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Prognostic significance of left atrial strain in sarcomere gene variant carriers without hypertrophic cardiomyopathy

Abstract Background Genetic testing of relatives of hypertrophic cardiomyopathy (HCM) patients has led to a large group of genotype‐positive, phenotype‐negative (G+/Ph−) subjects. Prediction of progression to overt HCM in these subjects is challenging. While left atrial (LA) strain is reduced in HCM patients it is currently unknown whether this parameter can be used to predict HCM phenotype progression. Methods This study includes 91 G+/Ph− subjects and 115 controls. Standard echocardiographic parameters as well as left ventricular global longitudinal strain (LV GLS) and LA reservoir strain (LASr) were assessed for each patient. Logistic and Cox proportional hazard regression analyses were used to investigate predictors of G+/Ph− status and HCM during follow‐up. Results Independent predictors of G+ status included pathological Q waves (OR 1.60 [1.15–2.23], p < .01), maximal wall thickness (MWT: OR 1.10 [1.07–1.14], p < .001), mitral inflow E wave (OR 1.06 [1.02–1.10, p = .001), A wave (OR 1.06 [1.03–1.10], p < .001), LV GLS (OR .96 [.94–.98], p < .001), and LASr (OR .99 [.97–.99], p = .03). In univariable Cox regression analysis, male sex (HR 2.78 [1.06–7.29], p = .04), MWT (HR 1.72 [1.14–2.57], p = .009) and posterior wall thickness (HR 1.65 [1.17–2.30], p = .004) predicted HCM during a median follow‐up of 5.9 [3.2–8.6] years, whereas LASr did not (HR .95 [.89–1.02], p = .14). There were no significant predictors of HCM after multivariable adjustment. Conclusion LASr is significantly impaired in G+/Ph− subjects and is an independent predictor of G+/Ph− status, but did not predict HCM development during follow‐up.


INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease with a prevalence ranging between 1:200 and 1:500. A pathogenic sarcomere gene variant is detected in up to two-thirds of cases. 1 Genetic testing of relatives of patients with HCM has led to the identification of a large group of patients who carry pathogenic variants causing HCM, without left ventricular (LV) hypertrophy. Repeated follow-up of this genotype-positive, phenotype-negative (G+/Ph−) group is advised, primarily due to the age-related penetrance of HCM.
A substantial portion of these subjects will remain free of HCM during their lifetime. 2 Although a myriad of features have been implicated as part of the pre-clinical phenotype of HCM, [3][4][5][6]  of LA size. [7][8][9] The LA aids the LV in maintaining cardiac output, and remodels in the setting of LV diastolic dysfunction with elevated filling pressures, as well as in the presence of LV hypertrophy, LV outflow tract obstruction, mitral regurgitation, and possibly by primary atrial alterations as well, ultimately impairing LA function. 10 This is previously demonstrated in HCM patients using STE. 10,11 It is possible that LA strain is decreased in the G+/Ph− population as well, as abnormalities in diastolic function are often encountered in this group, 12,13 We hypothesize that subjects with a more severe pre-clinical phenotype (i.e., those with reduced LA strain) are more prone to develop HCM later in life. For this study, we measured LA reservoir strain (LASr), which represents the function of the LA as a reservoir for pulmonary venous return during ventricular contraction, reflecting LA compliance as the base of the LV descends during systole. The aims of this study are to quantify and compare LASr in G+/Ph− subjects and in healthy controls and to examine whether it predicts the development of HCM in G+/Ph− subjects.

Control group
The healthy control group consisted of 147 volunteers recruited in 2014-2015 and evaluated at our outpatient clinic, the protocol has been described in detail previously. 14  Echocardiographic images were transferred to a vendor-independent analysis system (Image Arena version 4.6, TomTec Imaging Systems, Unterschleißheim, Germany), whereby all STE measurements were performed using a chamber-specific wall motion tracking software (2D-CPA). Before attempting STE, the feasibility of LA strain analysis was judged by two investigators (RH, DB) by the following criteria: (1) the presence of an adequate apical four-chamber view with no LASr measurements were repeated in 20 random subjects approximately 9 months after the initial analysis (DB) and by a second reader (BLB), both with approximately 10 years of experience. LV strain anal-ysis was performed as previously described, 6 using standard four-, three-and two-chamber images.

Genetic testing
Genetic counseling and testing is routinely offered to probands with HCM visiting our cardiogenetic outpatient clinic. Subjects are considered G+ in case of a likely pathogenic or pathogenic variant (class 4 or 5) in a HCM-causing gene, in accordance with the American College of Medical Genetics and Genomics recommendations. 22 Cascade genetic screening is offered to close relatives targeting the specific variant found in the proband. G+ relatives are then referred for cardiac screening. The cardiogenetic testing procedure has been previously described. 23

Clinical characteristics
Of 160 G+/Ph− subjects screened for this study, 91 were ultimately included. One subject was excluded because of concomitant Tetralogy

Inter-and intra-reader reproducibility
Mean intra-and inter-reader differences for measurements repeated in 20 random subjects were −1.  A similar pattern was seen with LV GLS, which was increased in G+/Ph− subjects but also did not predict HCM, which is in line with earlier research conducted in our center. 6 The association of MWT with genotype-status and HCM during follow-up reflects clinical practice, in which subjects with borderline LVH will be monitored more closely.

DISCUSSION
Our study demonstrates, similar to others, the association of pathological Q waves with genotype-status. 3 25,26 The presence of atrial fibrosis is suggested by a high rate of recurrence of atrial fibrillation following pulmonary vein isolation in HCM patients. 27 Furthermore, a reduction in LASr reflects the LA's response to increased LA afterload secondary to poor LV compliance. Given that the latter is observed in sarcomere gene variant carriers without hypertrophy, 6,12 this offers an explanation for the current study's observations as well.
This study has several limitations. The study population was relatively small, particularly when comparing G+/Ph subjects with and without HCM. The vast majority of subjects had variants in the MYBPC3 gene, and study results might not be applicable to cohorts comprising different sarcomere gene variants. Many TTE studies were performed in an era in which the LA was not particularly focused on. However, we excluded studies with suboptimal visualization of the LA. Importantly, even though measurements were performed by experienced sonographers, intra-and inter-reader agreement of LASr measurements was only moderate. We cannot exclude the possibility of non-dedicated LA images interfering with the reliability of measurements even though we excluded many, and also speculate that software dedicated to LA strain analysis will improve this. While studies with suboptimal quality for strain measurements were excluded, comparison of LASr and LV GLS values with those from other studies must be done with caution, given the differences in vendors and methodologies.

CONCLUSION
LASr is decreased in G+/Ph− subjects compared to healthy controls and independently predicts G+/Ph− status. LASr values were similar in G+/Ph− subjects who do and do not develop HCM during follow-up, and cannot be used to predict the occurrence of HCM.