isolated left ventricular enlargement  or positive genetic testing results in an unaffected individual). If you are a cardiovascular specialist and would like further review and discussion of this quite technical, but important point, please see our Publications.

Once FDC is diagnosed, pursue stepwise screening. Stepwise screening is progressive screening of first degree relatives of those found to be affected. Thus, first degree relatives of individuals with IDC should be advised to undergo screening (history, exam, ECG, echo) by their physician. If cardiac abnormalities are discovered in any of these relatives (step one of stepwise screening), a full cardiovascular evaluation should follow. For any additional relatives discovered to have IDC, stepwise screening (step 2) should be advised for their first-degree relatives. Thus, it is possible that stepwise screening will identify affected individuals throughout an extended family. A more detailed example of stepwise screening is also given in the For Families section. This clinical recommendation may also identify large kindreds for research. (See Referring Patients for Research Purposes).

In some larger families the most appropriate method to assign affected status in relatives may be to use left ventricular end-diastolic dimension, with or without some measure of fractional shortening (e.g., see Hershberger RE, Ni H, Crispell KA. Familial dilated cardiomyopathy: new echocardiographic diagnostic criteria for classification of family members as affected. J Cardiac Failure 1999;5:203-212, PMID:10496193). Other diagnostic criteria have also been proposed (Mestroni L, Maisch B, McKenna W, et al. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J 1999;20:93-102. PMID:10099905).

Routine screening beyond first-degree relatives of affected individuals is probably not indicated for clinical purposes, based on our experience. However, affected individuals in some extended families could easily be missed, and thus we suggest the following: (1) comprehensive medical evaluations of any family members with unexplained cardiovascular symptoms, and (2) screening of some second and/or third degree relatives for FDC may be appropriate in some families with particularly troublesome, aggressive or life-threatening disease in the setting of variable age of onset.

We recommend the use of ACE inhibitors and/or beta blockers in family members determined to be affected, following conventional guidelines and community practice standards.

According to the HFSA guidelines, genetic counseling is recommended for all patients with DCM (of unknown cause, IDC) and their family members. Genetic counseling for DCM involves obtaining a family history, identifying at-risk family members, discussing screening options, assessing the most useful genetic test and interpreting results, as well as helping patients to emotionally adjust to having or being at risk for a heart condition.  The educational component of genetic counseling involves informing the patient and family regarding the disease transmission and family risks. Counseling should emphasize that the clinical course of DCM is unpredictable, and ranges from one that is relatively benign with conventional treatment to one of progressive heart failure, and advanced disease resulting in heart transplantation or sudden cardiac death. When FDC is identified, affected family members should also be informed that they have a heritable condition with a genetic risk to their offspring (up to a 50% probability with Mendelian autosomal dominant inheritance). Finally, those who are genetically at risk but have no evidence of LVE should be counseled about the age-dependent penetrance, the possibility of future disease presentation, and clinical recommendations including future surveillance screening or screening at any time with symptoms of cardiac dysfunction.

Ongoing Periodic Surveillance Clinical Screening. According to the HFSA guidelines, surveillance screening (history, exam, ECG, echo) is indicated at the following intervals or at any time that symptoms occur:

Interval if genetic testing is negative and/or if clinical family screening is negative	Screening interval if a mutation is present
Every 3-5 years beginning in childhood	Yearly in childhood: every 1-3 years

According to the HFSA guidelines, clinical genetic testing should be considered for patients with DCM (of unknown cause, IDC). Any patient with IDC (with or without familial DCM) may benefit from clinical genetic testing. One quarter to one half of patients with IDC will likely have FDC, which is defined as two or more close relatives with IDC. Data from our recent publications, “Lamin A/C Mutation Analysis in a Cohort of 324 Unrelated Patients with Idiopathic or Familial Dilated Cardiomyopathy,” ,”Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy,” and “Coding Sequence Rare Variants Identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 From 312 Patients With Familial or Idiopathic Dilated Cardiomyopathy” support this recommendation.

The first family member to be tested should be the family member with the clearest diagnosis of IDC. This patient is usually the index patient, but in some families the index patient is deceased and no DNA is available. Considering clinical genetic testing in a patient with a questionable IDC diagnosis or those with little or no evidence of cardiovascular disease may be performed in these scenarios, however, negative results will not be informative. This is because it will be impossible to determine if the person tested negative because he or she does not carry the family gene mutation or because the family gene is not evaluated by the genetic test. The detection rate of currently available genetic tests is approximately 40%. While a positive genetic test result identifying a DCM-causing mutation may aid in a more accurate diagnosis, thus impacting management decisions, surveillance, and therapy, genetic testing is most important in the management of your patient’s family. First degree relatives of an individual with a DCM gene variant each have a 50% chance of carrying the same gene mutation, which significantly increases their chance of developing DCM. At-risk relatives may therefore wish to undergo genetic testing to determine if they have the family variant, as screening and surveillance for DCM are indicated. Because of incomplete, age dependent penetrance and variable expressivity, the symptoms, age of onset, disease features and severity can be very different among members of the same family. Some family members with the gene variant  may have severe disease, while others may have only minor heart muscle and/or rhythm problems. Still others may have no cardiac symptoms or signs of heart problems. “Unaffected” individuals who have a DCM gene variant (those who have the variant but have no evidence of clinical disease as per cardiovascular screening) still have a 50% chance of passing the variant on to each of their offspring, who again could fall anywhere in the clinical spectrum.

A negative test result in the index patient only rules out genetic disease caused by the gene(s) tested. In this case, genetic testing of asymptomatic family members for that gene(s) is not useful. As more genes become available for clinical genetic testing for DCM, the sensitivity of the test increases. Therefore, as the sensitivity of genetic testing panels increases, repeat testing is indicated for people with suspected genetic DCM with prior negative genetic testing results.