The prognostic role of right ventricular dysfunction in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) primarily affects the left ventricle (LV) sparing the right ventricle (RV) in vast majority of cases. However, several studies employing CMR have revealed that myocardial hypertrophy may also involve the RV. To assess RV size and function in a large prospectively cohort of HCM patients and to evaluate whether these parameters in association with other MR findings can predict cardiac events. Two participating centers prospectively included patients with known or suspected HCM between 2011 and 2017. CMR studies were performed with three different scanners. Outcome measures were a composite of ventricular arrhythmias, hospitalization for HF and cardiac death. Of 607 consecutive patients with known or suspected HCM, 315 had complete follow-up information (mean 65 ± 20 months). Among them, 115 patients developed major cardiac events (MACE) during follow-up. At CMR evaluation, patients with events had higher left atrium (LA) diameter (41.5 ± 8 mm vs. 37.17 ± 7.6 mm, p < 0.0001), LV mass (156.7 vs. 144 g, p = 0.005) and myocardial LGE (4.3% vs. 1.9%, p = 0.001). Similarly, patients with events had lower RV stroke volume index (42.7 vs. 47.0, p = 0.0003) and higher prevalence of both RV hypertrophy (16.4% vs. 4.7%, p = 0.0005) and reduced RV ejection fraction (12.2% vs. 4.4%, p = 0.006). In the multivariate analysis, LA diameter and RV stroke volume index were the strongest predictors of events (p < 0.001 and p = 0.0006, respectively). Anatomic and functional RV anomalies detected and characterized with CMR may have may have a major role in predicting the prognosis of HCM patients.


Introduction
Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes with a prevalence of 1:500 in the general population that is characterized by cardiac hypertrophy, unexplained by the loading conditions, non-dilated left ventricle (LV) and normal or increased ejection fraction. The disease is associated with a risk of adverse cardiac events such as severe arrhythmias, progressive heart failure (HF), and sudden cardiac death (SCD) [1][2][3]. It is also one of the more common cause of SCD in young individuals and athletes [4]. In HCM patients, myocardial fibrosis is an important substrate for both life-threatening arrhythmias and adverse cardiac remodeling [5]. This has been confirmed by histopathological studies that showed a high burden of fibrosis in both young adults [6] with SCD and older patients with end-stage HF. The presence and extent of late gadolinium enhancement (LGE) on cardiac magnetic resonance 1 3 (CMR) has recently emerged as a promising tool for SCD risk stratification in patients with HCM [7][8][9][10][11][12][13]. The left ventricle (LV) is mainly affected by the myocyte disorder, while the right ventricle (RV) is spared from hypertrophy in the vast majority of cases. However, several studies employing CMR have revealed that myocardial hypertrophy may also involve the RV [14][15][16][17][18]. Moreover, previous studies have addressed the relationship between RV size and function and clinical outcome in HCM patients. In particular, increased wall thickness and dysfunction of the RV have been shown to predict more symptomatic disease and poorer prognosis [17,18]. Although RV ejection fraction (RVEF) of HCM patients tends to be within the "normal" range, it has been demonstrated that RVEF may predict clinical outcomes in patients with cardiomyopathy [19,20]. To the best of our knowledge, few studies have focused on RV size and function and their relationship with cardiac outcome in HCM patients. Thus, we aimed to assess RV volume and function in a large prospectively gathered cohort of HCM patients and to evaluate whether these parameters together with several other CMR features (including extent of LV fibrosis) may predict cardiac events at long-term follow-up.

Population
Two participating centers, the Centro Cardiologico Monzino, Milan, Italy (center A) and the Humanitas Research Hospital, Milan, Italy (center B) prospectively included patients with known or suspected HCM between January 2011 and April 2017 (center A) and between January 2011 and November 2017 (center B). The diagnosis of HCM was defined according to the European Society of Cardiology guidelines (maximal LV wall thickness of ≥ 15 mm on echocardiography, in the absence of any other cardiac or systemic disease that would be capable of producing myocardial hypertrophy, such as afterload abnormalities like aortic valve stenosis or arterial hypertension [2]. Clinical and CMR data were collected at each center by two experienced physicians. Each institution's ethical committee approved the protocol and all patients gave written informed consent.

CMR protocol
CMR studies were performed with a 1.5-T Discovery MR450 scanner (GE Healthcare, Milwaukee, Wisconsin) in center A. In center B, a 1.5-T CVi scanner (GE Healthcare, Milwaukee, Wisconsin), a 1.5-T Achieva (Philips Medical Systems, Best, Netherlands) or a 1.5-T Aera scanner (Siemens, Erlangen, Germany) were used. Dedicated cardiac software, phased array surface receiver coils, and electrocardiogram triggering were used. Breath-hold steadystate free precession cine imaging was performed in vertical and horizontal long-axis orientations and in short-axis orientations. A stack of short-axis slices encompassing the right and left ventricle from base to apex was used for biventricular volumes, mass, and systolic function assessment. For detecting myocardial fibrosis, we used a contrast-enhanced, breath-hold, segmented T1-weighted inversion-recovery gradient-echo sequence with the LGE technique (i.e., LGE imaging).

CMR analysis
All CMR studies were analyzed by expert readers with considerable experience in CMR studies (12 years of experience, Level 3 certified expert), blinded to patient clinical history and data. The short-axis stack was used for calculating RV and LV size and function. Endocardial and epicardial boundaries were delineated in end-diastole and end-systole with a dedicated software (Circle Cardiovascular Imaging, cvi42 version 5.3.2, Calgary, Canada). Based on these data, the following parameters were calculated: RV and LV enddiastolic volumes (RVEDV and LVEDV, respectively), RV and LV end-systolic volumes (RVESV and LVESV, respectively) as well as RV and LV ejection fraction (RVEF and LVEF, respectively), and LV mass. Each volume or mass parameter was indexed to body surface area and expressed as mL/m 2 or g/m 2 , respectively. Additionally, each image was inspected for detecting RV and LV hypertrophy, and the maximal wall thickness of the left and right ventricle was recorded. The presence and amount of scar was assessed using 2D LGE sequences. LGE was defined as hyperintense myocardium with a signal intensity > 5 SDs above the mean signal intensity of normal myocardium. For quantitation of LGE, inner and outer myocardial edges were manually delineated.
LGE was determined semi-automatically as a percentage of total myocardium.

Follow-up
All patients underwent clinical visits or telephone interviews performed at each center by experienced cardiologists blinded to CMR data. During the visits Holter monitoring were reviewed. Outcome measures were a composite of ventricular arrhythmias (non-sustained ventricular tachycardia, i.e. occurrence of 3 or more consecutive ventricular beats 1 3 for less than 30 s, or sustained ventricular tachycardia), hospitalization for HF and cardiac death due to ventricular arrhythmias or refractory HF, malignant arrhytmias at the interrogation of the internal cardioverter defibrillator.

Statistical analysis
Unpaired t-test or Kruskal-Wallis test were performed to compare continuous variables between patient without events and those with combined events, while chi-square test or Fisher's exact test were performed for analysis that involved categorical variables. Univariate and multivariate Cox regression was employed to investigate potential predictors for combined event. The covariates included in the multivariate analysis were selected through epidemiological approach. Continuous variables are presented as mean ± SD, skewed variables as median with interquartile range (IQR), while categorical variables are shown as absolute numbers and percentages.

Population
Of 607 consecutive patients with known or suspected HCM considered for enrollment, 279 were excluded from the analysis because of unconfirmed HCM or diagnosis of other myocardial diseases at CMR (n = 231), poor image quality (n = 36) and lack of informed consent and authorization (n = 12). Of the remaining 328 patients, 13 were lost to follow-up, whereas 315 (96%) had complete followup (mean 65 ± 20 months, up to 82 months) information ( Fig. 1).

Clinical data
There was no difference between patients with or without MACE in terms of age, BMI and cardiovascular risk factors including family history of HCM and SCD. Prevalence of dyspnea and heart failure symptoms at the time of CMR were higher in patients with events than in those without events.  Table 3 reports the CMR predictors of events at univariate analysis. The hazard ratio (HR) was high in patients with higher LA diameter (HR = 1.06, p > 0.001), impaired LVEF (HR = 2.06, p = 0.0005) and LVESV index (HR = 2.37, p = 0.0002), higher LV mass (HR = 1.8, p = 0.02) and pathological LVSV index (HR = 1.6, p = 0.03). High HR was also found in patients with high LV thickness (HR = 5.5, p < 0.0001) and higher percentage of myocardial LGE (HR = 1.02, p = 0.001). Regarding RV parameters, reduced RVEF (HR = 2.5, p = 0.001) and RVSV index (HR = 2.08, p = 0.018) were the best predictors of events. At multivariate analysis, LA diameter and RVSV index were the strongest predictor of events (HR = 1.05; p < 0.001 and HR = 0.9, p = 0.0006, respectively) ( Table 4).

Main findings of the study
Most of the literature data on HCM have focused on LV changes, while few studies have characterized RV abnormalities using CMR [21][22][23][24]. The main finding of our study is that RV anomalies assessed with CMR in HCM patients, such as increased wall thickness, dilatation and systolic dysfunction have a significant role in predicting prognosis in addition to those of the LV. In particular, we found that when LV hypertrophy was associated with increased RV thickness the rate of MACE was significantly higher. Indeed, RV hypertrophy was identified in 16.4% of patients with events and in 4.7% only of patients without events. Moreover, the rate of lower RVSV index, a major parameter of RV systolic function, was significantly higher in patients who had events than in those without events (21.2% vs. 13%, respectively). The presence of RV systolic dysfunction was also the strongest independent predictor of events at multivariate analysis. A potential explanation for this result lies in the fact that in   a disease such as HCM, which is characterized primarily by LV involvement, hypertrophy and disarray of LV cardiac myocytes may lead to changes in RV deformation and compromised dynamics [25]. In agreement with this hypothesis, experimental studies demonstrated the significant LV contribution to RV systolic function [19,20]. Similarly, several clinical studies in patients with congenital heart disease have demonstrated that RV function depends on LV dynamics [21,[26][27][28][29][30][31], highlighting the interdependence of the two ventricles. However, only limited data are available regarding the factors that can affect RVEF in patients with HCM. Finocchiaro et al. showed that RV dysfunction, defined as an echocardiographic elevated RV myocardial performance index (RVMPI) and a reduced tricuspid annular plane systolic excursion (TAPSE), was found in 71% of HCM patients [32]. Of note, RV dysfunction based on RVMPI was more frequently observed in patients with LV dysfunction and pulmonary hypertension and TAPSE reduction was independently associated with an increased likelihood of death or transplantation [32].

Prognostic impact of RV dysfunction
The prognostic impact of RV dysfunction observed in our study is in line with the study by Hiemstra et al. [33] who evaluated standard and advanced echocardiographic measurements of RV function, including RV 4-chamber longitudinal strain (RV4CLS) and RV free wall longitudinal strain (RVFWLS). They found that impaired RV4CLS, together with LV global longitudinal strain (GLS) and the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), were associated with adverse outcome in terms of all-cause mortality and heart failure development. Interestingly, in their study RV dysfunction defined as a RVEF below 45% was present in 1.8% patients only, suggesting that reduced RVEF may be a late sign of RV dysfunction. Moreover, they also observed that the presence of LV LGE was associated with higher RVEF and smaller RV cavity. In agreement with this finding, we also noticed that patients showing LV LGE had a small and hyperkinetic RV. This observation is intriguing and may be related to the capability of a smaller ventricle to increase the ejection fraction in order to maintain the stroke volume. In addition to demonstrating the important prognostic significance RV function, our study further confirms the results of previous CMR studies regarding the left side of the heart in HCM patients. Indeed, the presence of LV LGE has always been considered as indicative of myocardial fibrosis and an unfavorable prognostic factor in HCM patients [34]. Our study confirms that LGE (quantified as a % of LV mass) is a major prognostic marker (p = 0.001 in predicting MACE). Finally, many retrospective and observational echocardiographic studies have demonstrated that a greater LA size is associated with adverse events in HCM patients, particularly increasing the risk of heart failure and atrial fibrillation [35,36] . Our findings confirm that a simple parameter such

Study limitations
The main limitation of our study is the lack of calculation of T1 mapping and extracellular volume (ECV) in our population. This was due to the fact that dedicated software of T1, T2 mapping and ECV measurements became available in clinical practice after the end of patient enrollment. Other limitations are the lack of genetic and histological confirmation of HCM. Moreover the assessment of myocardial deformation, e.g. CMR analysis of the strain, was not performed in our population.

Clinical perspectives of the study
Right ventricle anomalies assessed with CMR in HCM patients, such as increased wall thickness, dilatation and systolic dysfunction have a significant role in predicting prognosis in addition to those of the left ventricle.

Conclusions
In addition to the presence and extent of LV fibrosis and LA enlargement, anatomical and functional RV anomalies (abnormal thickness and impaired RVSV index) detected and characterized with CMR may have a major role in determining the prognosis of HCM patients.