Clinical significance of central systolic blood pressure in LV diastolic dysfunction and CV mortality.

BACKGROUND AND AIMS: Cardiovascular (CV) disease is the major cause of death in patients with end-stage kidney disease (ESKD). Left ventricular (LV) diastolic dysfunction reflects LV pressure overload and is common in patients with ESKD. Recently, there have been studies on the usefulness of central blood pressure (BP); however, the relationship between central BP and LV diastolic dysfunction is not clear in dialysis patients with preserved systolic function. The purpose of this study was to investigate the clinical implication of central BP on LV diastolic dysfunction and CV mortality in the ESKD patients with preserved LV systolic function.
METHODS: This prospective observational cohort study investigated the effect of LV diastolic dysfunction on CV mortality in the ESKD patients with preserved systolic function using echocardiography. Vascular calcification was evaluated using the abdominal aortic calcification score, and aortic stiffness was determined by measuring pulse wave velocity (PWV). The predictors of CV mortality were analyzed using Cox proportional hazard analysis.
RESULTS: The subjects were comprised of 61 patients, with an average age of 54 years, 20 males (32.8%), and 25 diabetics (41.0%). There were 39 patients on hemodialysis and 22 patients receiving peritoneal dialysis treatment. During the mean follow-up period of 79.3 months, 16 patients (26.2%) died, and 7 patients (11.4%) died of CV events. The central systolic BP and diabetes were independent risk factors for LV diastolic dysfunction. In addition, patients with LV diastolic dysfunction had an increased CV mortality. When left atrial volume index and PWV were adjusted, the E/E' ratio was found to be a predictor of CV mortality.
CONCLUSIONS: Central systolic BP and diabetes were found to be significant risk factors for LV diastolic dysfunction. LV diastolic dysfunction can independently predict CV mortality in dialysis patients with preserved LV systolic function.

Introduction

Left ventricular (LV) diastolic dysfunction is frequently observed in dialysis patients and is associated with heart failure and higher cardiovascular (CV) mortality. The prevalence and severity of LV diastolic dysfunction gradually increase as kidney function deteriorates, and it occurs in approximately 54.3% of patients on hemodialysis (HD), even in those without apparent symptoms [1]. The known risk factors of LV diastolic dysfunction are age, hypertension, diabetes, ischemic heart disease, and LV hypertrophy (LVH). These factors are often associated with the development of myocardial fibrosis and decreased ventricular compliance [2]. LVH is frequently complicated, accompanied by myocardial fibrosis and LV dysfunction [3]. These structural changes predispose the cardiovascular system of patients with ESKD to LV dysfunction. Of note, regression of LVH in patients with end-stage kidney disease (ESKD) was found to have a favorable and independent effect on CV mortality [4, 5].

The most important cause of mortality in patients with ESKD is cardiovascular disease (CVD); 50% of dialysis patients die of CVD [6, 7]. CVD-related risk factors and adaptive alterations include LVH and LV dilatation with concomitant LV systolic and diastolic dysfunction [8]. The pathophysiologic adjustment of ESKD includes endothelial dysfunction, volume or pressure overload, and LV systolic and diastolic dysfunction [9]. These alterations are also thought to play an important role in CV morbidity and mortality [8]. Kang et al. stated that LV diastolic dysfunction is an independent predictor of CV events in patients with ESKD with preserved systolic function [10]. Furthermore, the tissue Doppler imaging (TDI) parameters may reflect the impairment of LV pressure overload and diastolic dysfunction defined by TDI, and is an independent predictor of mortality in patients with ESKD with preserved LV systolic function [11].

Central blood pressure (BP) exhibits a strong association with LV filling pressure and LV diastolic dysfunction [12], and the measurement of central BP is better related to future CV events compared to brachial BP [13, 14]. However, there is limited data evaluating the value of predicting CV risk via central BP measurement in patients with ESKD [15]. Furthermore, the clinical implication of central BP and LV diastolic dysfunction on CVD mortality remains unclear. Therefore, the purpose of this study was to determine the impact of LV diastolic dysfunction on CV mortality in patients with ESKD with preserved systolic function and to analyze the relationship between central BP and LV diastolic dysfunction.

Materials and methods

Study population

This single-center prospective observational study enrolled patients who had undergone HD or peritoneal dialysis (PD) from April 1, 2011, to December 31, 2013. In addition, patients were followed to assess CV mortality until May 31, 2020. This study was conducted at Hallym University Kangnam Sacred Heart Hospital (Seoul, Korea). It involved patients with ESKD who were older than 20 years and who had been undergoing HD or PD for more than 3 months. Patients with CVD within the last 3 months; ejection fraction (EF) of less than 50% or mitral regurgitation (MR) grade II or higher; or history of active infection, malignancy, chronic lung disease, or rheumatoid disease were excluded from the study. This study was approved by the Institutional Review Board of Hallym University Kangnam Sacred Hospital (IRB No: 2010-08-061). Informed written consent was obtained from each patient before participation in the study.

Clinical and biochemical parameters

CVD was defined as a history of coronary, arrhythmia, peripheral vascular disease or cerebrovascular disease. Hypoalbuminemia was defined as a serum albumin level of less than 4.0 g/dL and a hemoglobin level of less than 10 g/dL. Requiring treatment with an erythropoiesis stimulation agent was defined as anemia. Baseline parameters including demographic, laboratory, and dialysis-related data were collected during study enrollment. Blood samples were obtained before the midweek dialysis session of HD patients and 2 hours after the first PD exchange with 1.5% dextrose dialysate of PD patients using standard techniques. The following data were measured: levels of hemoglobin, blood urea nitrogen, serum creatinine, calcium, phosphorus, albumin, total cholesterol, triglyceride, intact parathyroid hormone, alkaline phosphatase, and high-sensitivity C-reactive protein. Kt/V was calculated using the logarithmic estimate of the Daugirdas method [16].

Estimation of central blood pressure

The central BP, pulse pressure, and augmentation index (AI) were measured by pulse waves detected in the radial artery pressure waveforms using the HEM-9000AI (Omron Healthcare, Kyoto, Japan) [17]. The augmentation of central BP is a manifestation of early wave reflection and is the boost of pressure from the first systolic shoulder to the systolic pressure peak. Augmentation is calculated as the difference between the second and first systolic shoulder of the central pressure wave curve, and AI is expressed as the percentage of augmentation from PP. Because AI is influenced in an inverse and linear manner by heart rate according to Wilkinson et al. [18], it was normalized for a heart rate of 75 bpm (AI@75). For HD patients, central BP, pulse pressure, and AI were measured before and after dialysis.

Assessment of brachial-ankle Pulse Wave Velocity (PWV), Ankle Brachial Index (ABI) and Abdominal Aortic Calcification (AAC)

The brachial-ankle PWV was obtained using a waveform analyzer (VP-2000; Colin Co Ltd, Komaki, Japan) as previously described [19]. ABI was measured according to the recommended method [20]. The AAC of the subjects was measured at the start of the study. The AAC score was calculated using a previously validated method by Kauppila et al. [21]. Lateral lumbar radiographs were obtained using a standard radiographic equipment. The severity of the anterior and posterior aortic calcification was graded individually on a 0–3 scale for each lumbar segment (L1–L4), and the results were summarized to develop the AAC score (range 0–24).

Echocardiography

Transthoracic echocardiograms were performed at baseline on the non-dialysis day for HD patients or during the dwell phase of PD patients and were obtained by fundamental imaging (two-dimensional), M-mode, and tissue Doppler imaging (TDI)) using a 2.5-MHz transducer and a commercial ultrasound system (Vivid 7, GE Vingmed Ultrasound AS, Horten, Norway). Chamber dimension, wall thickness, and LV ejection fraction (EF) were measured (M-mode), and the mitral annular velocities were obtained by tissue Doppler imaging (TDI). The left atrial (LA) dimension was determined from M-mode echocardiograms using a leading-edge to leading-edge technique, measuring the maximal distance between the posterior aortic root wall and the posterior LA wall at the end systole [22]. LA enlargement was defined as a larger left atrial volume index (LAVI) of 34 mm/m2 in both sexes [23, 24]. We measured the early transmitral flow velocity (E), early mitral annular velocity (E’), and calculated the E/E’ ratio. The E/E´ ratio reflects the mean LV diastolic pressure, and an E/E’ ratio of greater than15 indicates LV diastolic dysfunction [25]. Based on the report, LV diastolic dysfunction was defined as an E/E’ ratio greater than 15. LV mass was calculated using the formula LV mass (g) = 0.8 × [1.04 × (left ventricle internal dimension diastole (LVIDd) + posterior wall (PW) + inter-ventricular septum diastole (IVSd))3 - (LVIDd)]3 − 0.6, and LV mass index (LVMI) was calculated as LV mass (in g)/ body surface area. According to the current American and European guidelines, LVH was defined as an LVMI of at least 115 g/m2 in men and 95 g/m2 in women [26]. LV systolic function was assessed by calculating the EF using a modified Simpson’s method, and LV systolic dysfunction was defined as EF <50% [27]. Echocardiography was performed by an experienced specialist who was blinded to patient information.

Statistical analysis

Statistical analyses were performed using the SPSS software version 21 (IBM Corp., Armonk, NY, USA). Summary statistics are expressed as means ±, standard deviations, or medians for continuous variables, and as frequencies or percentages for categorical variables. Continuous variables were analyzed using the Mann–Whitney U test. Spearman’s correlation coefficient analysis was used to evaluate the linear relationship between two continuous variables. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. The patients were divided into two groups according to their E/E’ ratio. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors of LV diastolic dysfunction. The Kaplan–Meier method for survival analysis, and log-rank test were used to compare the survival rate differences between patients with and without LV diastolic dysfunction. Cox proportional- hazards regression models were constructed to evaluate the influence on CV mortality. A p-value of less than 0.05 was considered statistically significant.

Results

Baseline characteristics

Of the 75 patients, only 61 participated in this study, excluding 14 patients with an EF of less than 50% or an MR grade of II or higher. The study subjects were divided into two categories: with or without LV diastolic dysfunction based on the E/E’ ratio of 15. The mean age of the 61 patients was 54.1±12.5 (range, 29–81 years), and 20 patients (32.8%) were men (Table 1). The underlying cause of ESKD was diabetes in 25 patients (41.0%). Among all patients, 25 (41.0%) had a past history of CVD. The mean dialysis vintage was 50.8 (range, 4–249) months. Overall, 67.2% of the patients had LVH and 44.3% had an E/E’ ratio of 15 or higher. When compared based on the E/E’ ratio of 15, the central systolic BP and pulse pressure were significantly higher in the higher E/E’ ratio group than in the lower E/E’ ratio group (p<0.005). PWV and AAC scores were significantly increased in patients with a higher E/E’ ratio (p<0.05), but the ABI did not differ between the two groups. LA dimension and LAVI were significantly higher in the higher E/E’ ratio than in the lower E/E’ ratio group (p<0.05). There was no difference in the ratio of LVH between the two groups. Serum levels of hemoglobin and albumin did not differ between the two groups.

Table 1

Baseline characteristics of the study population according to E/E’ ratio at baseline.

	All	E/E’ ratio ≤15	E/E’ ratio >15	p value
	(n = 61)	(n = 34)	(n = 27)
Demographic data
Age, years	54.1±12.5	52.3±13.5	56.5±10.7	0.180
Male, n (%)	20 (32.8)	12 (35.3)	8 (29.6)	0.363
HD, n (%)	39 (63.9)	19(55.9)	20(74.1)	0.114
Comorbidities, n (%)
Diabetes Mellitus	25 (41.0)	7 (20.6)	18 (66.7)	0.001
Cardiovascular disease	25 (41.0)	11 (32.4)	14 (51.9)	0.104
Dialysis vintage, years	4.1±3.9	3.6±2.9	4.9±4.9	0.206
BMI, kg/m2	22.6±3.3	22.9±3.4	22.3±3.1	0.439
Kt/V	1.52±0.28	1.57±0.25	1.46±0.31	0.119
Central systolic BP, mmHg	150.2±26.6	141.7±25.8	160.9±23.9	0.004
Central diastolic BP, mmHg	79.4±13.9	81.2±11.4	77.0±16.7	0.255
Central pulse pressure, mmHg	70.5±22.8	60.8±20.6	82.8±19.6	0.000
AI, %	80.4±17.2	77.1±17.6	84.6±12.6	0.078
AI@75, %	80.7±16.5	77.8±17.6	84.4±14.4	0.121
PWV, m/sec	1.68±0.4	1.58±0.37	1.82±0.42	0.018
ABI	1.47±1.20	1.18±0.10	1.21±0.12	0.236
Presence of AAC, n (%)	33 (54.1)	15(44.1)	18(66.7)	0.121
AAC score	3.4±4.7	2.1±3.4	5.0±5.6	0.020
Laboratory data
Hemoglobin, g/dL	10.1±1.0	10.1±0.9	10.2±1.0	0.605
hs-CRP, mg/L	2.7±4.6	2.8±5.4	2.6±3.1	0.868
Albumin, g/dL	3.9±0.4	3.9±0.4	3.9±0.4	0.487
Total cholesterol, mg/dL	151.9±35.9	147.6±32.9	157.6±39.6	0.270
iPTH, pg/mL	187.4±186.6	170.3±160.7	210.5±217.9	0.391
Calcium, mg/dL	8.6±0.8	8.6±0.8	8.7±0.8	0.969
Phosphorus, mg/dL	4.6±1.5	4.6±1.7	4.9±1.3	0.959
Echocardiography
LAD, mm	54.9±23.8	49.2±23.5	62.1±22.6	0.035
LAVI, ml/m2	33.6±13.1	29.9±12.8	38.2±12.2	0.012
LVMI, g	128.6±41.6	121.0±40.9	138.2±41.2	0.110
LVH, n (%)	41(67.2%)	22 (64.7)	19 (70.3)	0.425
EF, %	64.4±6.6	66.4±6.2	61.9±6.5	0.009

AI, augmentation index; AI@75, augmentation index and normalized for heart rate equal 75 beats/minute, ABI, ankle brachial index; AAC, abdominal aortic calcification; BMI, body mass index; BP, blood pressure; LAD, left atrial dimension; LAVI, left atrial volume index; LVMI, Left ventricular mass index; LVH, left ventricular hypertrophy; E, early diastolic mitral inflow velocity; E`, early diastolic mitral annular velocity; EF, ejection fraction; hs-CRP, high-sensitivity C-reactive protein; iPTH, intact parathyroid hormone.

LV diastolic dysfunction and predictors of CV mortality

The mean follow-up duration was 79.3±40.0 months. A total of 16 (26.2%) patients died during the follow-up period. Seven (43.8%) of the 16 deaths were due to CVD. Three out of seven died from myocardial infarction, one from sudden cardiac death, and the other three from stroke. Of all the deaths, 9 were because of infections such as pneumonia, peritonitis, and sepsis. All-cause mortality was not significantly different between patients with or without LV diastolic dysfunction (p = 0.283). However, Kaplan-Meier survival analysis showed that the cumulative incidence rates of CV mortality were significantly higher in patients with LV diastolic dysfunction (log-rank test, p = 0.021, Fig 1). The E/E’ ratio was a significant risk factor, as revealed by multivariate Cox regression proportional hazard analysis for CV mortality (hazard ratio [HR] = 1.150, 95% confidence interval [CI] = 1.010–1.309, p = 0.034; Table 2).

Fig 1

Kaplan-Meier survival curves for CV mortality according to LV diastolic dysfunction.

CV mortality was significantly higher in patients with LV diastolic dysfunction (log-rank test, p = 0.021).

Table 2

Cox regression analysis of proportional hazard for CV mortality.

	Univariate			Multivariate
	Hazard ratio	95% CI	p value	Hazard ratio	95% CI	p value
Age, year	1.017	0.960~1.078	0.570
Male	1.624	0.363~7.258	0.526
HD over PD	1.372	0.266~7.071	0.706
History of CVD	1.959	0.438~8.755	0.379
BMI, kg/m2	1.129	0.931~1.370	0.218
Central systolic BP, mmHg	1.007	0.979~1.036	0.613
Central diastolic BP, mmHg	0.964	0.893~1.041	0.347
PWV, m/sec	1.001	1.000~1.003	0.078	1.001	0.998~1.003	0.638
Presence of AAC	2.141	0.415~11.036	0.363
Hypoalbuminemia	1.196	0.268~5.351	0.814
Anemia, g/dL	1.081	0.242~4.830	0.919
hs-CRP, mg/L	1.007	0.866~1.170	0.930
LAVI, ml/m2	1.053	1.001~1.108	0.046	1.038	0.977~1.102	0.226
E/E’ ratio	1.189	1.068~1.324	0.002	1.150	1.010~1.309	0.034

AAC, abdominal aortic calcification; BP, blood pressure; CVD, cardiovascular disease; BMI, body mass index; LAVI, Left atrial volume index; PWV, pulse wave velocity; PP, pulse pressure; HD, hemodialysis; PD, peritoneal dialysis; E, early diastolic mitral inflow velocity; E`, early diastolic mitral annular velocity.

Independent risk factor for LV diastolic dysfunction

In univariate logistic regression analysis, the risk factors for LV diastolic dysfunction were identified as diabetes, central systolic BP, PWV, and AAC score. However, multivariate logistic regression analysis showed that central systolic BP (HR = 1.034, 95% CI = 1.002–1.068, p = 0.036) and diabetes (HR = 9.373, 95% CI = 2.382–36.883, p = 0.001) were significant independent risk factors for LV diastolic dysfunction (Table 3). Central systolic BP showed a significant positive correlation with the E/E’ ratio (r = 0.441, p = 0.000; Fig 2A) and LAVI (r = 0.394, p = 0.005, Fig 2B). In addition, PWV (r = 0.510, p = 0.000) and AAC score (r = 0.286, p = 0.025) had a significant positive correlation with central systolic BP. However, central diastolic BP had no correlation with the E/E’ ratio, LAVI, PWV, and AAC score.

Table 3

Univariate and multivariate logistic regression analysis for LV diastolic dysfunction.

		Univariate			Multivariate
	Beta	Hazard ratio	P value	Beta	Hazard ratio	P value
		(95% CI)			(95% CI)
Age, year	0.022	1.023(0.980~1.067)	0.304
Male	0.000	1.000(0.350~2.858)	1.000
DM	2.043	7.714(2.433~24.456)	0.001	2.238	9.373(2.382~36.883)	0.001
HD versus PD	0.714	2.042(0.707~5.895)	0.187
Central systolic BP	0.031	1.031(1.008~1.055)	0.007	0.034	1.034(1.002~1.068)	0.036
Central diastolic BP	-0.015	0.985(0.949~1.023)	0.434
BMI, kg/m2	-0.075	0.928(0.791~1.089)	0.360
Dialysis vintage, years	-0.016	0.985(0.856~1.132)	0.827
PWV, m/sec	0.002	1.002(1.000~1.003)	0.027	-0.001	0.999(0.997~1.001)	0.490
AAC score	0.148	1.160(1.023~1.314)	0.020	0.155	1.168(0.989~1.378)	0.067
Hypoalbuminema	-0.223	0.800(0.290~2.205)	0.666
Anemia, g/dL	0.018	1.018(0.364~2.845)	0.973
Calcium, mg/dL	0.066	1.068(0.572~1.994)	0.836
Phosphorus, mg/dL	0.034	1.034(0.739~1.447)	0.844
iPTH, pg/mL	0.001	1.001(0.999~1.004)	0.333
hs-CRP, mg/L	-0.015	0.985(0.879~1.103)	0.792

AAC, abdominal aortic calcification; BMI, body mass index; DM, diabetes mellitus; SBP, systolic blood pressure; iPTH, intact parathyroid hormone; PWV, pulse wave velocity; HD, hemodialysis; PD, peritoneal dialysis.

Fig 2

A) Central systolic BP had positive correlation with E/E’ ratio (r = 0.441, p <0.001), B) Central systolic BP and LAVI had positive correlation (r = 0.394, p = 0.005).

Discussion

This study revealed that LV diastolic dysfunction increased CV mortality in patients receiving HD and PD. The E/E’ ratio was a significant factor for CV mortality. Central systolic BP was a significant independent risk factor for LV diastolic dysfunction. Furthermore, central systolic BP had a significant positive correlation with E/E’ ratio and LAVI.

Elevated LV filling pressure is the main physiological finding in LV diastolic dysfunction and is associated with symptom onset [2]. The E/E’ ratio and LAVI have been shown to reliably assess LV diastolic dysfunction in dialysis patients as well as in the general population [28]. LV diastolic dysfunction is an independent predictor of CV morbidity and mortality in the general population and in dialysis patients [10]. Recently, Kang et al. showed the implications of LV diastolic dysfunction on CV events in incident dialysis patients with preserved LV systolic function [10]. The difference between the aforementioned study and the present study is that we studied LV diastolic dysfunction on CV mortality in maintenance HD and PD patients. Moreover, Yu et al. suggested that LV diastolic dysfunction as evaluated by TDI is an independent predictor of hospitalization and all-cause mortality in dialysis patients with preserved LV systolic function [11]. In that study, 9.1% of all patients had diabetes and only 4% had a history of CVD. However, 41% had diabetes and 41% had a history of CVD in our study. For these reasons, it is judged that there is a difference in the results. Moreover, there was no mention of the effect of LV diastolic dysfunction on CV mortality in the aforementioned study.

Subherwal reported that central BP is independently associated with LV filling pressure and LV diastolic dysfunction in the general population [12]. Summarizing the research literature reported to date, central BP had a significant association with LV diastolic dysfunction, which has been shown to be a predictor of CV events and mortality in patients with ESKD. However, there has been no study between central BP and LV diastolic dysfunction on CV mortality in ESKD patients with preserved LV systolic function.

BP has been traditionally measured in the peripheral arteries. However, there is increasing evidence that central BP might be superior to peripheral BP in the prediction of CVD events [29]. The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm and Conduit Artery Function Evaluation (CAFE) demonstrated the impact of central BP on the risk of CVD on the general population [30, 31]. However, clinical implications of central BP are rare in ESKD patients with preserved LV function. Increased aortic afterload by central BP results in LV diastolic dysfunction, characterized by impaired LV relaxation and increased LV end-diastolic pressure. Consequently, elevated central BP may contribute to LV diastolic dysfunction [12]. In a study involving 180 people who received dialysis treatment, brachial BP had no predictive value for mortality after adjustment. However, central BP was more powerful than brachial BP in the prediction of overall mortality [32]. However, the value of central BP measurements in predicting CVD outcome has been studied mostly in the general population with hypertension, but not in detail in patients with ESKD [33]. Mahboob et al. reported that elevated central BP is associated with a higher risk of CVD outcomes in patients with CKD (eGFR between 20 and 70 ml/min per 1.73 m2) [15]. In the present study involving chronic dialysis patients, central systolic BP had a strong positive correlation with the E/E’ ratio and PWV. In addition, central systolic BP was a significant risk factor for LV diastolic dysfunction in ESKD patients with preserved LV systolic function. However, Kanako et al. insisted measuring central BP was useful in detecting minute changes in arteries, which would not change the brachial BP [34]. In contrast, Ichihara et al. [35] observed a significant reduction in PWV with treatment in dialysis patients. Thus, it seems that the arteries in dialysis patients can respond to adequate treatment on the basis of this study. Moreover, Mahboob et al. [15] reported that the measurement of central BP may be useful in patients with CKD to determine their risk of CVD. Therefore, measurement of central BP may be suitable even for dialysis patients despite advanced arterial disease due to chronic inflammation and advanced arterial calcification [34].

Although there are some reports that hypertension affects CV mortality in dialysis patients [36, 37], there are few studies on central BP and CV mortality in dialysis patients. Since the number of subjects was small and the observation period was not long enough, our study might not show significant association between central systolic BP and CV mortality. In addition, numerous risk factors are involved in the pathogenesis of CVD in dialysis patients. There are well-known traditional risk factors such as diabetes and hypertension as well as non-traditional risk factors such as chronic volume overload, anemia, inflammation, oxidative stress, chronic kidney disease–mineral bone disorder and other aspects of the ‘uraemic milieu’ [38]. Further research should be performed to reveal the relationship between central systolic BP and CV outcome.

Diabetes is one of the most important metabolic conditions responsible for LV diastolic dysfunction. Although the exact cause has not yet been identified, diabetic cardiomyopathy has been proposed recently. Clinically, it is well known that LV diastolic function deteriorates with advancing age despite preserved LV systolic function. In particular, impaired glucose tolerance could contribute to the early deterioration of LV diastolic function among middle aged apparently healthy subjects [39]. Similarly, in this study, patients with diabetes had significantly more LV diastolic dysfunction. Furthermore, DM was identified as a strong risk factor for LV diastolic dysfunction with HR of 9.373 (p = 0.001). However, we think further research is warranted to generalize our results.

Tullio et al. reported that increased BMI (>25 kg/m2) was associated with worse LV diastolic function independent of LV mass and associated risk factors in general population [40]. However, unlike the general population, among HD patients BMI is related to mortality inversely. The explanation for this interesting paradox is unknown [41]. Agarwal et al. shows a significant and inverse relationship of BMI with unadjusted LVMI, but multivariate analysis removed the statistical association of BMI with LVMI [42]. We did not find any studies on BMI and LV diastolic dysfunction in dialysis patients. In our study, BMI was not a significant risk factor for LV diastolic dysfunction in a univariate analysis (p = 0.360). Furthermore, overweight and obesity with a BMI value of 25 or higher were not a significant risk factor for LV diastolic dysfunction in this study (p = 0.465). The authors believe that studies on BMI, LV diastolic dysfunction, and CV mortality in dialysis patients are of great value.

The prevention and treatment of LV diastolic dysfunction in patients with ESKD may alleviate or regress LVH. Since central systolic BP was found to be a significant risk factor for LV diastolic dysfunction in this study, it is believed that CV mortality may be reduced by meticulous monitoring and control of central systolic BP.

This study has several limitations. First, this was a single-center study with a small sample size. Second, an observational study may only provide an associative link but not a causative link; therefore, we cannot rule out the possibility of unmeasured confounding factors that can influence the implications of CV outcomes. Third, if echocardiography was performed at least every other year, more accurate and clear results could have been obtained. Lastly, we did not sequentially examine the patients for the presence of CV outcomes or risk factors such as nutritional, inflammatory, and volume status during the follow-up period, which would have yielded more informative results.

Conclusion

LV diastolic dysfunction can independently predict CV mortality in dialysis patients with preserved LV systolic function. The E/E’ ratio was an independent predictor of CV mortality in dialysis patients. In addition, central systolic BP was a significant independent risk factor for LV diastolic dysfunction.

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3 Mar 2021

PONE-D-20-35155

Central blood pressure and diastolic dysfunction predict CV mortality in dialysis patients with preserved systolic function

PLOS ONE

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I thoroughly enjoyed reading this report showing patients with LV diastolic dysfunction had

increased risk of CV mortality and that central systolic BP and diabetes were amongst the strongest predictors

of diastolic dysfunction. However, the lack of diagnostic information captured during the follow-up period slightly dampened my enthusiasm regarding the mechanism for CV mortality.

Despite their being no difference between clinical groups, I thought it was odd that BMI was not included as a predictor for LV diastolic dysfunction in the univarite and multivariate analyses given it being such and important risk factor in other CVDs, e.g. T2DM.

In the discussion, the authors did a good job summarizing extant literature that corroborates their findings, however there is no discussion pertaining to the next steps in this research. For example, the sample appears to not consist of individuals with elevated BMI. Would similar findings be expected?

Reviewer #2: This study was a single-center, prospective, observational study enrolled patients treated with HD or PD at Hallym University Kangnam Sacred Heart Hospital, which aimed to examine the impact of LV diastolic dysfunction on CV mortality in patients with ESKD with preserved systolic function and to analyze the relationship between central BP and LV diastolic dysfunction. In the present study, the authors revealed that LV diastolic dysfunction increased CV mortality in patients receiving HD and PD, in which E/E' ratio was a significant factor for CV mortality. Further, central systolic BP was a significant independent risk factor for LV diastolic dysfunction, and central systolic BP had a significant positive correlation with E/E’ ratio and LAVI. This reviewer considers that it was interesting, but that this paper has only a small impact. This reviewer has some criticisms as described below.

Major comments:

1. Title. The authors indicated that LV diastolic dysfunction, but not central systolic BP, could independently predict CV mortality in dialysis patients with preserved LV systolic function. And, central systolic BP was a significant independent risk factor for LV diastolic dysfunction. Therefore, the title “central blood pressure and diastolic dysfunction predict CV mortality” is wrong.

2. In the Results section, the authors indicated 16 deaths during the follow-up period, including 7 CV deaths and 9 other deaths, including pneumonia, peritonitis, and sepsis. In 7 patients, which of CV deaths occurred (heart failure, arrhythmia, etc.)?

3. Not only central systolic BP but also DM was a strong predictor of LV diastolic dysfunction. How did the authors consider this issue?

4. Discussion section, ref. 12 part. What was “Sumeet”?

5. Conclusion. It is known that LV diastolic dysfunction can predict CV mortality in dialysis patients. The combination of central systolic BP seems to be new, but it was not a predictor for CV mortality. How are the authors able to report new findings in the present study?

Minor comment:

6. Introduction. Line 5. Blank seems to be necessary between “[1].” and “The”.

7. Figure 1. “Left ventricular dysfunction” should be “Left diastolic dysfunction”.

**********

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Reviewer #1: No

Reviewer #2: No

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19 Mar 2021

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I thoroughly enjoyed reading this report showing patients with LV diastolic dysfunction had increased risk of CV mortality and that central systolic BP and diabetes were amongst the strongest predictors of diastolic dysfunction. However, the lack of diagnostic information captured during the follow-up period slightly dampened my enthusiasm regarding the mechanism for CV mortality.

Despite their being no difference between clinical groups, I thought it was odd that BMI was not included as a predictor for LV diastolic dysfunction in the univarite and multivariate analyses given it being such and important risk factor in other CVDs, e.g. T2DM.

In the discussion, the authors did a good job summarizing extant literature that corroborates their findings, however there is no discussion pertaining to the next steps in this research. For example, the sample appears to not consist of individuals with elevated BMI. Would similar findings be expected?

Thank you very much for your kind suggestion. Tullio et al. reported that increased BMI (>25 kg/m2) was associated with LV diastolic dysfunction independent of LV mass and associated risk factors in general population (J Am Coll Cardiol 2011;57:1368–74). However, unlike the general population, lower BMI was related to mortality among hemodialysis patients (Hypertension.2011;58:1014-1020.). The exact reason for this interesting paradox is unknown. Meanwhile, Agarwal et al. showed an inverse relationship of BMI with unadjusted LVMI, but multivariate analysis removed the statistical significance. Unfortunately, Agarwal et al. did not perform further analysis to show relationship between BMI and LVDD. We could not find any studies on BMI and LVDD in dialysis patients. In our study, BMI was not a significant risk factor for LVDD in a univariate analysis (p=0.360). Furthermore, overweight and obesity with a BMI value of 25 or higher were not a significant risk factor for LVDD in a univariate analysis in this study (p=0.465). We believe that further studies on BMI, LVDD, and CV mortality in dialysis patients should be warranted and will be a great value. We have added the results of univariate analyses for BMI in Table 2 and Table 3. We have also added above description to the discussion section.

Reviewer #2: This study was a single-center, prospective, observational study enrolled patients treated with HD or PD at Hallym University Kangnam Sacred Heart Hospital, which aimed to examine the impact of LV diastolic dysfunction on CV mortality in patients with ESKD with preserved systolic function and to analyze the relationship between central BP and LV diastolic dysfunction. In the present study, the authors revealed that LV diastolic dysfunction increased CV mortality in patients receiving HD and PD, in which E/E' ratio was a significant factor for CV mortality. Further, central systolic BP was a significant independent risk factor for LV diastolic dysfunction, and central systolic BP had a significant positive correlation with E/E’ ratio and LAVI. This reviewer considers that it was interesting, but that this paper has only a small impact. This reviewer has some criticisms as described below.

Major comments:

1. Title. The authors indicated that LV diastolic dysfunction, but not central systolic BP, could independently predict CV mortality in dialysis patients with preserved LV systolic function. And, central systolic BP was a significant independent risk factor for LV diastolic dysfunction. Therefore, the title “central blood pressure and diastolic dysfunction predict CV mortality” is wrong.

Thank you for making an important comment. We sincerely apologize for the confusion. We have changed the title to “Clinical significance of central systolic blood pressure in LV diastolic dysfunction and CV mortality” to reflect the reviewer's comments.

2. In the Results section, the authors indicated 16 deaths during the follow-up period, including 7 CV deaths and 9 other deaths, including pneumonia, peritonitis, and sepsis. In 7 patients, which of CV deaths occurred (heart failure, arrhythmia, etc.)?

Thank you for making an important point. Three out of seven died from myocardial infarction, one from sudden cardiac death, and the other three from stroke. We have added the above description in the result section.

3. Not only central systolic BP but also DM was a strong predictor of LV diastolic dysfunction. How did the authors consider this issue?

Thank you for making an important point.

Diabetes is one of the most important metabolic conditions responsible for LVDD. Although the exact cause has not yet been identified, recently, diabetic cardiomyopathy has been proposed. Clinically, it is well known that LV diastolic function deteriorates with advancing age despite preserved LV systolic function. In particular, impaired glucose tolerance could contribute to the early deterioration of LV diastolic function among middle aged apparently healthy subjects. (Eur Heart J Cardiovasc Imaging 2020 Aug 1;21(8):885-886). Similarly, in this study, patients with diabetes had significantly more LVDD. Furthermore DM was identified as a very strong factor for LVDD with hazard ratio (HR) of 9.373 (p=0.001). The number of patients included in this study is small and cannot be generalized, but we think more research is needed. We have added what the reviewer points out to the discussion section.

4. Discussion section, ref. 12 part. What was “Sumeet”?

We are sorry for our mistake. There were some typos. We have amended the text as follows: Subherwal reported that central BP is independently associated with LV filling pressure and LV diastolic dysfunction in the general population [12].

5. Conclusion. It is known that LV diastolic dysfunction can predict CV mortality in dialysis patients. The combination of central systolic BP seems to be new, but it was not a predictor for CV mortality. How are the authors able to report new findings in the present study?

Thank you for making an important point.

Although there are reports that hypertension affects CV mortality in dialysis patients (Hypertension. 2010;55:762–768, Hypertension. 2017;70:435–443) there are few studies on central BP and CV mortality in dialysis patients. We think that because the number of subjects was small and the observation period was not long enough, this study did not show significant results for central SBP on CV mortality. In addition, numerous risk factors involved in the pathogenesis of CVD in dialysis patients. This is likely due to cardiac dysfunction as well as non-traditional risk factors, such as chronic volume overload, anemia, inflammation, oxidative stress, chronic kidney disease–mineral bone disorder and other aspects of the ‘uraemic milieu’ (Nephrol Dial Transplant. 2018 Oct 1;33(suppl_3):iii28-iii34). Further research is likely to be needed. We have added what the reviewer points out to the discussion section.

Minor comment:

6. Introduction. Line 5. Blank seems to be necessary between “[1].” and “The”.

Thank you for the important point. We have amended the text as you have recommended.

7. Figure 1. “Left ventricular dysfunction” should be “Left diastolic dysfunction”.

Thank you for the important point. I modified it as reviewer comment.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

12 Apr 2021

Clinical significance of central systolic blood pressure in LV diastolic dysfunction and CV mortality

PONE-D-20-35155R1

Dear Dr. Lee,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Yoshihiro Fukumoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: This reviewer considers that the authors have well responded. This reviewer has no further comment.

**********

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Reviewer #2: No

14 Apr 2021

PONE-D-20-35155R1

Clinical significance of central systolic blood pressure in LV diastolic dysfunction and CV mortality

Dear Dr. Lee:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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