Rare Disease Report


Rare Diseases in Cardiology

The World Health Organization has determined that heart disease is the world’s No. 1 killer. Although the vast majority of cardiological conditions are fairly common or very common, rare cardiovascular problems continue to strike people around the globe.

Rare cardiological conditions fall into various categories, including certain types of arrhythmias (eg, Wolff-Parkinson White syndrome, supraventricular tachycardia), lipidemias (eg, familial combined hyperlipidemia, homozygous familial hypercholesterolemia, lysosomal acid lipase deficiency), gene-based congenital heart defects (eg, arrhythmogenic right ventricular dysplasia, Brugada syndrome, familial hypertrophic cardiomyopathy, long QT syndrome, hypertrophic obstructive cardiomyopathy, Holt-Orams syndrome, Marfan syndrome, tetralogy of Fallot), benign and cancerous tumors (eg, atrial myxoma), and cardiovascular consequences that occur as a result of other rare conditions, such as Hutchinson-Gilford progeria syndrome, Duchenne muscular dystrophy, and Fabry disease.

Diagnosis-Related Issues

Something called the “horse versus zebra syndrome” may sound like the beginning of a comedy routine, but it actually represents a major diagnosis challenge about which cardiologists joke only wryly. They treat so many examples of common diseases (the “horses”), that when a patient presents with an atypical disease (the “zebra”), an initial misdiagnosis can result.

Proper diagnosis, and later, proper care, can be aided by a team-based approach, in which the team members bring their different skills and strengths to the table. A rare cardiac genetic disease, for instance, may present with a broad pathological spectrum requiring different experts to collaborate for the best overall care. In other cases, a rare heart condition may result in neurological issues or a rare neurological condition may cause cardiological problems. Often, a referral from a primary care doctor to a cardiologist is only the beginning, not the conclusion, of the diagnostic process.

Online Resources

Diagnostic tests and procedures:

Lists of rare conditions:

FDA-approved orphan drugs:


Among the time-tested strategies that address cardiovascular conditions are lifestyle changes (eg, smoking cessation, dietary modifications, increased exercise, stress management), traditional pharmaceutical agents (eg, angiotensin-converting enzyme inhibitors, aldosterone inhibitors, angiotensin-2 receptor blockers, beta-blockers, calcium channel blockers, statins), and various medical/surgical procedures (eg, angioplasty, coronary artery bypass grafting). Often, regimens involve combining 2 or more of the above strategies.

Within the last few years, the first gene-based therapies have emerged from the laboratory and onto the market: in October 2012, European Union (EU) regulators—who generally have a more liberal track record than the FDA regarding the approval of new therapies for rare diseases—moved more swiftly than their American counterparts and approved alipogene tiparvovec (Glybera), the first gene therapy for a rare lipidemia (familial chylomicronemia syndrome) in the EU or the United States. To this day, it remains approved only by the EU. Lomitapide (Juxtapid) and mipomersen sodium (Kynamro)—approved in December 2012 and January 2013, respectively—were among the first genetic agents to obtain FDA approval in the United States for the treatment of a rare cardiologic condition. Both share an indication (homozygous familial hypercholesterolemia), were first in their respective therapeutic classes, work by inhibiting proteins key to low-density lipoprotein cholesterol production, and are typically prescribed as combination therapy in conjunction with conventional lipid-lowering agents.

Other approved orphan therapies for cardiologic issues include:

  • Amiodarone (Cordarone, Nextrone, Pacerone) and sotalol (Betapace) for bidirectional tachycardia and familial ventricular tachycardia
  • Metreleptin (Myalept) for lipodystrophy
  • Alglucosidase alfa (Myozyme) for Pompe disease
  • Ambrisentan (Letairis), bosentan (Tracleer), and macitentan (Opsumit) for pulmonary arterial hypertension

Clinical Trials

Despite the progress achieved by conventional treatments, heart disease death rates remain stubbornly high. The need for novel treatment pathways, especially for rare coronary diseases associated with high mortality, is pressing. Current trends in research emphasize next-generation gene-based therapy that utilizes nonviral or viral gene delivery vectors to correct genetic abnormalities, via enzyme replacement or gene silencing (depending upon whether the source of the given condition is due to an overabundance or a deficiency).

Several phase 3 clinical trials currently underway for rare coronary diseases are investigating the following:

  • Eisenmenger syndrome (macitentan, bosentan)
  • Homozygous familial hypercholesterolemia (CER-001, evolocumab)
  • Long QT Syndrome (GS-6615)
  • Familial combined hyperlipidemia (laropiprant, alirocumab)

Advocacy Support and Information

Rare-disease advocacy groups offer valuable help, support, resources, and information for patients, caregivers, and physicians. These organizations also help to establish a sense of community among those affected by rare diseases.

For a complete list of advocacy groups for rare coronary diseases, refer to Appendix B of this resource guide. Below are a few examples:

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