3.1. Baseline characteristics
Overall, 1230 HF patients that met the inclusion criteria were identified, of whom 93 patients withHFrEF(7.5%), 56 patients withHFmrEF (4.5%) and1081 patients withHFpEF (87.8%). Baseline characteristics of the total cohort three HF categorieswere presented in Table 1.
The overall population was 78.28±9.00years of age. The difference of age in patients withHFrEF (75.41±9.23) and those with HFpEF (78.60±8.91) werestatistically significant (p<0.05). With respect to gender, the different proportion of male/female in HFrEF and HFpEF was statistically significant with p <0.01. No significant difference in smoking and alcohol use was found between any two of these three HF groups.
In terms of vital signs, pulse was significantly lower in patients with HFpEF than patients with HFrEF(p<0.01) while systolic blood pressure (SBP) was significantly higher in patients with HFpEF than patients with HFrEF (p<0.01). SBP in patients with HFmrEF was significantly higher than patients with HFrEF (p<0.05). The only difference for body mass index (BMI) in these 3 HF groups was found between HFpEF and HFmrEF groups, whereas diastolic blood pressure (DBP) and body temperature were not significantly different among all the HF groups.
Table 1. Baseline characteristics and vital signs among the 3 groups
|
All Patients
|
HFrEF
(A. n=93)
|
HFmrEF
(B. n=56)
|
HFpEF
(C. n=1081)
|
P (A v B)
|
P (A v C)
|
P (B v C)
|
LVEF (%)
|
60.13 (25.13)
|
33.27 (4.81)
|
44.16 (2.58)
|
63.26 (25.12)
|
<.01
|
<.01
|
<.01
|
Male
|
826(67.15)
|
77 (82.80)
|
43(76.79)
|
706(65.31)
|
NS
|
<.01
|
NS
|
Female
|
404(32.85)
|
16(17.20)
|
13(23.21)
|
375(34.60)
|
NS
|
<.01
|
NS
|
Smoke
|
309(25.12)
|
32(34.41)
|
19(33.93)
|
258(23.87)
|
NS
|
NS
|
NS
|
Alcohol
|
195(15.85)
|
20(21.51)
|
10(17.86)
|
165(15.26)
|
NS
|
NS
|
NS
|
Age
|
78.28 (9.00)
|
75.41 (9.23)
|
77.05 (9.61)
|
78.60 (8.91)
|
NS
|
<.05
|
NS
|
BMI(kg/m2)
|
24.84 (14.29)
|
23.80 (5.36)
|
26.08 (2.93)
|
24.87 (15.27)
|
NS
|
NS
|
<.05
|
Pulse(bpm)
|
76.16 (14.66)
|
84.09 (19.59)
|
80.08 (17.64)
|
75.32 (13.79)
|
NS
|
<.01
|
NS
|
SBP(mmHg)
|
129.74 (29.31)
|
119.95 (20.45)
|
135.34 (23.74)
|
130.29 (30.01)
|
<.01
|
<.01
|
NS
|
DBP(mmHg)
|
72.79 (12.06)
|
71.68 (12.14)
|
73.98 (12.02)
|
72.82 (12.06)
|
NS
|
NS
|
NS
|
Temperature (℃)
|
36.44 (0.33)
|
36.43 (0.26)
|
36.47 (0.40)
|
36.44 (0.33)
|
NS
|
NS
|
NS
|
Categorical variables were presented as Count (%). Continuous variables were presented as Mean (SD).SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BMI: Body mass index; bpm: Beat per minute; NS: Not significant.
3.2. Comorbidity
Comorbid diseases and interventions included but not limited to malignancy, hypertension, chronic obstructive pulmonary disease (COPD), diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, percutaneous coronary intervention (PCI), pacemaker and cerebrovascular accident/transient ischemic attack(CVA/TIA), unstable angina pectoris (UAP), high uric acid and gout (HUGA). The frequency of all the comorbidities above had no significant difference between patients with HFmrEF and HFrEF.
However, patients with HFpEF more frequently had comorbid peripheral artery disease(PAD) (p<0.05), but less frequently had acute myocardial infarction(AMI) (p<0.05), comorbid kidney disease (CKD) (p<0.05), coronary artery disease (CAD) (p<0.01) than those with HFrEF. Patients with HFmrEF more frequently had comorbid AMI (p<0.01), infection (p<0.05) and CAD (p<0.05) than those with HFpEF. The result of pair-wise comparisons of comorbid diseases among the three HF groups werelisted in Table 2.
Table 2. Comorbidities among the 3 groups
Comorbidity
|
All Patients
|
HFrEF
(A. n=93)
|
HFmrE
(B. n=56)
|
HFpEF
(C. n=1081)
|
P (A v B)
|
P (A v C)
|
P (B v C)
|
Malignancy
|
136(11.06)
|
12(12.90)
|
5(8.93)
|
119(11.01)
|
NS
|
NS
|
NS
|
Hypertension
|
815(66.26)
|
52(55.91)
|
36(64.29)
|
727(67.25)
|
NS
|
NS
|
NS
|
COPD
|
54(4.39)
|
2(2.15)
|
1(1.79)
|
51(4.72)
|
NS
|
NS
|
NS
|
Dyslipidemia
|
201(16.34)
|
8(8.60)
|
7(12.50)
|
186(17.21)
|
NS
|
NS
|
NS
|
Atrial fibrillation
|
233(18.94)
|
20(21.51)
|
16(28.57)
|
197(18.22)
|
NS
|
NS
|
NS
|
Diabetes mellitus
|
426(34.63)
|
36(38.71)
|
20(35.71)
|
370(34.23)
|
NS
|
NS
|
NS
|
CKD
|
180(14.63)
|
23(24.73)
|
13(23.21)
|
144(13.32)
|
NS
|
<.05
|
NS
|
Anemia
|
96(7.81)
|
11(11.83)
|
3(5.36)
|
82(7.59)
|
NS
|
NS
|
NS
|
AMI
|
88(7.15)
|
16(17.20)
|
11(19.64)
|
61(5.64)
|
NS
|
<.05
|
<.01
|
Infection
|
208(16.91)
|
23(24.73)
|
17(30.36)
|
168(15.54)
|
NS
|
NS
|
<.05
|
PCI
|
88(7.45) *
|
12(12.90)
|
6(10.71)
|
70(6.48)
|
NS
|
NS
|
NS
|
Pacemaker
|
70(5.69) *
|
4(4.30)
|
6(10.71)
|
60(5.55)
|
NS
|
NS
|
NS
|
CVA_TIA
|
244(20.64) *
|
16(17.20)
|
12(4.55)
|
216(19.98)
|
NS
|
NS
|
NS
|
PAD
|
428(34.80)
|
21(22.58)
|
16(28.57)
|
391(36.17)
|
NS
|
<.05
|
NS
|
CAD
|
723(58.78)
|
70(75.27)
|
42(75.00)
|
611(56.52)
|
NS
|
<.01
|
<.05
|
UAP
|
73(5.94)
|
6(6.45)
|
2(3.57)
|
65(6.01)
|
NS
|
NS
|
NS
|
HUAG
|
154(12.52)
|
18(19.35)
|
8(14.29)
|
128(11.84)
|
NS
|
NS
|
NS
|
Data was presented as Count (%).
*: Only 1182 patients had information on PCI, Pacemaker and CVA-TIA.
3.3. Laboratory Assessments
Laboratory assessments were performed for all enrolled HF patients and the pair-wise comparisons among the 3 groups was listed in Table 3. The levels of NT-proBNP, and BNP were the value of log transformation before analysis. The following laboratory parameters:NT-proBNP,BNP,cardiac troponin,WBC, neutrophil%, BUN, serum sodium, uric acid,weresignificantly higher in patients with HFmrEF than those with HFpEF.In addition, NT-proBNP, LDH, BNP,WBC, neutrophil%,BUN, serum creatinine, serum sodium, D-dimer were also significantly higher in patients with HFrEF than those with HFpEF.But the levels ofcreatinekinase-MB and cardiac troponin were significantly higher in patients with HFpEF than with HFrEF.As for uric acid, there was no significant difference between these two groups. Meanwhile, the levels of BNP, LDH, and serum creatinine were significantly higher in patients with HFrEF than those of HFmrEF.
The other lab parameters observed but not mentioned above, including C-reactive protein, fasting blood glucose (FBP),serum potassium, hemoglobin etc., were comparable between any two of the three HF groups without any significant difference.
Table 3. Laboratory Parameters among the 3 groups
Lab Variable
|
All Patients
|
HFrEF
(A. n=93)
|
HFmrEF
(B. n=56)
|
HFpEF
(C. n=1081)
|
P (A v B)
|
P (A v C)
|
P (B v C)
|
Log (NT-proBNP)
|
6.21 (1.37)
|
9.81 (0.52)
|
7.49 (1.35)
|
6.00 (1.16)
|
NS
|
<.05
|
<.05
|
Log (BNP)
|
4.77 (1.05)
|
6.68 (0.95)
|
5.95 (1.16)
|
4.57 (0.85)
|
<.01
|
<.01
|
<.01
|
CK-MB (ng/mL)
|
21.0 (74.0)
|
7.0 (28.5)
|
23.8 (68.1)
|
22.1 (77.2)
|
NS
|
<.05
|
NS
|
LDH (U/L)
|
212.4 (188.8)
|
326.2 (271.7)
|
256.2 (208.1)
|
202.3 (177.7)
|
<.05
|
<.01
|
NS
|
Cardiac troponin (ng/mL)
|
2.0 (18.2)
|
1.0 (3.8)
|
11.9 (40.4)
|
1.6 (17.4)
|
NS
|
<.01
|
<.01
|
WBC (109/L)
|
6.0 (3.2)
|
6.9 (3.7)
|
7.3 (4.1)
|
5.8 (3.0)
|
NS
|
<.05
|
<.05
|
Neutrophil (%)
|
60.6 (12.8)
|
66.1 (13.3)
|
67.2 (14.5)
|
59.9 (12.5)
|
NS
|
<.01
|
<.01
|
C-reactive protein (mg/L)
|
19.8 (48.1)
|
38.9 (89.6)
|
69.1 (133.3)
|
16.7 (35.9)
|
NS
|
NS
|
NS
|
BUN (mmol/L)
|
7.6 (4.2)
|
10.3 (5.7)
|
8.4 (4.1)
|
7.4 (4.0)
|
NS
|
<.01
|
<.01
|
Serum creatinine (umol/L)
|
78.1 (72.9)
|
118.5 (113.9)
|
83.0 (53.7)
|
74.8 (68.5)
|
<.05
|
<.01
|
NS
|
Serum Sodium (mmol/L)
|
138.8 (15.5)
|
139.2 (4.2)
|
139.8 (3.7)
|
138.7 (16.5)
|
NS
|
<.01
|
<.05
|
Serum Potassium (mmol/L)
|
5.3 (3.1)
|
4.8 (2.4)
|
4.8 (2.9)
|
5.3 (3.2)
|
NS
|
NS
|
NS
|
Serum Calcium (mmol/L)
|
2.0 (0.4)
|
2.1 (0.4)
|
2.0 (0.4)
|
2.0 (0.4)
|
NS
|
NS
|
NS
|
FBP (mmol/L)
|
8.1 (3.0)
|
6.7 (1.5)
|
11.1 (5.2)
|
8.1 (2.9)
|
NS
|
NS
|
NS
|
Hemoglobin A1c (%)
|
6.8 (4.7)
|
6.4 (1.0)
|
6.6 (1.6)
|
6.9 (4,8)
|
NS
|
NS
|
NS
|
Hemoglobin (g/L)
|
135.3 (37.3)
|
133.2 (34.4)
|
128.2 (30.5)
|
135.8 (37.8)
|
NS
|
NS
|
NS
|
D-dimer (ug/ml)
|
1.3 (2.1)
|
2.1 (3.1)
|
1.2 (1.4)
|
1.3 (2.0)
|
NS
|
<.01
|
NS
|
TSH (mIU/L)
|
2.3 (3.4)
|
2.5 (1.8)
|
2.3 (3.5)
|
2.3 (3.4)
|
NS
|
NS
|
NS
|
Uric acid (umol/L)
|
279.6 (165.0)
|
339.1 (228.4)
|
330.4 (160.4)
|
274.9 (161.2)
|
NS
|
NS
|
<.05
|
Data was presented as Mean (SD). Independent t-test was used to compare the lab variables.
Log (NT-proBNP): Log transformation of NT-proBNP; Log (BNP): Log transformation of BNP; CK-MB: Creatine kinase-MB; LDH: Lactic acid dehydrogenase;WBC: White blood cell; BUN, Blood urea nitrogen; FBP: Fasting blood glucose; TSH:Thyrotropin stimulating hormone; NS: Not significant
3.4. Mortality rate
The mortality result of HFmrEF, HFpEF and HFrEF patients are shown in Table 4.There were 92 overall deaths (7.47%) in the HF patients during the study period, with a slightly higher unadjusted mortality rate seen in HFmrEF group (10.71%) than in HFpEF group (7.31%) or in HFrEF group (7.53%). However, there was no significant difference for the mortality rate among these three HF groups.
Table 4. Mortality rate among the 3 groups
|
All patients
|
HFrEF
|
HFmrEF
|
HFpEF
|
P (A v B)
|
P (A v C)
|
P (B v C)
|
Death
|
92 (7.47)
|
7(7.53)
|
6(10.71)
|
79(7.31)
|
NS
|
NS
|
NS
|
Data was presented as count (%). The χ2 test was used to compare variables.
3.5 Risk factors associated with HFmrEF,HFrEF and HFpEF
The univariate analysis of the associated factors with HFmrEF, HFpEF and HFrEF was shown asforest plots inFigure 2 and multivariable logistic regression analysis was performed to obtainthe odds ratios(Table 5).
Table 5. Mortality of 3 groups adjusted for risk factors
|
Model 1
|
Model 2
|
Model 3
|
Model 4
|
Type
|
OR (95%CI)
|
P
|
OR (95%CI)
|
P
|
OR (95%CI)
|
P
|
OR (95%CI)
|
P
|
HFpEF
|
Reference
|
Reference
|
Reference
|
Reference
|
HFmrEF
|
1.55 (0.58, 3.51)
|
0.33
|
1.52 (0.57, 3.46)
|
0.35
|
1.32 (0.48, 3.03)
|
0.097
|
1.31 (0.48, 3.02)
|
0.35
|
HFrEF
|
1.11 (0.45, 2.36)
|
0.80
|
1.11 (0.45, 2.36)
|
0.80
|
0.97 (0.39, 2.08)
|
0.161
|
0.94 (0.37, 2.03)
|
0.80
|
OR: oddsratio; CI: confidence interval.
Model 1: adjusted for age and gender. Model 2: adjusted for age, gender, smoke and alcohol. Model 3: adjusted for age, gender, smoke, alcohol and baseline cardiovascular disease. Model 4: adjusted for age, gender, smoke, alcohol and baseline cardiovascular disease, COPD, diabetes and hypertension.
The resultsof univariate and multivariable logistic regression indicatedthatcomorbidatrial fibrillation, AMI and infectionwere associated with HFmrEF, whereas female gender, old age, comorbid hypertension and PADwere associated with HFpEF, and CAD, kidney disease were associated with HFrEF (see Table 6).
Among all baseline characteristics and clinical parameters, AMI had the highest odds ratio for HFmrEF (4.21), while female and CAD had the highest odds ratio for HFpEF (2.55) and HFrEF (3.02), respectively.
Our univariate analysis also indicated that baseline characteristics, comorbid features and laboratory results were comparable between HFmrEF patients and HFrEF patients, which were displayed in Supplemental Figure 1 after the reference section.
Table 6. Risk factors associated with HFmrEF, HFpEF and HFrEF.
For HFmrEF
|
OR (95% CI)
|
P
|
Atrial fibrillation
|
1.86 (1.01, 3.42)
|
0.05
|
AMI
|
4.21 (2.06, 8.63)
|
<.01
|
Infection
|
2.37 (1.30, 4.32)
|
<.01
|
For HFpEF
|
Sex (Female)
|
2.55 (1.45, 4.50)
|
<.01
|
Age
|
1.05 (1.02, 1.07)
|
<.01
|
Hypertension
|
2.36 (1.46, 3.82)
|
<.01
|
PAD
|
1.89 (1.11, 3.22)
|
0.02
|
For HFrEF
|
CAD
|
3.02 (1.80, 5.08)
|
<.01
|
Kidney disease
|
2.19 (1.25, 3.84)
|
<.01
|