the incidence rate and prognostic factors of heart failure-related adverse events in hypertrophic cardiomyopathy: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-2845615/v1

Introduction heart failure is a common comorbidities of hypertrophic cardiomyopathy（HCM）, The mortality and hospitalization rates of heart failure-related in patients with HCM is constantly increasing，However, Prognosis and risk assessment of heart failure-related adverse events（HF-RAEs）in patients with HCM is controversial. Therefore, this study aimed to systematically review and conduct a meta-analysis of the incidence rate and predictors of HF-RAEs in patients with HCM.

Methods PubMed, Embase, Web of science, and Cochrane library were searched to identify studies that compared the incidence rate and predictors of HF-RAEs in patients with HCM. The outcomes of interest included the incidence rate and predictors of HF-RAEs, such as sex, atrial fibrillation, hypertension, left ventricular ejection fraction (LVEF), left atrial diameter.

Results fourteen studies comprising 6,903 patients were included. The pooled results showed a higher incidence (11%) of HF-RAEs in patients with HCM. Some clinical and imaging parameters, such as male gender (HR = 1.963, 95% CI (1.354, 2.847)), atrial fibrillation（HR=2.60,95%CI（1.87,3.61））, left atrial diameter (HR = 1.06, 95% CI (1.04, 1.07)) ,and LVEF (HR=0.96,95%CI(0.95,0.97)) could be used as predictors of the occurrence of HF-RAEs in patients with HCM, while hypertension (HR=1.47,95%CI (0.99,2.20) could not.

Conclusion Patients with HCM have a higher incidence of HF-RAEs. Clinical indicators, as well as imaging parameters could predict the risk of HF-RAEs in patients with HCM. These risk factors should be closely monitored to effectively prevent the occurrence of HF-RAEs in HCM.

hypertrophic cardiomyopathy

heart failure

prognosis

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease with a varied natural course and outcomes[1].Sudden death is among the most common adverse outcomes in HCM, and the latest guidelines provide clear indications and proven strategies for risk stratification, early prevention, and treatment of it[2]. Therefore, the occurrence and the course of the sudden death in HCM will be reversed , and the heart failure-related adverse events(HF-RAEs) in HCM have become particularly prominent due to the constantly increasing incidence and hospitalization rates of heart failure in patients with HCM，which will seriously affect the quality of patient survival and increases the burden of medical care[3-4].

previously, the recognized cause of HCM heart failure was left ventricular outflow tract obstruction, resulting in late left ventricular hypokinesis, which was reversed by septal resection or alcohol septal ablation therapy [5]. In contrast, in recent year, studies have found that Some patients with HCM with certain gene mutations exhibit progressive left ventricular dysfunction, and this advanced refractory heart failure poses a great challenge for the treatment of patients with HCM [6]. Rowin et al. [7] conducted a large-scale of long-term follow-up studies showing that patients with HCM have a variable disease progression, with nearly half of HCM patients experienced a poor prognostic course, with the most common adverse prognosis being New York Heart Association class III or IV. approximately 11% of patients experience advanced heart failure at various times during their clinical course. Therefore, the progression and management of heart failure in HCM have become the focus of interest for both national and international scholars.

Currently, a number of studies have begun to investigate the occurrence of HF-RAEs and the potential predictive value of various clinical and imaging parameters in patients with HCM[8-21]. However, the ability of these parameters to predict HF-RAEsin HCM is controversial. Therefore, this systematic review and meta-analysis aim to explore the incidence and predictors of HF-RAEs in patients with HCM, with the goal of providing powerful evidence for early clinical identification of individuals at risk for HF-RAEs in HCM, and implementing timely intervention and close follow-up for them.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. The review was registered in the International Register of Systematic Review (PROSPERO) Registry: CRD42022385183. All analyses were based on previously published studies. Therefore, no ethical approval and patient consent were required.

literature search

All records retrieved from the database search were systematically assessed by three independent authors (MJ, TM and AD) based on titles and abstracts. Articles that met the inclusion criteria were subsequently screened for full-text eligibility. Study selection was performed with the use of document management software Endnote. Any disagreement during each phase was resolved through collegial discussion.

Inclusion criteria were as follows: (i) studies reporting HF-RAEs in patients with HCM；and (ii) studies with outcomes that included multivariable cox hazard regression analysis to identify predictors for HF-RAEs in patients with HCM.

Exclusion criteria were: (i) case reports, conference abstracts, editorials, comments, systematic reviews, meta-analyses, and guidelines, (ii) studies that enrolled fewer than 80 patients with HCM and (iii) articles in languages other than English.

Outcomes definition

HF-RAEs were defined as follows : (i) Heart failure-related death，(ii) progression to NYHA class III–IV,or cardiac decompensation, (iii) heart failure hospitalization.

Data extraction and outcomes

Data from the included studies were independently extracted by two authors (MJ and TM) using excel sheet. The following data were extracted: sample size, Incidence of HF-RAEs，hazard ratio and its 95% confidence interval for predictors for HF-RAEs and follow-up time. Additionally, data on study design and cohort baseline characteristics, such as age, sex, associated comorbidities( including hypertension, atrial fibrillation), and imaging parameters (i.e. left atrial diameter, LVEF),were also collected.

Risk of bias

All studies included in the review were independently evaluated by two co-authors (MJ and TM) to assess their quality and the risk of bias.

we used a customized version of the Newcastle–Ottawa Scale (NOS) for cross-sectional studies, which consisted of 5 items across 3 domains (selection, comparability, outcomes), with a maximum of 5 points. studies with a score of 5 or lower was considered at high risk of bias. To assess publication bias, funnel plots were visually inspected for asymmetry,and Egger’s test was performed and reported. trim and fill method was used if there was a significant publication bias.

Statistical analysis and result interpretation

All meta-analytic statistical analyses were performed with StataMP14（64-bit）in this study. Cochran's Q tests and Galbraith plot was used to assess heterogeneity among the included studies and estimate the I²statistic. If I² > 50%, significant heterogeneity was considered to be present, and a random effects model was used to synthesize incidence rate and hazard ratio data . If I²< 50%, merge using fixed benefit model.

Study selection

A total of 993 potentially relevant records were retrieved from four databases, among which 417 duplicated studies and 65 studies inconsistent research types were removed automatically by software. 403 of 451 studies were excluded by reading titles and abstracts. Subsequently, Only 14 of 48 studies that were identified as eligible by preliminary screening met the absolute inclusion criteria after reading the full text. these 14 articles were included in the quantitative meta-analysis. The details of our screening process are illustrated in Fig1.

Study characteristics

The main characteristics and demographics of the studies are summarized in Tables 1. A total of 6903 patients were studied, comprising of 4,495 males（65%）and 2,408 females（35%）.

Risk of Bias assessment results

Our meta-analysis included a total of 14 cohort studies, of which 11 were high quality studies with NOS scores of 7-9, and 3 were medium quality studies with NOS scores of 6. The quality assessment results for each study are shown in Table 2.

Table 1 Main characteristics of selected studies in the meta-analysis
Study (years)	country	NOS	Cohort (N)	Events(n)	Average age n（%）	Males N(%)	hypertension(%)	AF n(%)	LVEF (mean±SD）	LAD (mean±SD)	Follow up time (years)
van Velzen etal (2018)	Netherlands	8	1007	46	52 ±16	620(62)		213 (21)			6.8(3.2 -10.9)
Li et al (2021)	China	8	263	34	50 ± 15.5	125(51)			62.7 ± 10.5		2.4 ± 1.0
Magri et al (2016)	Italy	8	620	84	49±16	425(69)				42.3±7.4	3.8(2.3–5.3)
Wang et al (2014)	China	7	621	89	47.5±15.2	460(74)		78 (13)		39.8±6.7	4(2-7)
Lee et al (2022)	Korea	7	835	58	56.3 ± 12.2	612(73)					6.4(4.1–9.2)
Yang et al (2018)	China	6	98	17	58.3 ± 13.9	66(67)			59.3 ± 5.0		1.4 ± 0.8
Javidgonbadi et al (2019)	Sweden	6	251	40	70 ±23	128(60)	94 (37.5)				14.4±8.9
Magri et al (2020)	Italy	6	371	52	49 ± 16	238(64)				43 ± 7	5.4(2.3-8.1)
Zegkos et al (2021)	US	9	250	27	50.8 ± 15.8	168(67)			69.2 ± 9		2.5 ± 1.2
Lu et al (2020)	US	7	728	37	53.3±14.7	451(62)					2.0(1.0-4.7)
Lee et al (2022)	Korea	7	414	51	58.3±12.8	272(66)	179 (42.3)	60 (14)	63.9±6.5	45.5±7.0	6.9(3.7–10.0)
Jang et al (2020)	Korea	7	202	17	63 ± 14	141(70)	104 (51.5)	47 (23)			2.83(1.3–4.7)
Maron et al (2016)	US	8	249	24	41±17	167(67)			63±7	40 ±7	6.5(5.4-7.9)
Ledieu et al (2020)	France	7	994	115	55±15	686(69)			65.4±10.7	43.6±8.2	4.0± 2.0

AF: atrial fibrillation; LVEF: left ventricular ejection fraction; LAD: left atrial diameter

Table 2 NOS scores of selected studies in the meta-analysis

study	Selection	Comparability	Outcome	score
van Velzen et al 2018	※※※※	※	※※※	8
Li et al 2021	※※※	※※	※※※	8
Magri et al 2016	※※※※	※	※※※	8
Wang et al 2014	※※※※	※	※※	7
Lee et al 2022	※※※※	※	※※	7
Yang et al 2018	※※※※	※	※	6
Javidgonbadi et al 2019	※※	※	※※※	6
Magri et al 2020	※※※	※	※※	6
Zegkos et al 2021	※※※※	※	※※	7
Lu et al 2022	※※※	※※	※※	7
Lee et al 2022	※※※※	※※	※※※	9
Jang et al 2020	※※※	※※	※※	7
Maron et al 2016	※※※※	※※	※※	8
Ledieu et al 2020	※※※	※	※※※	7

Assessment of outcomes

Incidence of HF-RAEs

In this study, 14 studies[8-21]were included to evaluate the of the incidence of HF-RAEs, heterogeneity analysis showed that I²=89.64%>50%, and P=0.00<0.05，indicating high heterogeneity among the studies. The Galbraith plot shown in Fig 2 could not identify the sources of heterogeneity. Therefore，Regression analysis was conducted to explore whether the following variables were possible causes of the heterogeneity of the incidence of HF-RAEs: mid-cohort years, sample size, and geographical location (Europe, Asia or America) And Newcastle-Ottawa Rating (NOS) scores (7 or <7). The results showed that none of the above covariables was a statistically significant source of heterogeneity (all p>0.05) (Table 3). Finally, the random effects model was applied to combine the effect size, as shown in Fig 3. Publication bias was examined using Eggers test with Begg’s funnel plots. The results showed that the funnel plot is symmetrical and there is no publication bias（P=0.084）,according to Eggers test, shown in Fig 4.

Table 3 Regression analysis to explore possible causes of the heterogeneity of the incidence of HF-RAEs

Covariates	Number of studies (Total=19)	Coefficient	SE	P-value
mid–cohort year
<5years	8	1.024857	0.0247676	0.330
>5 years	6
Sample size
<500	8	1.036176	0.0272254	0.201
>500	6
Geographical location
Europe	5	1.033229	0.0373104	0.385
Asia	6
America	3
NOS scores
≥7	11	0.9444475	0.0374029	0.175
<7	3

prognostic factors of HF-RAEs

sex6 studies reported the predictive value of gender for HF-RAEs in patients with HCM. heterogeneity analysis showed that there was no heterogeneity among the studies(I2=29.4%，p=0.215). The fixed-effect model was used to combine the hazard ratio, as shown in Fig5 (a). T The sensitivity analysis results showed that the result of the above fixed effects is stable and reliable, shown in Fig6(a). Random deletion of any single study did not affect the results of this study, which indicates that the results of the above fixed effects are stable and reliable. Publication bias was examined using Begg’s funnel plots，as shown in Fig7(a). The results showed obvious asymmetry of funnel plot.

therefore, trim and fill method was used for analysis. the results were still statistically significant (P<0.05) and there was no heterogeneity after the addition of 3 studies. Furthermore, the fixed-effect model was used to combine the hazard ratio (HR=1.963,95%CI(1.354,2.847)).

atrial fibrillation

4 studies reported the predictive value of atrial fibrillation for HF-RAEs in patients with HCM. heterogeneity analysis showed that there was no heterogeneity among the studies（I2=15.3%，p=0.316）. the fixed-effect model was used to combine the hazard ratio（HR=2.60,95%CI（1.87,3.61））as shown in Fig5(b). Sensitivity analysis showed in Fig6(b), in addition, there is no publication bias based on Eggers test (P=0.364) and Begg’s funnel plots, shown in Fig7(b).

hypertension

3 studies reported the predictive value of hypertension for HF-RAEs in patients with HCM. heterogeneity analysis shows that there was no heterogeneity among the studies(I2=25.7%，p=0.260). The fixed-effect model was used to combine the hazard

ratio（HR=1.47,95%CI（0.99,2.20））, as shown in Fig5(c). The sensitivity analysis Sensitivity analysis showed in Fig6(c). Moreover, there was no publication bias based on Eggers test (P=0.492) and Begg’s funnel plots, shown as Fig7(c).

LVEF

6 studies reported the predictive value of LVEF for HF-RAEs in patients with HCM. heterogeneity analysis showed that there was no heterogeneity among studies(I2=0.0%，p=0.781). The fixed-effect model was used to combine the hazard ratio (HR=0.96,95%CI(0.95,0.97)), as shown in Fig5(d). Sensitivity results showed in Fig6(d).there is no publication bias based on Eggers test (P=0.674)and Begg’s funnel plots ,shown as Fig7(d).

left atrial diameter

6 studies reported the predictive value of left atrial diameter for HF-RAEs in patients with HCM. heterogeneity analysis showed that there was a Moderate heterogeneity among the studies(I2=69.4%，p=0.006). Therefore, we further plotted the Galbraith plot, and the results showed that there was one study [21] that was the main source of heterogeneity. Therefore, the study was deleted and there was no heterogeneity in the remaining four studies（I2=16.0%，p=0.312）. The fixed effect model was used to combined the hazard ratio (HR = 1.06, 95% CI (1.04, 1.07)) of the remaining studies, as shown in Fig5(e). Sensitivity results showed in Fig 6(e). there was no publication bias based on Eggers test (P=0.062) and Begg’s funnel plots, shown as Fig7(e).

This systematic review and meta-analysis explored the incidence and predictors of HF-RAEs in patients with HCM. The main outcomes we focused on were incidence rate and predictors. The results showed a higher incidence (11%) of HF-RAEs in patients with HCM. Some clinical and imaging parameters, such as male gender (HR = 1.963, 95% CI (1.354, 2.847)), atrial fibrillation（HR=2.60,95%CI（1.87,3.61））, left atrial diameter (HR = 1.06, 95% CI (1.04, 1.07)) ,and LVEF (HR=0.96,95%CI(0.95,0.97)) could be used as predictors of the occurrence of HF-RAEs in patients with HCM, while hypertension (HR=1.47,95%CI(0.99,2.20) could not.

Epidemiological surveys have shown that despite a decrease in mortality from heart failure,its global morbidity and hospitalization rates continue to rise, making it a worldwide public health problem[22-23]. In a contemporary registry of 1,739 individuals with HCM in Europe, the prevalence of symptomatic heart failure was 67%, with 17.4% of patients experiencing New York Heart Association III–IV symptoms [24]. As heart failure is a common comorbidities of HCM, the characteristics of its occurrence and progression in patients with HCM have not been fully revealed. Therefore, our meta-analysis further explored the occurrence and risk factors of HF-RAEs in HCM. The incidence rate of HF-RAEs in HCM was 11%(95%CI 8%-13%) in our pooled analysis with high heterogeneity. the source of the heterogeneity in incidence remained unidentified by meta-regression , and we speculate that it may be related to the underlying status of the included population and differences in the range of HF-RAEs among studies. Overall, the incidence of HF-RAEs in HCM was high.

Atrial fibrillation is an independent predictor of total mortality in patients HCM, with a four-fold increased risk of death in atrial fibrillation compared with sinus rhythm [25-26]. Growing evidence suggests that atrial fibrillation may be a key factor in the occurrence of HF-RAEs in patients with HCM [27-28]. Our meta-analysis confirmed that atrial fibrillation significantly increased the risk of HF-RAEs in patients with HCM （HR=2.60,95%CI（1.87,3.61））.In a machine prediction model for HF-RAEs in patients with HCM, it was noted that gender, comorbidities (e.g., hypertensive，atrial fibrillation), LVEF, left ventricular outflow tract obstruction, and left ventricular wall thickness could be valid predictors [29], whereas in the combined results of our meta-analysis, hypertension did not predict the occurrence of HF-RAEs in patients with HCM. (HR=1.47,95%CI (0.99,2.20)).

Earlier studies have indicated that hypertension plays an important role in the progression of heart failure [30-31]. Similar to HCM, hypertension can induce hypertrophy of the left ventricular septal or the entire left ventricle leading to cardiac remodeling and impaired cardiac function [32]. Interestingly, a recent study examined the effect of hypertension on the prognosis of HCM, and found that in the cohort without septal resection ,HCM patients without hypertension had a higher risk of cardiovascular death and all-cause death compared to those with hypertension[33]. these findings partially support our results that hypertension is not a predictor of adverse outcomes in patients with HCM, including HF-RAEs in HCM. However, due to the small sample size in this study, the influence of hypertension on HF-RAEs in HCM remains further confirmation in the future.

LVEF is a crucial factor for the diagnosis, classification and treatment of heart failure [34]. research has shown that an increase in LVEF can largely improve the prognosis of patients with heart failure [35].Our pooled results demonstrated that an increase in LVEF was associated with a corresponding decrease risk of HF-RAEs in patients with HCM (HR=0.96,95%CI(0.95,0.97)). Therefore, regular monitoring of LVEF in patients with HCM is beneficial for early detection and prognostic risk assessment of HF-RAEs, providing an crucial foundation for clinical prevention and treatment. In recent years, with the advancement of imaging technology, the evaluation of left ventricular function has become more diversified. techniques such as Ultrasonic speckle-tracking and cardiac magnetic resonance can more accurately and directly reflect the changes in left ventricular function by detecting myocardial motion and the degree of myocardial fibrosis [36-37]. Studies have suggested that parameters such as left ventricular global strain and late gadolinium enhancement will all be expected to be reliable predicators for HF-RAEs in patients with HCM [38-40].

Consistent with the model predictions of Fahmy et al [29], we found that gender can be a predictor of HF-RAEs in HCM, with male patients having a significantly higher risk of HF-RAEs in HCM compared with female patients (HR=1.963,95% CI (1.354,2.847). Therefore, in the management of patients with HCM, male patients should be monitored more closely to prevent the occurrence of HF-RAEs.

Furthermore, our study demonstrated that an increase in left atrial diameter is associated with an increased risk of HF-RAEs in HCM (HR=1.06,95%CI (1.04,1.07)). Other studies suggested that functional parameters such as left atrial volume index and left atrial strain can also serve as effective predictors [16][19]. Thus, evaluating left atrial parameters may be useful in predicting the risk of HF-RAEs in HCM patients.

In recent years, it has been shown that the deletion of MLP myosin and mutations in the MYH7 R4 gene have been confirmed to be involved in the induction of HCM heart failure phenotype, which may be the initiating factors contributing to poor prognosis associated with heart failure[41-42]. Some studies have further explored the finding , demonstrating that pathogenic sarcomere mutations in HCM and some new mutations, such as tin-truncating variants(TTNtv), may serve as predictors of HF-RAEs[43-44].

Limitations

There are several limitations to our study. Firstly, the small sample size of the included studies is small, and overall, there is some variability in the range of HF-RAEs among the 14 studies, and subgroup analysis based on this cannot be conducted, which may contribute to the strong heterogeneity of the pooled results of the incidence of HF-RAEs in patients with HCM. Secondly, some latest imaging parameters, such as left atrial volume index, left ventricular strain, as well as other parameters like genetic mutations ,have not been extensively studied, and we failed to perform meta-analysis to summarize relevant results. There areas require further attention in future studies.

Patients with HCM have a higher incidence of HF-RAEs Certain clinical indicators, such as gender, atrial fibrillation, as well as imaging parameters like LVEF and left atrial diameter could predict the risk of HF-RAEs in patients with HCM. These above risk factors should be paid closely attention during the diagnosis and treatment of HCM to effectively prevent the occurrence of HF-RAEs.

HCM hypertrophic cardiomyopathy

HF-RAEs heart failure-related adverse events

LVEF left ventricular ejection fraction

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published

article.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was received in conducting this study.

Author contributions

Conceptualization: AD, MJ and TM; Methodology: MJ, TM and YS; Formal analysis and investigation: MJ, TM and AD; Writing of original draft preparation: MJ; Writing of review and editing: MJ, TM XW and YS; Supervision: AD. All authors read and approved the final manuscript.

Acknowledgements

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No competing interests reported.

the incidence rate and prognostic factors of heart failure-related adverse events in hypertrophic cardiomyopathy: A systematic review and meta-analysis

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