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. 2014 Jul 23;16(9):686–692. doi: 10.1111/jch.12376

Plasma Cardiotrophin‐1 Levels are Associated With Hypertensive Heart Disease: A Meta‐Analysis

Kangxing Song 1,2,†, Shuxia Wang 1,3,†, Bihui Huang 4,†, Amelia Luciano 4, Roshni Srivastava 1, Arya Mani 1,5,✉
PMCID: PMC4159421  NIHMSID: NIHMS606806  PMID: 25052897

Abstract

Cardiotrophin‐1 (CT‐1) is a member of the interleukin 6 cytokine superfamily. Plasma CT‐1 levels have been associated with heart failure and hypertension in small independent studies. Whether plasma CT‐1 levels are associated with progression of hypertensive heart disease is poorly understood. The authors carried out a meta‐analysis using published studies and electronic databases. Relevant data were extracted using standardized algorithms. Additional data were obtained directly from investigators when indicated. A total of 18 studies were included that reported on association between CT‐1 level and hypertension (n=8), cardiac hypertrophy (n=9), and heart failure (HF) (n=10). The serum levels of CT‐1 were significantly higher in patients with hypertension (standard mean difference [SMD], 0.85; 95% confidence interval [CI], 0.64–1.06 fmol/mL), left ventricular hypertrophy (SMD, 0.88; 95% CI 0.60–1.17 fmol/mL), or HF (SMD, 0.66; 95% CI, 0.51–0.80 fmol/mL) compared with controls. Subgroup analysis revealed CT‐1 levels to be highest in patients with hypertension‐induced hypertrophy with HF, followed by patients with hypertension‐induced left ventricular hypertrophy without HF (SMD, 0.52; 95% CI, 0.30–0.75 fmol/mL), patients with hypertension without left ventricular hypertrophy (SMD, 0.67; 95% CI, 0.46–0.88 fmol/mL) as compared with normotensive patients (SMD, 0.74; 95% CI, 10.45–1.04 fmol/mL). Increased plasma CT‐1 levels are associated with risk for HF in hypertensive patients. CT‐1 may serve as a novel biomarker in determining prognosis in hypertensive patients.

Heart failure (HF) is a global public health problem, affecting nearly 26 million people worldwide.1 Despite recent progress in discovery of novel drugs and device therapies, mortality and morbidity rates have remained constant over the past 2 decades.1 Hypertension is considered the leading cause of HF.2, 3, 4 Hypertensive heart disease is characterized by left ventricular hypertrophy (LVH), which represents functional and structural adaptations to increased afterload that ultimately lead to HF.5, 6

Evidence suggests that the severity of hypertension may not predict the risk for developing LVH and eventually congestive HF.7 Hypertensive heart disease is associated with increased risk of death, yet there have been few to no valuable biomarkers that predict the progression from isolated hypertension to hypertensive heart disease in clinical practices.8 Tissue and circulatory levels of inflammatory cytokines, including interleukin (IL) 6, are increased in patients with HF compared with controls.9 Cardiotrophin‐1 (CT‐1) is a member of the IL‐6 cytokine family, which acts on the glycoprotein (GP) 130 transmembrane receptor.10 The human CT‐1 gene is located on chromosome 16p11.1–16p11.2, which encodes a 201 amino acid protein.10 Recent evidence suggests that CT‐1 serves as a biomarker for LVH and impaired cardiac function in hypertensive patients11 and as an important intermediate product of the neurohormonal response to cardiac injury.12 However, these studies have small sample sizes and whether CT‐1 level is associated with the progression of hypertensive heart disease is poorly understood. The aim of this study was to examine whether CT‐1 could serve as a biomarker for predisposition for hypertensive cardiovascular diseases.

Methods

Literature Search

We systematically searched PubMed, Cochrane Library, and Embase databases and reviews and reference lists of relevant papers before February 2014 by using MeSH terms “cardiotrophin‐1” and “CT‐1” paired with the following terms: “hypertension,” “left ventricular hypertrophy,” “hypertrophy,” “heart failure,” “congestive heart failure,” “HT,” “CHF,” and “HF.”

Study Selection

Studies were selected based on all of the following criteria: (1) study design: case‐control study or prospective cohort studies; (2) study population: patients with hypertension, left ventricular hypertrophy with or without hypertension, HF, or impaired myocardial systolic function; and (3) availability of plasma CT‐1 levels.

Quality Assessment

The Newcastle‐Ottawa Scale (NOS)13 was used to assess the quality of the studies employed in this work. The NOS contains 8 items that are categorized into 3 dimensions: selection, comparability, and exposure for case‐control studies. We included only studies with 4 to 9 stars on the NOS scale in our meta‐analysis.

Data Extraction

The following data were extracted from each study: first author's name, year of publication, country, study population, sex, sample size, and CT‐1 level by two independent investigators.

Statistics and Analysis

All data were presented as mean±standard deviation (SD). The value of the SD was calculated if reported in the original article. For P values >.10 by heterogeneity test (χ2‐based Q test), a fixed‐effect model was used and for all others, a random‐effect model.14 As a result of significant heterogeneity of the overall study and its subgroups, a random‐effect model was performed. Heterogeneity was also assessed by I 2 test. The I 2 value was classified by the percentage of the observed study variability caused by heterogeneity rather than chance (I 2=0%–25%, no heterogeneity; I 2=25%–50%, moderate heterogeneity; I 2=50%–75%, large heterogeneity; I 2=75%–100%, extreme heterogeneity).15 Funnel plots were used to assess publication bias. Statistical analyses were performed with Stata software (version 12.0; Stata Corporation, College Station, TX) and REVMAN software (version 5.0; Cochrane Collaboration, Oxford, England).

Results

Search Results

A total of 336 articles were identified through the search, of which 313 were excluded because of either lack of relevance to the meta‐analysis or for not being related to human studies. Full text assessment of the 23 potentially relevant articles resulted in further exclusion of 5 studies (Figure 1). The reasons for exclusion were as follows: Plasma CT‐1 levels were not reported,16 not measured,17 not interpretable,18, 19 or not reported for patients with left ventricular systolic dysfunction.20

Figure 1.

Figure 1

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Flow chart outlining the process of search criteria and study selection.

Study Characteristics

Eighteen studies21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 were included in the meta‐analysis. Fourteen studies19, 20, 21, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35 had a case‐control design and 4 were prospective cohort studies.25, 26, 30, 38 For analysis of prospective cohort studies, the baseline CT‐1 levels were used. Ten studies measured the CT‐1 level in hypertensive populations19, 20, 21, 22, 23, 24, 27, 30, 34, 35; the other 8 studies measured CT‐1 level in patients with chronic HF,30, 31, 33, 34, 38 hypertrophic cardiomyopathy,27 dilated cardiomyopathy,28 or chronic kidney disease (CKD).35 The age of the patients varied from 44.1 to 69.5 years. The major characteristics of the studies are shown in the 1.

Table 1.

Characteristics of the Study Populations in the Included Studies on Hypertension, LVH, and HF

References Country Patients, No. Age, y Men, %
Case Control Cases Control Cases Control
Studies on hypertension
Gkaliagkousi 201424 Greece Hypertensives (n=45) Normotensives (n=25) 44.1±7.2 42.6±6.7 44.44 60
Gonzalez 200525 Spain Hypertensives with LVH (n=47) Normotensives (n=31) 60±2 55 (40–68) 70.21 74.19
Lopez 200537, 41 Spain Hypertensives (n=111) Normotensives (n=31) 57.55±0.86 54.97±1.17 69.37 74.19
Lopez 200726 Spain Hypertensives without LVH (n=67) Normotensives (n=31) 58±1 55 (40–68) 59.7 74.19
Lopez 200929 Spain Hypertensives without LVH (n=64) Normotensives (n=29) 56±1 50±2 53.13 75.86
Moreno 201321 Spain Hypertensives without LVH (n=42) Normotensives (n=18) 56±1 50±2 78.57 77.78
Pemberton 200523 New Zealand Hypertensives (n=59) Normotensives (n=31) 65.5±1.6 61.3±1.8 84.75 83.87
Ravassa 201322 Spain Hypertensives (n=278) Normotensives (n=25) 58.6±9.3 57.5±5.5 78 76
Studies on LVH
Gonzalez 200525 Spain Hypertensives with LVH persisted at follow‐up (n=24) Hypertensives with LVH regressed at follow‐up (n=23) 61±2 59±2 62.5 78.26
Lopez 200537, 41 Spain Hypertensives with LVH (n=57) Hypertensives without LVH (n=54) 59.33±1.06 55.67±1.33 73.68 64.81
Lopez 200726 Spain Hypertensives with LVH (n=51) Hypertensives without LVH (n=67) 59±1 58±1 64.71 59.7
Lopez 200929 Spain Hypertensives with LVH without heart failure (n=58) Hypertensives without LVH (n=64) 59±1 56±1 72.41 53.13
Monserrat 201127 Spain Hypertrophic cardiomyopathy (n=124) Normal control (n=29) – – 63 –
Moreno 201321 Spain Hypertensives with LVH (n=80) Hypertensives without LVH (n=42) 59±1 56±1 81.25 78.57
Ravassa 201322 Spain Hypertensives with LVH (n=178) Hypertensives without LVH (n=100) – – – –
Cottone 200735 Italy Hypertensives with LVH (n=14) Hypertensives without LVH (n=41) 50±12 56.36
Cottone 200735 Italy CKD with LVH (n=30) CKD without LVH (n=34) 57±16 56.25
Tsutamoto 200128 Japan DCM with large LVMI (n=26) DCM with small LVMI (n=25) 52.2±2.0 57.9±3.2 50 72
Studies on heart failure
Gonzalez 200732 Spain HF hypertensives (n=24) Non‐HF hypertensives (n=28) 31–81 39–75 70.83 60.71
Ng 200233 United Kingdom HF (n=40) Healthy patients (n=40) 56.3±2.1 56.2±2.7 85 77.5
Limongelli 201430 Italy HF (n=52) Healthy patients (n=60) 56±11 52±9 75 –
Lopez 200929 Spain Hypertensives with LVH and HF (n=39) Hypertensives with LVH without HF (n=58) 63±2 59±1 74.36 72.41
Lopez 201436 Spain Hypertensives with HF (n=31) Healthy patients (n=20) 63.65±2.21 59.15±3.48 81 80
Ravassa 201322 Spain Hypertensives with LVH and impaired MSF (n=67) Hypertensives with LVH and normal MSF (n=106) – – – –
Talwar 199931 United Kingdom HF (n=12) Healthy patients (n=10) 69.5 (64–81) 66.5 (56–79) 66.67 50
Talwar 200034 United Kingdom HF (n=15) Healthy patients (n=15) 66 (43–84) 60 (30–79) 73.33 40
Tsutamoto 200128 Japan HF (n=51) Healthy patients (n=16) 55 (17–78) 54 (26–75) 64.71 –
Tsutamoto 200738 Japan Nonsurvivors of HF (n=56) Survivors of HF (n=69) 64.3±15.4 60.1±11.6 64.9 80.7
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Abbreviations: CVD, cardiovascular disease; DCM, dilated cardiomyopathy; HF, heart failure; LVH, left ventricular hypertrophy; LVMI, left ventricular myocardial infarction; MSF, myocardial systolic function.

Association of CT‐1 Level With Hypertension, LVH, and HF

The meta‐analysis of CT‐1 level in patients with hypertension (8 studies) showed significantly higher levels in the hypertensive population compared with the control population (standard mean difference [SMD], 0.85; 95% confidence interval [CI], 0.64–1.06 fmol/mL; P<.0001) (Figure 2). There was no significant calculated heterogeneity (heterogeneity χ2=0.037, I 2=39.8%; P heterogeneity=.113), indicating a robust association (Figure 2). A subgroup analysis of hypertension patients without LVH, specified in the 5 studies, further confirmed higher CT‐1 levels in patients with hypertension compared with normotensives (SMD, 0.74; 95% CI, 10.45–1.04 fmol/mL; P<.0001) (Figure 3). The measured heterogeneity for this analysis was slightly increased (heterogeneity χ2=0.059, I 2=52.9%; P heterogeneity=.075) (Figure 3).

Figure 2.

Figure 2

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Random‐effect meta‐analysis of standard mean differences (SMDs) (95% confidence interval [CI]) of cardiotrophin‐1 in overall patients with hypertension, left ventricular hypertrophy, and heart failure as compared with controls.

Figure 3.

Figure 3

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Subgroup random‐effect meta‐analysis of standard mean differences (SMDs) (95% CI) of cardiotrophin‐1 in hypertensive patients (including hypertension without left ventricular hypertrophy [LVH] vs normotensives, hypertensive LVH vs hypertension without LVH, hypertensive LVH with HF vs hypertensive LVH without heart failure).

Next, we performed the meta‐analysis of 9 studies that reported an association between plasma CT‐1 level and LVH. The result showed that the plasma CT‐1 level was higher in patients with LVH than those without LVH (SMD, 0.88; 95% CI, 0.60–1.17 fmol/mL; P<.001) (Figure 2), with a modest increase in degree of heterogeneity (heterogeneity χ2=0.157, I 2=77.9%; P heterogeneity<.001). The major confounding factor was the heterogeneity of the control population. While 7 studies used patients with hypertension without LVH as controls, 3 other studies used healthy participants, patients with CKD without hypertrophy, or patients with dilated cardiomyopathy (DCM) with low left ventricular mass index (LVMI) as controls (Table II). In addition, one study included cases with LVH and dilated cardiomyopathy. A subgroup analysis of hypertensive patients with LVH and without LVH showed that plasma CT‐1 levels are significantly higher in hypertensive patients with LVH compared with those without (SMD, 0.67; 95% CI, 0.46–0.88 fmol/mL; P<.0001) (Figure 3). Slightly increased heterogeneity was found in this analysis (heterogeneity χ2=0.041, I 2=52.4%; P heterogeneity=.05) (Figure 3).

Finally, we analyzed the data pooled from the 10 studies to determine whether plasma CT‐1 level correlated with HF. In these studies, cases were specified as patients with hypertension‐related HF or nonspecific HF, whereas controls consisted of either hypertensive patients with no HF or healthy participants. The results showed that plasma CT‐1 levels are significantly higher in patients with HF than in controls (SMD, 0.66; 95% CI, 0.51–0.80 fmol/mL) (Figure 2). The calculated heterogeneity was negligible (heterogeneity χ2=0, I 2=0%; P heterogeneity=.57). A subgroup analysis of patients with hypertension and HF caused by hypertensive heart disease revealed that CT‐1 levels are significantly higher in hypertensive patients with LVH and HF compared with those with LVH but without HF (SMD, 0.52; 95% CI, 0.30–0.75 fmol/mL; P<.00001) (Figure 3). No heterogeneity was found in the analysis (heterogeneity χ2=0, I 2=0%; P heterogeneity=.62) (Figure 3).

Publication Bias

Funnel plots for all studies except for patients with LVH (Egger test, P=.012) were symmetric, excluding significant publication bias (Figure 4). The publication bias was significantly lower in the subgroup analysis of patients with LVH and hypertension (Egger test, P=.05) (Figure 5).

Figure 4.

Figure 4

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Begg's funnel plot (with pseudo 95% confidence limits) of all studies included in the meta‐analysis. s.e indicates standard error; SMD, standard mean difference.

Figure 5.

Figure 5

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Begg's funnel plot (with pseudo 95% confidence limits) of subgroup studies of hypertension in the meta‐analysis. s.e indicates standard error; SMD, standard mean difference.

Discussion

Our meta‐analysis demonstrates that patients with hypertension, LVH, and HF have higher CT‐1 levels as compared with controls. The subgroup analysis of hypertensive patients revealed that those with hypertensive LVH and HF have the highest plasma CT‐1 levels, followed by those with hypertension‐induced LVH without HF and patients with hypertension without LVH compared with normotensive patients. Thus, CT‐1 may serve as a biomarker for the severity of heart disease in hypertensive patients.

Most studies19, 20, 21, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35 included in our analysis had a case‐control design. Four studies used prospective cohort designs.25, 26, 30, 38 To ensure comparability of the trials, baseline CT‐1 levels were used for the analysis of prospective cohort design. Two studies measured plasma CT‐1 level in relation to the regression of LVH.25, 26 The results suggested that plasma CT‐1 decreases in patients with the regression of LVH. Two studies30, 38 evaluated the prognostic role of CT‐1 in patients with HF. The results suggested that CT‐1 could be an independent predictor for cardiac events in patients with HF. The above prospective cohort studies suggest that CT‐1 may be useful in monitoring treatment efficacy and prognosis of patients with HF. Larger prospective, randomized, controlled trials are needed to confirm our findings.

CT‐1 is released from the myocardium, vascular endothelium, and adipose tissue.10 The synthesis and secretion of CT‐1 are regulated by a variety of factors, including mechanical stretch of the cardiac myocytes, hypoxia, and reactive oxygen species.6, 39 CT‐1 also causes hypertrophy in both neonatal and adult cardiomyocytes.40 The long‐term effect of CT‐1 on cardiac function, however, remains controversial. Paradoxically, a few studies have suggested CT‐1 to be cardioprotective.41 Therefore, the cardiovascular effect of CT‐1 remains to be determined by further studies.

Study Limitations

The present study has several limitations. The most limiting factor was the small sample size of most studies. The second limitation was the restricted number of subanalyses carried out in each study. This resulted in smaller sample size for the subanalysis. Finally, a major confounding factor was the heterogeneity among cases and controls. Therefore, careful selection of cases and controls in larger studies are required to firmly establish the association between CT‐1 levels and HF in hypertensive patients.

Conclusions

Our meta‐analysis provides strong support for the prognostic value of CT‐1 in patients with hypertension. Early detection of patients with elevated plasma CT‐1 levels may result in early implementation of effective preventive strategies to improve clinical outcomes. Future studies are needed to determine whether plasma CT‐1 levels should be routinely measured as a prognostic indicator and/or for monitoring response to treatment in hypertensive patients. Our findings also generate several hypotheses for future studies. As a member of the IL‐6 family of pro‐inflammatory cytokines, CT‐1 may be involved in inflammatory processes that lead to development of HF. Thus, whether CT‐1 has independent biological effects or is solely a biomarker of inflammation needs to be determined. Furthermore, if tight control of blood pressure will result in normalization of CT‐1 levels and improved outcome in patients with elevated levels should be examined. Finally, the effect of different classes of antihypertensive medications including those with known biological effects on myocardial function on cardiovascular outcome in patients with elevated CT‐1 levels has to be determined.

Disclosures

This study was supported by National Institutes of Health grant R01HL094784‐05 (to A.M.).

Conflicts of Interest

None.

J Clin Hypertens (Greenwich). 2014;16:686–692. © 2014 Wiley Periodicals, Inc.

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