Low prognostic nutritional index is associated with adverse outcomes in patients with hypertrophic cardiomyopathy

Aim: The aim of the study was to investigate poor nutritional status assessed by prognostic nutritional index (PNI) on the prognosis of patients with hypertrophic cardiomyopathy(HCM). Material and Methods: A total of 420 patients with HCM were assessed. The primary end point was deﬁned as the occurrence of CV death that included sudden cardiac death (SCD), death due to HF and cardioembolic stroke-related death. Results: During the follow-up, primary end point was developed in 25 (6.0%) patients. Receiver operating characteristic (ROC) analysis showed that using a cut-off level of 40, PNI predicted the occurrence of primary end point with a sensitivity of 76% and specificity of 76.7%. In the multivariate model, low PNI was significant predictor of the primary end point. Conclusion: This study showed that lowerPNI level is an independent predictor of CV death in patients with HCM.


Introduction
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiomyopathies characterized by ventricular hypertrophy, myocardial fibrosis, and impaired ventricular relaxation [1]. Myocyte hypertrophy and disarray, interstitial fibrosis as well as small vessel disease are main pathological trademarks of the myocardium in HCM [2]. The clinical course of HCM is highly variable, ranging from asymptomatic status with a normal life expectancy to adverse clinical outcomes such as severely limiting dyspnea, advanced heart failure (HF), systemic embolic events, stroke, malignant arrhythmic events and sudden cardiac death. The annual mortality rate of HCM patients is thought to be about 1%. Sudden cardiac death (SCD) and embolic stroke are major causes of death in patients with HCM [3,4]. In addition, some patients develop systolic dysfunction causing increased morbidity and mortality [5]. Identifying high-risk HCM patients plays a key role in risk stratification, treatment strategy selection, preventing complications and improving outcomes. Although a set of clinical risk factors and imaging results are investigated for risk stratification in HCM patients presently, the clinical outcomes of HCM are still broadly unpredictable given that HCM is generated by various etiologies, has a genetic diversity with heterogeneous and complex clinical expression and the pathophysiological mechanisms are very complicated.
In recent decades, much attention has been given to assess the role of inflammation and oxidative stress in both for pathogenesis and to determine the prognosis of HCM. Several studies established increased circulating inflammatory markers in HCM such as TNF-α, IL-6, MCP-1 and monocyte count to high-density lipoprotein cholesterol ratio(MHR), neutrophil-to-lymphocyte ratio (NLR) [6][7][8][9]. Recent studies have shown that poor nutritional status is associated with increased inflammation and neurohormonal activation, indicating poor prognosis in various cardiovascular diseases. Malnutrition, which is associated with decreased immune system function, impaired respiratory function and poor wound healing, has been shown to be a predictor of outcome in patients with chronic illness, including end-stage renal disease, malignancy and advanced HF [10,11]. Although nutritional status examination is more complex, objective and wellrecognised indices such as prognostic nutritional index (PNI) have been developed. PNI, calculated from the serum albumin concentration and total lymphocyte count, is a simple and objective indicator that assesses immuno-nutritional status of patients [12]. Some studies demonstrated that nutritional status measured by PNI is an independent prognostic factor in patients with various cardiovascular diseases such as acute or chronic HF, ST segment elevation myocardial infarction (STEMI), stable coronary artery disease (CAD). However this association has not been previously assessed in patients with HCM. The aim of the present study was to evaluate PNI on the clinical end points in patients with HCM.

Material And Methods Study population
The study population included 442 consecutive patients clinically diagnosed with HCM at our hospital between October 2003 and December 2016. A diagnosis of HCM was made based on the current guidelines of the American College of Cardiology / European Society of Cardiology (ACC/ ESC), was the presence of a hypertrophied left ventricle with a maximal wall thickness of ≥15 mm on echocardiography in patients without alternative explanations capable of producing a similar degree of hypertrophy or systemic diseases. Individuals with metabolic diseases (e.g, Anderson Fabry disease) and related syndromes (e.g, Noonan syndrome) were eliminated. Patients with clinical conditions other than cardiomyopathy that could increase plasma levels of inflammatory markers such as active cancer, active infection, renal or hepatic insufficiency, chronic inflammatory disease, congenital heart disease, cardiac valve disease were excluded from study. Also patients without a recorded measurement of admission laboratory parameters and sufficient clinical information were excluded. According to these exclusion criteria, 22 patients were excluded from the study and a total of 420 patients were included in the study. Data regarding clinical features, risk profiles, laboratory and echocardiographic parameters of all patients were collected from clinical follow-up visits, patients' files and the electronic database The present study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee.

Echocardiography
On admission to the hospital, all patients underwent transthoracic echocardiography using commercially available ultrasound equipment. They had undergone two-dimensional and M-mode echocardiography with continuous, pulsed and colour Doppler imaging at the time of diagnosis and the last follow-up visit with the Vivid 7 system (GE Healthcare, Wauwatosa, Wisconsin). EF was calculated by using modified Simpson method. Maximum wall thickness was accepted as the greatest thickness in any single segment and was evaluated at end-diastole on the basal, mid or apical short-axis views. LV outflow tract obstruction was measured either in a rest state or during a Valsalva maneuver. Obstructive HCM was defined as LV outflow tract obstruction >30 mmHg.

Laboratory parameters
Peripheral venous blood was drawn from the antecubital vein and was obtained in the morning after a 12-hour fast. All biochemical analyses were determined using standard methods. Body mass index (BMI) was calculated by dividing weight in kilograms by the square of height in metres. Patients were considered to have hypertension if their blood pressure was ≥140/90 mmHg or if they were taking any antihypertensive medication. Diabetes mellitus was defined as fasting blood glucose level of 126 mg/dL or greater and treatment with anti-diabetic medications. PNI was calculated using the following formula: 10 x serum albumin value (g/dL) + 0.005 x total lymphocyte count in the peripheral blood (per mm³). Patients were divided into two groups according to their admission PNI.

Definitions & study end points
The primary end point was defined as the occurrence of CV death that included sudden cardiac death (SCD), death due to HF and cardioembolic stroke-related death. SCD was accepted unexpected and instantaneous collapse leading to death due to any cardiac cause occurring in the absence of symptoms or within 1 h of the onset of symptoms in a patient who had previously experienced a relatively stable or uneventful clinical course or witnessed unexpected death. HF related death was accepted as death preceded by symptoms of heart failure >1h. [13]. The follow-up duration was commenced with the first visit and ended with the occurrence of death or the last visit. Follow up for clinical end points was performed by review of medical records in our hospital. We decided a cardiac event that occurred outside our hospital by phone calls with patients, their relatives and/or their general practitioners. The cause of death was assessed by evaluating the hospital records, official hospital release forms or death certificates obtained from National Survival Registry. All-cause death and presence of NYHA III-IV symptoms were defined as secondary end points.

Statistical analysis
Statistical analysis was performed using the SPSS 20.0 Statistical Package Program for Windows (SPSS, Inc., IL, and USA). Continuous variables were presented as mean ± SD and median with interquartile ranges of appropriate and categorical variables as frequency and percentage. Kolmogorov-Smirnov test was used to test normality of distribution. Differences between groups were evaluated by using Student's t test for normally distributed variables and Mann-Whitney U test for variables without normal distribution. The Chi-square or Fisher's exact test was used to compare categorical variables as appropriate. The association between PNI and development of adverse outcomes of HCM were estimated with univariate and multivariate Cox proportional hazards regression analyses. Survival estimates were calculated by the Kaplan-Meier method and the long-rank test was used for comparison. Receiver operating characteristic curve (ROC) analysis was used to determine the optimum cut-off levels of PNI to predict primary end point. A p-value < 0.05 (using a two-sided test) was considered significant.

Results
We assessed consecutive 420 patients with HCM in this study. Baseline clinical, demographic echocardiographic and laboratory characteristics of the study population were summarized in Table 1. A total of 244 patients (58.1%) were male, and the mean age of the study population was 48.4 ±15.2 years old. After a median (interquartile range) followup period of 6.0 (5.0-8.0) years, primary end point was developed in 25 (6%) subjects (sudden death in 10 (2.4 %), death for progressive HF in 14 (3.3 %) and cardioembolic stroke-related death in 1 (0.2 %)). Patients with CV death had a higher prevalence of atrial fibrillation (44.0% vs.18.2%, p =0.002), higher NYHA class (68.0% vs. 12.7%, p <0.001), higher left atrial diameter (LA) (43.8 ± 4.4 mm vs. 40.9 ± 5.4 mm, p = 0.013), lower ejection fraction (EF) (53.6 ±10.5 mm vs. 60.8 ±7.4 mm, p < 0.001) and higher level of C-reactive protein (CRP) (11.3 (4.8-22.7) vs. 4.8 (3.9-5.8), p< 0.001) compared the patients without CV death. Also serum albumin concentration, serum lymphocyte count and PNI values (37.5±5.0 vs. 43.7 ±4.8, p < 0.001) were significantly lower in patients with CVD than in patients without CV death. Follow-up data and clinical outcomes regarding primary and secondary end points were presented in Table 2. During follow-up period, all-cause death was observed in 34 subjects (8.1%) and presence of NYHA III-IV symptoms was observed in 66 subjects (15.7 %) which were the secondary end points among the study population. Low PNI values were significantly associated with both primary and secondary end points of the study.
We also compared baseline clinical characteristics of the study patients according to PNI levels ( Table 3). The patients in low PNI group (<; n = 140) had a higher prevalence of atrial fibrillation, higher NYHA class, larger LA dimension, larger left ventricular enddiastolic diameter (LVEDD), lower EF, higher values of CRP and lower values of lymphocyte and albümin counts than the patients in high PNI group.  .009 Data are presented mean ± SD or n (%).

Limitations
Our study has several limitations. First; this was a single center, retrospective, observational study. Second; PNI levels were evaluated only once and did not asses their changes over time during the follow-up period. Third; because of methodological limitations of retrospective analysis, it is not possible to define the exact causal relationship between PNI level and adverse cardiovascular outcomes. Hence, the small sample size may limit the power of statistical test in revealing significant predictors and demonstrating the effects of PNI on different subgroups. Further prospective investigations on larger cohorts are necessary to confirm our findings, to clarify the underlying mechanism and to elucidate the prognostic utility of PNI more accurately.

Conclusion and Future Perspectives
This study identified nutritional status assessed by the PNI, a simple index calculated from routine biochemistry and hemogram tests, as an independent predictor of long-term adverse cardiovascular outcomes in HCM patients. Lower PNI scores were associated with CV deaths in HCM patient. This result confirmed that nutritional and immunological situations are important when considering the long-term outcome in patients with HCM. Our study suggested that the PNI might be useful for risk stratification of HCM patients in clinical practice.
Further investigations on independent multicenter cohorts should be performed in order to validate our findings.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research
This study was performed in keeping with the principles outlined in the Declaration of Helsinki and approved by institutional ethics committee of our hospital.