Association between sarcoidosis and cardiovascular Outcomes: A systematic review and Meta-analysis.

Background: Sarcoidosis is a chronic inflammatory disorder of unknown etiology associated with high morbidity and mortality. Its association with cardiovascular outcomes is under-documented. Aim: The aim of this study was to assess the adverse cardiovascular outcomes in patients with sarcoidosis compared with that of non-sarcoidosis. Methodology: Online databases including PubMed, Embase and Scopus were queried from inception until March 2022. The outcomes assessed included all-cause mortality (ACM) and incidence of ventricular tachycardia (VT), heart failure (HF) and atrial arrhythmias (AA). Result: A total of 6 studies with 22,539,096 participants (42,763 Sarcoidosis, 22,496,354 Non-Sarcoidosis) were included in this analysis. The pooled prevalence of sarcoidosis was 13.1% (95% CI 1% to 70%). The overall mean age was 47 years. The most common comorbidities were hypertension (12.7% vs 12.5%), and diabetes mellitus (5.5% vs 4%) respectively. The pooled analysis of primary endpoints showed that all-cause mortality (RR, 2.08; 95% CI: 1.17 to 3.08; p = 0.01) was significantly increased in sarcoidosis patients. The pooled analysis of secondary endpoints showed that the incidence of VT (RR, 15.3; 95% CI: 5.39 to 43.42); p < 0.001), HF (RR, 4.96; 95% CI: 2.02 to 12.14; p < 0.001) and AA (RR, 2.55; 95% CI: 1.47 to 4.44); p = 0.01) were significantly higher with sarcoidosis respectively compared to non-sarcoidosis.
Conclusion: Incidence of VT, HF and AA was significantly higher in patients with CS. Clinicians should be aware of these adverse cardiovascular events associated with sarcoidosis.

Introduction

Sarcoidosis is a multisystem disorder of unknown etiology that presents with noncaseating granulomas in various organs [1], [2]. The characteristic features of sarcoidosis include bilateral hilar lymphadenopathy and reticular opacities in the lungs [3], [4]. Sarcoidosis may also affect extrapulmonary organs like the heart leading to cardiac sarcoidosis (CS) [5]. While the causes of CS are currently unknown, the disease may be caused by over-reaction of the immune system post-exposure to infectious agents such as viruses or bacteria, allergens of chemicals [6]. Sarcoidosis may also have a genetic component with family members five times more likely to contract the disease as compared to non-affected families [7]. The excessive inflammation and clustering of white blood cells is thought to cause the formation of granulomas. The disease generally affects the young population, between 25 and 45 years. Of note, individuals with CS also tend to have granulomas in other organs – most commonly the lungs [6].

In the United States, the incidence of sarcoidosis ranges from 5 to 40 cases per 100,000 population while it is considerably higher for African Americans, at 34 cases per 100,000 population. Globally the average incidence is 20 cases per 100,000 population in Sweden and 1.3 cases per 100,000 population in Japan [7]. Cardiac involvement occurs in 20–27% of sarcoid patients in the US and can be as high as 58% in Japan [8]. Studies have shown that clinically evident sarcoidosis involves the heart in at least 2–7 % of patients with sarcoidosis [9], but occult involvement is much higher (>20%) [10], [11]. However, more recent studies using advanced cardiac imaging in asymptomatic patients suggest that cardiac involvement can be as high as 30% [12].

Patients with sarcoidosis are at an increased risk of ventricular tachycardia as ventricular myocardium can become a focus for abnormal automaticity, and sudden cardiac death, although the precise incidence of ventricular arrhythmias in sarcoidosis patients is not well defined [13], [14]. A study additionally finds that ventricular tachycardia (23%) and progressive congestive heart failure (23%) are frequently reported with the latter being the second most frequent cause of mortality, after sudden death [15].

The likelihood of unfavorable cardiac outcomes, especially heart failure, ventricular tachycardia, and all-cause mortality in the patient population with sarcoidosis is under documented with very limited reports available in current literature. The objective of this study is to synthesize the risks of ventricular tachycardia, heart failure, atrial arrhythmias, and all-cause mortality due to cardiac sarcoidosis.

Methods

This study was carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 checklist and was performed according to established methods, as described previously [16], [17]. A prespecified study protocol was registered with PROSPERO: CRD42022313814.

Outcomes

The primary outcome of interest for this meta-analysis was all-cause mortality. The secondary outcomes of interest were the incidence of ventricular tachycardia, heart failure, and atrial arrhythmias (atrial fibrillation or atrial flutter).

Search strategy

We conducted a systematic literature search across the following databases: PubMed/MEDLINE, Embase, Cochrane Library, and Scopus. Predefined MeSH terms were used, by applying the BOOLEAN (“AND” and “OR”) logic. The following search terms were used: “sarcoidosis” OR “cardiac sarcoidosis” AND “arrhythmia” OR “ventricular tachycardia” OR “heart failure” OR “mortality.” The search was performed from inception until March 2022 without any language or date restrictions. All the studies were carefully screened and exported to Endnote 2020 library (Clarivate Analytics, USA). Two reviewers (VJ and SPA) reviewed the studies based on title and abstract. A third author (SB) arbitrated discrepancies regarding the inclusion of studies.

Eligibility criteria

Inclusion criteria:

Studies with patients aged ≥ 18 years.

Studies including intervention and control groups where the intervention group employed patients with diagnosed sarcoidosis, while the placebo/control group comprised patients without sarcoidosis.

Studies were required to report at least one of the desired outcomes, i.e., all-cause mortality, risk of VT, HF, atrial arrhythmias (atrial fibrillation or atrial flutter) and heart transplant.

Eligible study designs included RCTs, and prospective and retrospective cohort studies.

Exclusion criteria:

Animal studies, abstracts, editorials, commentaries, systematic reviews, single-patient case studies, letters, and studies with insufficient data were excluded.

Studies where a single arm was presented without comparators, and with non-compliant outcomes were also excluded.

Data extraction and statistical analysis

Data of the eligible selected studies such as demographic, comorbidities, risk factors, and outcomes of both groups were extracted into a shared spreadsheet by two authors (VJ and SPA). Baseline continuous variables were summarized as mean (SD), whereas dichotomous variables were described as frequencies or percentages. A conventional, two-arm meta-analysis for primary and secondary outcomes was performed, by adopting the Dersimonian and Laird random-effects model for the study variations [18]. The intervention arm (CS) comprises individuals having been diagnosed with sarcoidosis whereas the control arm (NS) comprises individuals without a diagnosis of sarcoidosis. Studies which reported hazard ratio was treated as risk ratio. Outcomes were reported as pooled risk ratios (RR) and their corresponding 95% confidence interval (95% CI). Statistical significance was met if 95% CI did not cross the numeric “1″ and the two-tailed P value was<0.05. The heterogeneity among studies was assessed using the Higgins I-squared (I2) statistical model with I2 values < 75% considered mild-moderate and ≥ 75% considered high [19]. For heterogeneity I2 > 75%, a leave-one-out method by excluding one study at a time, was utilized to explore the cause of heterogeneity and to confirm the stability of the results. Publication bias was performed for all the outcomes and was assessed through funnel plots and quantified using Egger’s regression test. All statistical work including analyses and graphical illustrations was conducted using STATA (version 17.0, StataCorp) [20].

VJ and JEC independently assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS) for cohort studies and cross-sectional studies [21]. NOS comprises 8 items within 3 domains, and a total maximum score of 9. A study with a score from 7 to 9 was considered to be of high quality; a score of 4–6 was considered to be high risk; whereas a score of 0–3 indicated a high risk of bias. In case of disagreement, a group-based discussion was conducted. The details of quality assessment are presented in Supplementary Table 2.

Results

Study selection

The preliminary database search using the pre-specified keywords yielded 3240 articles, of which 852 studies were excluded after the removal of duplicates. 2254 studies were further excluded post initial title and abstract screening based on the inclusion and exclusion criteria and comparison arm (CS and NS groups). Full-text review was conducted for the remaining 134 articles identified during the search period. 77 full-text articles were retrieved for screening. 63 studies were excluded as they either had unmatching target populations, were not primary research articles, or lacked a comparison arm. Hence, a total of 15 studies that met the eligibility criteria were included in our meta-analysis in which 13 studies are retrospective, and 2 studies are prospective in nature (Table 1). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram is depicted in Fig. 1.

Table 1

Baseline demographics, comorbidities and study characteristics of studies included in the meta-analysis.*.

Variables	Yafasova et al 2020[22]	Rosenthal et al 2021[23]	Louise D Te et al 2017[27]	Nery et al 2014[24]	Rossides et al 2021[25]	Ungprasert et al 2017[26]
Sample (n) Sarcoidosis/ Control	11834/47336	19762/22362202	2237/2237	11/21	8574/84192	345/345
Age, y(Mean)	43.625/43.625	NA	45/46	53.4/52.5	49.5/49.3	45.6/45.4
Female, %	45.7/45.7	NA	57.4/57.57	27.27/42.85	44.6/44.67	50.43/50.43
BMI, kg/m2 (mean)	NA	NA	NA	NA	NA	29.8/27.5
Follow-up(years)	8.68	NA	11.4	1.75	4.875	15.1
COMORBIDITY
HTN, %	9.4/9.4	NA	7.24/8.49	36.36/38.09	18.49/14.37	22/22
DM, %	4.47/4.47	NA	5.54/5.27	9.09/33.34	6.83/3.77	9/8
Dyslipidemia, %	NA	NA	0.94/0.89	NA	9.6/7.4	14/17
Previous MI, %	3.7/3.7	NA	NA	0/4.76	3.95/3.25	NA
Liver Disease, %	1.85/1.02	NA	NA	NA	9.64/7.38	NA
COPD, %	3.2/3.2	NA	4.92/5.45	NA	1.7/0.8	NA

Fig. 1

PRISMA Flow of the search strategy for systematic review and meta-analysis.

Baseline characteristics of included studies

A total of 6 studies [22], [23], [24], [25], [26], [27] were included in our analysis which comprised 42,763 patients in the cardiac sarcoidosis group and 22,496,333 patients in the non-sarcoidosis group. The pooled prevalence of sarcoidosis in our cohort is 13.1% (95% CI 1% to 70%). The overall mean age was 47 years, while the mean for sarcoidosis patients and non-sarcoidosis patients was 46 years and 47.2 years respectively. 54.6% of the entire cohort were male (53.5% Sarcoidosis vs 54.7% Non-sarcoidosis). Baseline comorbidities were comparable between the two groups of patients; hypertension (12.7% Sarcoidosis vs 12.5% Non-sarcoidosis), diabetes mellitus (5.5% Sarcoidosis vs 4% Non-sarcoidosis) and chronic kidney disease (1.7% Sarcoidosis vs 1% Non-sarcoidosis). The prevalence of ischemic heart disease was 3.8% in the sarcoidosis group and 3.4% in the non-sarcoidosis group. Follow-up duration ranged from 1.75 to 15.1 years with an average length of follow-up of 8.4 years.

Meta-Analytical findings

3 studies [22], [23], [27] reported data relevant to our primary outcomes that is all-cause mortality. The pooled analysis of primary endpoints showed that all-cause mortality was significantly higher in patients with CS compared to those without [RR, 2.08 (95% CI: 1.17 to 3.08), p = 0.01, I2 = 98.3%] (Fig. 2).

Fig. 2

Primary outcome forest plot- random effect of all-cause mortality.

Among the secondary outcomes, 3 studies [23], [24], [27] reported data relevant to the ventricular tachycardia, and 5 studies [22], [23], [24], [25], [26] reported on heart failure. The pooled analysis of secondary endpoints showed that incidence of ventricular tachycardia was significantly higher with CS groups compared to those without (RR = 15.3 (95% CI = 5.39 to 43.42, p < 0.001) with moderate heterogeneity (I2 = 60%). The pooled analysis showed that incidence of heart failure was significantly increased with CS compared to those without [RR = 4.96 (95% CI = 2.02 to 12.14), p < 0.001, I2 = 98%]. 2 studies reported data on atrial arrhythmias [22], [26]. It appeared that the incidence of atrial arrhythmias was significantly increased in patients with sarcoidosis [RR, 2.55 (95% CI 1.47 to 4.44), p = 0.01], I2 = 66.7%] (Fig. 3A-C). The quality assessment of the observational studies based on NOS for observational studies showed that there was low risk of bias across all studies. (Supplementary Table 1).

Fig. 3

Secondary outcome forest plot- random effect including (A) Ventricular Tachycardia, (B) Heart Failure (C) Atrial Arrhythmias.

Sensitivity analyses and publication bias

Leave-one-out analysis for heart failure showed that the results remained unaltered in terms of direction and magnitude, as the pooled analysis remained significant upon exclusion of individual study successively, thus confirming the robustness of results (supplementary Figure 1). No evidence of publication bias was found on visual inspection of funnel plots and Egger’s regression test (p = 0.63) for heart failure (Supplementary Figures 2).

Discussion

To the best of our knowledge, this is the first meta-analysis that assesses the incidence of adverse cardiovascular events associated with cardiac sarcoidosis. In the analysis, we found that the mean age of cardiac sarcoidosis patients was 46 years, which was comparable to the previous studies, i.e., 48 years, 50.6 years, and 54.7 years [28], [29], [30]. Considering cardiovascular risk factors, hypertension (12.7%) was the most common comorbidity in the sarcoidosis group [31].

The true prevalence of cardiac sarcoidosis remains uncertain for multiple reasons. Differences in prevalence worldwide is attributable to the lack of standardized diagnostic criteria for the disease [2]. Several mechanisms that linked sarcoidosis to cardiovascular events have been postulated. Most of the mechanisms pertaining to ventricular dysfunction and cardiac abnormalities are directly related to the granulomatous infiltration [32]. Autopsy studies correlate granulomas in the mid- and basal- interventricular septum to conduction disturbances and electrocardiographic abnormalities before death [33]. This granuloma-induced scar tissue develops around the atrioventricular and sinoatrial nodal artery, potentially impeding blood flow, and leading to abnormalities in electrical conduction [32]. Consequently, more than two in three incidents of ventricular arrhythmias are related to late-stage scar formation, with scar-based reentrant circuits leading to slow conduction areas [32].

Although granulomatous inflammations as seen with sarcoidosis can reduce organ functionality, the majority of instances are not life-threatening [32]. However, the fibrosis post granulomatous inflammation can be life-threatening, and may lead to rhythm disturbance, heart block or heart failure [32], [34]. In our study, heart failure was found to be significantly higher in patients with sarcoidosis as compared to non-sarcoidosis patients. Rosenthal and colleagues conducted a study to evaluate the incidence of HF in sarcoidosis and found that HF was significantly higher in those with sarcoidosis (240/1000) than in those without sarcoidosis (12/1000) (P < 0.001)[23]. Similarly, Yafasova and colleagues found a high incidence of HF among patients with sarcoidosis as compared to the non-sarcoidosis control groups [22]. Such trends, which are under-reported, warrant a call to action across cardiovascular societies and at the physician level to conduct adequate screening to diagnose the condition, particularly in those patients diagnosed with sarcoidosis [32]. It is still unclear if the sarcoidosis itself leads to heart failure or whether corticosteroids aggravate diabetes mellitus and/or hypertension and worsen the existing heart failure due to CS. Current guidelines recommend the use of both immunosuppressants to treat cardiac sarcoidosis and/or cardiovascular therapy to treat rhythmic disturbances and ventricular dysfunction [32].

With current recommendations, it is essential to apply early interventions and improve the quality of life of patients living with symptoms of heart failure due to cardiac sarcoidosis. The international statement for the management of sarcoidosis was developed in 1999 by the American Thoracic Society (ATS), European Respiratory Society (ERS), and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) [35]. Two primary decisions of who and when to treat individual sarcoidosis patients include the risk of organ failure/mortality and quality of life [35]. In 2014, the Heart Rhythm Society directed an expert consensus statement on arrhythmia management of CS [36]. The document targeted recommendations and guidance for CS such as treating extracardiac sarcoidosis, screening for cardiac involvement, stratifying the risk of sudden death, managing arrhythmias for electrophysiologists and cardiologists, considering indications for implantable cardioverter-defibrillators, establishing the criteria for diagnosing CS, and finally identifying any gaps in data to help guide clinicians and researchers [36]. The guidelines suggest that cardiac transplantation may be the only viable option for patients with advanced CS [36]. In 2021, the European Respiratory Society’s (ERS) guidelines on the treatment of cardiac sarcoidosis stated that glucocorticoids were recommended for patients with functional heart diseases including cardiomyopathy, dysrhythmias or heart block [35]. However, the level of evidence ERS collated was very low, and there were multiple biases and confounders in the available studies. Majority of the data used in the support of glucocorticoids has been indirect, and the studies have covariates in addition to other outcome predictors [35]. A caveat is that the risk of mortality is high with CS due to reduced left ventricular function; in addition, glucocorticoid use is associated with improved left ventricular ejection fraction [35]. Hence, ERS’s task force members conclude that the dangers of CS can be mitigated with glucocorticoids treatment in clinically relevant CS [35]. However, there is insufficient evidence for treatment with immunosuppressants [35].

Cardiac sarcoidosis and its correlation to conduction abnormalities and tachyarrhythmias has been reported in literature [36]. In our study, the incidence of VT was found to be significantly higher in the sarcoidosis group as compared to the control group. Recent Heart Rhythm Society Consensus guidelines on sarcoidosis have recommended screening patients with unexplained ventricular tachycardia and cardiomyopathy for sarcoidosis and these patients can be considered for Implantable cardioverter defibrillator (ICD) implantation. The epidemiologic data on cardiovascular morbidity in sarcoidosis is sparse and disparate. Our study, for the first time, crystallizes the available data on cardiovascular outcomes in sarcoidosis patients.

A National Inpatient Sample spanning 2010–2014 reported by Desai and colleagues found that nearly one-fifth of sarcoidosis patients suffered from arrhythmias – atrial arrhythmias being the most common subtype (10.97%), followed by ventricular tachycardia (1.97%) [37]. Atrial arrhythmias are not uncommon and are now being recognized as the first clinical manifestation of CS; this study reports collated analytical findings to overcome the data paucity. Our study finds that 440 of 12,179 (36.1%) sarcoidosis individuals had atrial arrhythmia, compared to 1,277 of 47,681 (26.8%) in the non-sarcoidosis group. Supraventricular tachycardia occurs in around one in three patients with sarcoidosis and 96% of patients have documented symptoms associated with atrial arrhythmia [32]. As described earlier, the mechanisms are linked to the granulomatous infiltrate and scar formation. The rising incidence of arrhythmias in current literature, coupled with deteriorating outcomes, and high mortality among patients with sarcoidosis highlights the importance of early diagnosis and therapeutic care.

In our study, all-cause mortality was significantly higher in patients with sarcoidosis as compared to controls, consistent with results in current literature. A study conducted by Etinger and colleagues evaluated the mortality rates due to sarcoidosis in comparison to matched controls from 2000 to 2016; the authors found that there was higher mortality with sarcoidosis (17.8% vs. 10.7%, p < 0.001) [38]. Gonen and colleagues reported deaths with a mean follow-up of 68 months among 15% patients with sarcoidosis as opposed to 9% reported for the control group (9%) [39]. Mortality is multifactorial in the cardiac sarcoidosis, with the leading cause of mortality being heart failure, as reported by Yazkai et al. [40].

Limitations

First, the lack of randomized controlled trials to-date and the observational nature of the included studies meant that the causal-effect relationships could not be established and that the evidence derived from this study may be limited. Second, the number of literatures comparing the risk of future cardiovascular events between these groups are sparse, with several outcome of interest including MACE and stroke being not available in these studies. Third, data on the treatment received by these patients were not reported in most of the studies. Lastly, the observed heterogeneity across the included studies, confounding risk factors, and different criteria to diagnose CS may have affected the implications of the results.

Conclusion

This study finds a higher risk of developing heart failure among participants with sarcoidosis than their matched cohorts, over differing durations of follow ups. A higher risk of developing ventricular arrhythmias, including ventricular tachycardia has been documented employing a representative sample size. There are conflicting results regarding prophylactic ICD implantation in these patients, and further studies are needed to guide management. Finally, we report a higher mortality risk associated with sarcoidosis, that may be associated with the increased risk of heart failure and/or VT that we have reported. Detailed and timely diagnosis utilizing cardiovascular examination techniques are essential to decrease mortality and burden from the disease among patients with sarcoidosis, particularly with cardiac involvement.

Data Availability Statement.

All data used for the purpose of this study is available online or in the Supplementary file.

CRediT authorship contribution statement

Vikash Jaiswal: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Song Peng Ang: Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Zouina Sarfraz: Writing – original draft. Swatika Butey: Writing – original draft. Harshwardhan Vinod Khandait: Writing – original draft. David Song: Writing – original draft. Jia Ee Chia: Writing – original draft. Dipnsha Maroo: Writing – original draft. Muhammad Hanif: Writing – original draft. Mohammed Ghanim: Writing – original draft. Raja Chand: Writing – review & editing. Monodeep Biswas: Writing – original draft, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.