Hypertrophic cardiomyopathy (HCM) is a relatively common genetic cardiac disorder that can appear at any age. It affects men and women equally and is a leading cause of sudden cardiac death (SCD), especially in young adults.1 This is the most devastating result of its natural history. Although there have been numerous studies of HCM patients, no risk stratification strategy will ever be able to predict SCD with absolute certainty.

The neutrophil-to-lymphocyte ratio (NLR) is an easily accessible and widely available novel hematological marker of oxidative stress damage. It also serves as a good prognostic marker and has been studied in patients with infectious diseases, as well as in cases of oncological, hematological, immunological, and cardiac disorders, using a complete blood count, the most commonly performed test in hospitals. Previous research has revealed that it has significant prognostic value, in addition to various positive correlations. The predictive value of NLR in peripheral arterial disease and calcific aortic stenosis, as well as in prognostication of the presence, severity, and extent of coronary artery disease, heart failure, and many other cardiovascular disorders has already been demonstrated.2,3 A high NLR is associated with poor prognosis in the majority of studies. Although the relationship between NLR and almost all cardiovascular disorders has been investigated, the importance of NLR in HCM remains unclear. To the best of our knowledge, few studies have been conducted on the prognostic significance of the correlation between NLR and HCM.

In this study, we aimed to assess whether the presence of high NLR is associated with poor prognosis in HCM and whether NLR is associated with echocardiographic parameters, cardiac arrhythmia, or predicted five-year risk of SCD.

A total of 97 patients (58 male and 39 female) with HCM comprised the patient group, and the control group consisted of 74 age- and gender-matched subjects without HCM (29 male and 45 female). The participants’ demographic and clinical characteristics are summarized in Table 1. There were no significant differences between the patient and control groups with regard to age, gender, or body mass index. Hypertension, hyperlipidemia, diabetes, smoking, and total cholesterol were not statistically different between the two groups.

Medical treatments administered to participants in the patient and control groups are shown in Table 1. Values of NRL, LVMI, nonsustained VT, LA diameter, peak LVOTG, RWTI, and syncope were significantly higher in the patient group than in the control group (2.0±1.3 vs. 1.3±0.3, p<0.001; 178±48 vs. 77±18 g/m2, p<0.001; 16 [16.5%] vs. 0, p<0.001; 42±4.7 vs. 34.6±3.3 mm, p<0.001; 40±38 vs. 0 mmHg; 0.62±0.24 vs. 0.39±0.05, p<0.001; and 11 [11.3%] vs. 0, p<0.003, respectively).

Comparisons of NRL between the groups according to fQRS, LVEF, VT, five-year SCD risk, QTc, syncope, and presyncope in patients with HCM are shown in Table 2. NLR was significantly higher in patients with fQRS, VT, and presyncope than in those without (fQRS [n=59], NLR: 2.2±1.6 vs. no fQRS [n=38], NLR: 1.6±0.4, p=0.031; VT [n=16], NLR: 2.7±2.6 vs. no VT [n=81], NLR: 1.9±0.8, p=0.030; presyncope [n=28], NLR: 2.5±2.1 vs. no presyncope [n=69], NLR: 1.8±0.7, p=0.020) (Figure 1a, c and f). NLR was significantly higher in patients whose left ventricular ejection fraction (LVEF) was <60% (LVEF ≤59.9% [n=16], NLR: 2.7±2.7 vs. LVEF >60% [n=81], NLR: 1.9±0.7, p=0.017) (Figure 1b). NLR was significantly higher in patients whose predicted five-year risk of SCD was over 6% and whose QTc interval was greater than 440 ms (predicted five-year SCD risk >6% [n=39], NLR: 2.4±1.8 vs. ≤5.9% [n=57], NLR: 1.8±0.6, p=0.022; QTc >440 ms [n=35], NLR: 2.7±1.9 vs. ≤439 ms [n=62], NLR: 1.6±0.5, p=0.001) (Figure 1d and e).

Figure 1.

Neutrophil-to-lymphocyte ratio and (a) fragmented QRS, (b) ejection fraction, (c) ventricular tachycardia, (d) predicted five-year risk of sudden cardiac death, (e) corrected QT, and (f) presyncope in patients with hypertrophic cardiomyopathy. fQRS: fragmented QRS; LVEF: left ventricular ejection fraction; NLR: neutrophil-to-lymphocyte ratio; QTc: corrected QT interval; SCD: sudden cardiac death; VT: ventricular tachycardia.

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Correlations between NLR and demographic findings, biochemical parameters, acute phase reactants, and echocardiographic results are presented in Table 3. A statistically significant correlation was found only between QTc and NLR (r=0.251, p=0.013).

In the present study, we investigated whether NLR could be a predictor of cardiac events. The study's most important findings are the following: (1) NLR was significantly higher in HCM patients compared to age- and gender-matched controls; (2) a high NLR appears to be associated with ventricular arrhythmic events in patients with HCM; (3) NLR was significantly associated with QTc interval; (4) a high NLR appears to be associated with the presence of fQRS; and (5) NLR appears to be significantly higher in the high-risk group, those who demonstrated a predicted SCD risk of over 6%.

In the past few years, several studies have been conducted on NLR in patients with both cardiac and noncardiac diseases.8,9 Activated neutrophils represent nonspecific systemic inflammation, and lymphocytes are a marker of the immune system physiological stress response. NLR integrates these two important and opposite immune pathways, and thus serves as a measure of both systemic inflammation and stress response.10 A high NLR has been associated with poor prognosis in most of these studies. In particular, inflammation plays a key role in the initiation and progression of cardiovascular disease. A previous study showed a correlation between NLR and severity of chronic heart failure. NLR may reflect increased sympathetic drive, and therefore oxidative stress and cytokine production, because of the possible influence of the autonomic nervous system on leukocyte subtype distribution.11 Activated neutrophils are known to play a direct role by adhering to and penetrating the ventricular myocardium and releasing reactive oxygen species, cytokines, and hydrolytic enzymes.12 This leads to extracellular matrix remodeling and reparative processes.13 It was perhaps for this reason that LVEF was under 60% in patients with high NLR in the present study.

The precise mechanism of this inflammatory pathway remains unknown; systemic inflammation can lead to infiltration of the myocardium with inflammatory cells, and this condition may cause irregular interstitial fibrosis in atrial and ventricular tissue. Relationships have been demonstrated between the development of atrial fibrillation and interleukin 8, interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) levels, and increased white blood cell (WBC) count.14 Leukocytes release pro-inflammatory cytokines, such as tumor necrosis factor-alpha, IL-6, and C-reactive protein, and can activate neutrophils to release a variety of proteolytic enzymes such as myeloperoxidase, acid phosphatase, and elastase, which facilitate increased tissue destruction and can lead to direct deleterious effects on the myocardium, resulting in irregular fibrous thickening and the formation of arrhythmia foci in the ventricles.15 NLR has been linked to increased risk of ventricular arrhythmias during percutaneous coronary intervention (PCI).10 Chatterjee et al. reported that pre-procedural elevated WBC count, neutrophilia, and elevated NLR were significant predictors of ventricular arrhythmia in patients undergoing PCI.10 In the present study, NLR was higher in patients with VT, a finding consistent with previous studies. This result suggests that more attention should be paid to the possibility of ventricular arrhythmias in patients with high NLR.

The role of QT and QTc prolongation and fQRS in HCM patients has been studied.16–18 Changes in the myocardium caused by LVH lead to heterogeneity in action potentials and to increased duration of repolarization. These result in an increase in QT or QTc interval.19 Kulan et al. demonstrated a significant relation between QTc interval and LVH.20 Similarly, Gray et al. showed that a QTc interval ≥439 ms, independently of the presence of conventional risk factors, predicts appropriate implantable cardioverter-defibrillator (ICD) therapies in HCM patients, with a more than three-fold increase in the risk of appropriate therapies compared to those without prolonged QT.17 It is possible that a separate mechanism (e.g. myocardial fibrosis) may account for QTc prolongation in HCM. In the present study, we observed longer QTc intervals in patients with high NLR. Likewise, it is known that fQRS complexes in multiple ECG leads are associated with myocardial scarring or fibrosis.5,16 Such changes in the myocardium may lead to heterogeneous ventricular activation, which could manifest as fQRS on ECG.5,20 Fractionated electrograms consisting of multiple discrete deflections have been observed in regions where islands of viable myocardial tissue are interspersed with abundant fibrous tissue. In the present study, NLR was significantly higher in patients with fQRS.

The current European guidelines on HCM recommend a practical risk prediction model for SCD in patients with HCM.5 This model, known as HCM Risk-SCD, is relatively simple and easy to calculate and helps guide therapeutic decision-making. According to this method, a predicted five-year SCD risk of over 6% indicates that the patient is at high risk and an ICD should be considered. In the present study, we observed that NLR was significantly higher in patients with a predicted five-year SCD risk over 6%. As discussed above, nonsustained VT caused by irregular myocardial fibrosis may be responsible for higher SCD risk. Our findings indicate that five-year SCD risk may be higher in patients with high NLR.

This was not an epidemiological or randomized study. The sample size (n=97) of HCM patients was relatively small. We included only adult HCM patients; elite athletes and individuals with metabolic diseases (e.g. Anderson-Fabry disease) and relevant syndromes (e.g. Noonan syndrome) were excluded. Inflammatory parameters such as IL-6, tumor necrosis factor-alpha, hs-CRP, and myeloperoxidase were not simultaneously measured and compared with NLR because they are generally not available in daily practice. We were unable to examine all of our patients with CMRI because some patients had pacemakers and some refused to participate.

It is well known that inflammation contributes to progression of cardiac dysfunction and plays a role in worsening of clinical status. Calculation of NLR is a noninvasive, inexpensive, and readily available tool. NLR was significantly higher in patients with HCM compared to the control group. A high NLR is associated with a higher five-year risk of SCD in patients with HCM.

The authors received no financial support for the research, authorship, and/or publication of this article.

The authors have no conflicts of interest to declare.