*2.3. TTNtv Are Associated with Late Presentation Of DCM, Are More Pathogenic in European Ancestry, and Are Associated with Early Atrial Arrhythmias*

The mechanism of haploinsufficiency leading to abnormal metabolism and increased stress is in keeping with the described human cardiac phenotypes of TTNtv. Mutations of *TTN* are the most common cause of genetic cardiomyopathy and account for 20–25% of genetic DCM [11]. TTNtv are associated with a later presentation (47.9 years) and greater longevity (70.4 years) compared to other genetic and non-genetic causes of cardiomyopathy [24,44]. While patients with TTNtv often present later in life, there is evidence that carriers have pre-symptomatic cardiac dysfunction with eccentric cardiac remodeling as detected by MRI [35]. In a study of 71,000 patients who have been genotyped and undergone cardiac phenotyping, pathogenic TTNtv defined as PSI > 0.9 imparted an increased risk of reduced systolic function regardless of symptoms. In addition, patients with pathologic TTNtv had high risk of developing DCM compared to controls. Interestingly, risk of developing DCM with pathologic TTNtv was associated with ethnicity. Patients with European ancestry and TTNtv had increased odds of developing DCM compared to healthy controls (odds ratio 18.7). Patients with African ancestry and TTNtv had odds of developing DCM that were nearer to the general population (odds ratio 1.8) [45]. While TTNtv have not been closely associated with life threatening ventricular arrhythmias, they are associated with development of atrial arrhythmias including atrial fibrillation. In a case control study of a cohort of 2781 who developed atrial fibrillation before age 66, TTNtv were found in 2.1% of patients compared to 1.1% of controls (odds ratio 1.76). In patients who develop very early atrial fibrillation before age 30, TTNtv were found in 6.5% of patients (odds ratio 5.94) suggesting TTNtv impart increased risk of developing very early atrial fibrillation [46].

## *2.4. TTNtv Are Associated with Worse Outcomes When Combined with Additional Cardiac Risk Factors*

Although TTNtv are associated with late development of DCM, when combined with additional risk factors for cardiomyopathy they are associated with earlier presentations and worse outcomes. This suggests a two hit hypothesis for development of TTNtv cardiomyopathy where *TTN* haploinsufficiency increases metabolic stress and when combined with additional risks such as age, toxins, pregnancy or acquired disease can lead to development of DCM [47]. In recent case reports of patients who developed anthracycline associated chemotherapy-induced cardiomyopathy (CCM) and underwent genetic studies, TTNtv were discovered [48]. In a larger study of 213 patients with CCM, TTNtv were present in 7.5% of patients compared to 1.1% of controls. In addition, patients with CCM and TTNtv had more severe cardiac dysfunction and increased risk of atrial fibrillation compared to patients with CCM without a TTNtv [49]. These data suggest that TTNtv when combined with exposure to cardiotoxic chemotherapy increases risk for development of cardiomyopathy. Similar evidence is seen in alcohol cardiomyopathy (ACM), which is a toxic cardiomyopathy related to excessive alcohol consumption. In 141 patient with ACM screened for genetic causes, TTNtv were present in 9.9% of ACM patients compared to 0.7% in controls [50]. Using a multivariate analysis comparing patients with TTNtv versus patients without TTNtv who consume excessive alcohol but do not have clinical ACM, patients with TTNtv had an 8.7% reduction in left ventricular ejection fraction compared to patients without TTNtv [50]. In addition, TTNtv have been associated with increased risk of peripartum cardiomyopathy. In 172 women with peripartum cardiomyopathy, TTNtv were discovered in 65% of patients compared to 4.7% in healthy controls [51]. These results suggest that genetic testing to identify TTNtv in patients with cardiomyopathies of alternative etiologies may be beneficial for prognostication and family screening.
