Table 1 shows the baseline characteristics of the total population (n = 280) as well as the variables included in each score. Mean age of this sub-cohort was 72.1 (4.9) years, 26.4% were women, 45% patients had heart failure with reduced ejection fraction (HFrEF) (LVEF < 35%), and most patients were in NYHA functional class II (67.5%) with the remaining in NYHA class III. Hypertension was present in 80% of participants and 45% were current or former smokers; 29% had diabetes and 71% had CAD. During the follow-up period (mean = 81 months, SD = 33; median = 96 months), 95 (34%) patients met the primary outcome. The sample selection criteria as well as the comparison of this sub cohort’s baseline characteristics to the source cohort has previously been reported [29], however, this study analyzed 10 year follow up rather than the previously reported 4 year follow up.
Table 1
Baseline characteristics of the study participants and variables included in each prognostic score
| Total | Prognostic Score |
Characteristic | n = 280 | SHFM | FRS | MAGGIC | CLP |
Age (years), mean ± SD | 72 ± 4.9 | ✓ | ✓ | ✓ | |
NYHA (II/III), n | 188/91 | ✓ | | ✓ | |
Male, n (%) | 206 (74) | ✓ | ✓ | ✓ | |
Body mass index (kg/m2), mean ± SD | 26.8 ± 3.4 | | | ✓ | |
Heart rate (bpm), mean ± SD | 73 ± 13.0 | | | | |
Systolic blood pressure (mm Hg), mean ± SD | 134 ± 19 | ✓ | ✓ | ✓ | |
Diastolic blood pressure (mm Hg), mean ± SD | 81 ± 11 | | | | |
Years since first diagnosis of CHF | 5.2 ± 5.6 | | ✓ | | |
Laboratory, mean ± SD | | | | | |
Creatinine (µmol/L) | 107 ± 27.9 | | | ✓ | |
Hemoglobin (g/dL) | 21.6 ± 2.4 | ✓ | | | |
Sodium (mEq/L) | 141.4 ± 3.3 | ✓ | | | |
Uric acid (µmol/L) | 356 ± 127 | ✓ | | | |
Total Cholesterol (mmol/L) | 5.1 ± 1.6 | | | | |
HDL cholesterol (mmol/L) | 1.2 ± 0.5 | | ✓ | | |
LDL cholesterol (mmol/L) | 3.4 ± 1.3 | | | | |
Triglycerides (mmol/L) | 1.7 ± 1.0 | | | | |
Lymphocytes (%)* | | ✓ | | | |
NT-proBNP (pg/mL) | 793 (331–1765)† | | | | ✓ |
PC 16:0/18:2 (µg/dl) | 36810 (32435–40015)† | | | | ✓ |
TAG 18:2 (µg/dl) | 121 (76.5-256.4)† | | | | ✓ |
SM d18:1/23:1, SM d18:2/23:0, SM d17:1/24:1 (µg/dl) | 1342 (1134–1596)† | | | | ✓ |
Cardiac Imaging, mean ± SD | | | | | |
LVEF (%) | 36 ± 9.5 | ✓ | | ✓ | |
LVDed (mm) | 58.8 ± 9.2 | | | | |
LVDes (mm) | 45.5 ± 9.7 | | | | |
LVVed (mL) | 152.7 ± 63.9 | | | | |
LVVes (mL) | 101.1 ± 51.6 | | | | |
LAes (mm) | 45.3 ± 7.2 | | | | |
E/e' | 12 ± 9.2 | | | | |
E/A | 1 ± 0.8 | | | | |
Deceleration time (ms) | 226 ± 80 | | | | |
Comorbidities, n (%) | | | | | |
Diabetes | 82 (29) | | ✓ | ✓ | |
Hypertension | 224 (80) | | | | |
Coronary artery disease | 200 (71) | ✓ | | | |
Smokers | 125 (45) | | ✓ | ✓ | |
Hyperlipidemia | 162 (58) | | | | |
COPD | 9 (3) | | | ✓ | |
Medication, n (%) | | | | | |
ACE inhibitor | 247 (88) | ✓ | | ✓ | |
Allopurinol | 0 (0) | ✓ | | | |
ARB | 115 (41) | ✓ | | | |
Beta Blocker | 203 (73) | ✓ | | ✓ | |
Diuretics | 219 (78) | | | | |
Diuretic Dose mg/kg per day | 0.32 ± 0.31 | ✓ | | | |
Glycoside | 59 (21) | | | | |
Aspirin | 216 (77) | | | | |
Nitrate | 146 (52) | | | | |
Antiarrhythmic agent | 42 (15) | | | | |
Statin | 114 (41) | ✓ | | | |
Caption: |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CE 18:2, triacylglycerol 18:1/18:0/18:0; COPD, chronic obstructive pulmonary disease; E/A, ratio of the early (E) to late (A) ventricular filling velocities; E/e', ratio between early mitral inflow velocity and mitral annular early diastolic velocity; LAes, left atrial end systole; LDL, low-density lipoprotein; NYHA, New York Heart Association; HDL, high-density lipoprotein; LVDed, left ventricular diameter end diastole; LVDes, left ventricular diameter end systole; LVVed, left ventricular volume end diastole; LVEF, left ventricular ejection fraction; LVVes, left ventricular volume end systole; mg/kg, milligrams per kilograms; NTpro-BNP, N-terminal pro–B-type natriuretic; PC 16:0/18:2, phosphatidylcholine 16:0/18:2; SM d18:1/23:1, SM d18:2/23:0, SM d17:1/24:1, the sum of the 3 isobaric sphingomyelin species SM d18:1/23:1, SM d18:2/23:0, and SM d17:1/24:1 |
*Imputed using the median, 31%, of the normal range 20–40% |
† Median (Interquartile Range) |
All variables were available for each score except for the lymphocytes (%) variable in the SHFM score, which was imputed as previously described. The SHFM model had the highest number of variables (n = 17), followed by MAGGIC (n = 13), FRS (n = 7), and CLP (n = 4). There were 10 overlapping variables which were included in at least 2 scores. The SHFM score included the most medication (n = 6) and laboratory (n = 5) variables while MAGGIC included the most clinical (n = 7) and demographic variables (n = 3).
Table 2 shows the univariate Cox Regression results. The CLP (HR = 2.38, p < 0.001), SHFM (HR = 2.01, p = 0.002, and MAGGIC (HR = 1.10, p < 0.001) scores were significantly associated with the outcome while FRS was not. Figure 1 shows the AUC change over time (IAUC) for the 4 prognostic scores with the comparison of Uno’s concordance statistics for hypothesis testing. The IAUC was 0.53, 0.61, 0.68 and 0.78 for FRS, SHFM, MAGGIC and CLP, respectively. Harrell’s c statistics at 10 year follow up show similar results (Supplemental Table 1). The three traditional scores were all significantly different (p < 0.001) from the CLP score according to Uno’s difference in concordance statistic (Supplemental table 2).
Table 2
Prognostic Scores and Univariate Hazard Ratios
Score | HR (95% CI) | p value |
SHFM | 2.01 (1.29–3.13) | 0.0022 |
FRS | 1.02 (0.97–1.07) | 0.5291 |
MAGGIC | 1.10 (1.05–1.14) | < .0001 |
CLP | 2.38 (1.95–2.92) | < .0001 |
Caption: Unadjusted Cox proportional hazard models of 10-year outcome for cardiovascular mortality. Total subjects, n = 280. Total events, n = 95. SHFM (Seattle Heart Failure Model), FRS (Framingham Risk Score), and MAGGIC (Meta-analysis Global Group in Chronic Heart Failure), and Cardiac Lipid Panel Risk Score (CLP). |
Figure 2 shows the hierarchical cluster dendrogram mapped to illustrate the assignment of patients into their respective clusters and the associated color map shows the range of each prognostic score and their distribution within each cluster. Hierarchical clustering grouped the patients in separate clusters accounting for the noise between smaller clusters. Each observation was treated as a unique cluster, and this method: (1) identified the two similar or close clusters, and (2) merged the two most similar clusters. Using this clustering technique, similar prognostic score data from participants were grouped together, such that the members in the same group were more similar to each other than the members in the other groups. We can infer from the cluster centres and cluster memberships that CLP risk score was better at grouping patients with respect to their cardiovascular mortality risk and associated clinical characteristics compared to the other three scores. The survival curves for each risk cluster are shown in Fig. 3. Rates of mortality were: low risk cluster (23%), moderate risk cluster (41%) and high-risk cluster (54%). Supplemental Fig. 1 shows the constellation plot on a two-dimensional plane with nodes and links to describe relationship among component nodes. This plot is an alternate depiction of the dendrogram and illustrates the length between clusters and a balanced structure. Supplemental Fig. 2 shows the scatterplot matrix of all 4 scores and clusters to illustrate the relationships between each prognostic score and risk cluster assignment.
Table 3 shows the cohort characteristics and the prognostic score distribution for each risk cluster. The three clusters were: low risk, n = 148; moderate risk, n = 74; high risk, n = 58. Most characteristics were different across risk clusters, with 28 out of the 50 cohort characteristics significantly different across the 3 clusters. In particular, patients in the highest risk cluster were older, with lower LVEF, higher NT-proBNP, and experienced a higher frequency of events. All prognostic scores were significantly different across their respective risk clusters. Of the continuous risk scores (FRS, SHFM, MAGGIC), only FRS had its highest mean score in the high-risk cluster. The categorical CLP score showed a skewed distribution of higher risk scores (3–4) in the moderate and high-risk clusters. In the high-risk cluster, the majority of subjects were scored with highest possible CLP score of 4.
Table 3
Comparison of Cohort Characteristics and Prognostic Scores
| Cluster 1 Low Risk | Cluster 2 Moderate Risk | Cluster 3 High Risk | p-value |
Characteristic | n = 148 | n = 74 | n = 58 | |
Age (years), mean ± SD | 71 ± 4.2 | 73 ± 4.9 | 74 ± 5.2 | < .0001a |
NYHA (II/III), n | 121/26 | 47/27 | 20/38 | < .0001c |
Male, n (%) | 95 (64) | 64 (87) | 47 (81) | 0.0005b |
Body mass index (kg/m2), mean ± SD | 27.3 ± 3.5 | 26.7 ± 3.2 | 25.9 ± 3.6 | 0.0620a |
Heart rate (bpm), mean ± SD | 73 ± 12.6 | 73.1 ± 11.6 | 74.5 ± 15.4 | 0.9746a |
Systolic blood pressure (mm Hg), mean ± SD | 138.5 ± 21.5 | 132.4 ± 14.2 | 125.2 ± 13.6 | < .0001a |
Diastolic blood pressure (mm Hg), mean ± SD | 82.6 ± 12.3 | 80.1 ± 9.7 | 77.3 ± 8.5 | 0.0133a |
Years since first diagnosis of CHF | 5.5 ± 5.8 | 4.7 ± 4.8 | 5.1 ± 6.2 | 0.6249a |
Cardiac Death, n (%) | 34 (23) | 30 (41) | 31 (54) | 0.0001b |
Laboratory, mean ± SD | | | | |
Serum creatinine (µmol/l) | 99.4 ± 24 | 109.4 ± 22.9 | 122.9 ± 34.9 | < .0001a |
Hemoglobin (g/dL) | 21.6 ± 2.2 | 21.7 ± 2.8 | 21.2 ± 2.4 | 0.1927a |
Sodium (mmol/L) | 141.9 ± 3.1 | 140.5 ± 3.6 | 141.5 ± 3.0 | 0.0428a |
Uric acid (µmol/L) | 327.7 ± 116.7 | 384.6 ± 119 | 383.4 ± 138.6 | 0.0007a |
Total Cholesterol (mmol/L) | 5.3 ± 1.6 | 5.0 ± 1.5 | 4.7 ± 1.6 | 0.0271a |
HDL cholesterol (mmol/L) | 1.3 ± 0.5 | 1.2 ± 0.4 | 1.1 ± 0.3 | 0.0441a |
LDL cholesterol (mmol/L) | 3.6 ± 1.3 | 3.5 ± 1.3 | 3.0 ± 1.2 | 0.0105a |
Triglycerides (mmol/L) | 1.8 ± 1.1 | 1.7 ± 1.9 | 1.6 ± 0.8 | 0.5955 |
Lymphocytes (%)* | 31 | 31 | 31 | N/A |
NT-proBNP (pg/mL) | 506.3 (307–1228)† | 985.1 (346–1935)† | 1453 (609–3704)† | < .0001a |
PC 16:0/18:2 (µg/dl) | 36975 (33143–40948)† | 36550 (32575–39015) † | 34840 (29710–38818) † | 0.0252 a |
TAG 18:2 (µg/dl) | 126 (73–272)† | 120 (90–182) † | 97.8 (64–275) † | 0.5915 a |
SM d18:1/23:1, SM d18:2/23:0, SM d17:1/24:1 (µg/dl) | 1432 (1212–1699)† | 1233 (1080–1490) † | 1256 (1046–1361) † | < .0001a |
Cardiac Imaging, mean ± SD | | | | |
LVEF (%) | 39.4 ± 9.2 | 33.8 ± 7.9 | 30.0 ± 8.4 | < .0001a |
LVDed (mm) | 57.4 ± 8.6 | 59.7 ± 9.2 | 61.5 ± 9.9 | 0.0094a |
LVDes (mm) | 43.5 ± 8.8 | 47.1 ± 9.7 | 48.5 ± 10.6 | 0.0021a |
LVVed (mL) | 140.7 ± 56.2 | 160.1 ± 74.3 | 173 ± 62.3 | 0.0017a |
LVVes (mL) | 88 ± 43.3 | 111 ± 58.8 | 120.8 ± 52.6 | < .0001a |
LAes (mm) | 44.2 ± 6.7 | 45.4 ± 7.4 | 47.7 ± 7.7 | 0.0146a |
E/e' | 11.3 ± 8.0 | 11.1 ± 7.6 | 14.2 ± 13.2 | 0.2632a |
E/A | 0.9 ± 0.6 | 1.2 ± 0.9 | 1.3 ± 0.8 | 0.0922a |
Deceleration time (ms) | 235.6 ± 80.7 | 221 ± 63.7 | 210.8 ± 90.8 | 0.0572a |
Comorbidities, n (%) | | | | |
Diabetes | 28 (19) | 34 (46) | 20 (35) | 0.0001b |
Hypertension | 119 (80) | 62 (84) | 43 (74) | 0.3823b |
Coronary artery disease | 95 (64) | 58 (78) | 47 (81) | 0.0168b |
Smokers | 48 (32) | 53 (71) | 24 (41) | < .0001b |
Hyperlipidemia | 87 (59) | 43 (58) | 32 (55) | 0.8716b |
COPD | 5 (3) | 4 (5) | 0 (0) | 0.2143 |
Medication, n (%) | | | | |
ACE inhibitor | 132 (89) | 66 (89) | 49 (84) | 0.6127b |
Allopurinol | 0 (0) | 0 (0) | 0 (0) | N/A |
ARB | 55 (37) | 30 (41) | 30 (52) | 0.1602b |
Beta Blocker | 123 (83) | 48 (65) | 32 (55) | < .0001b |
Diuretics | 36 (24) | 14 (19) | 11 (19) | 0.5523b |
Diuretic Dose mg/kg, mean ± SD | 0.26 ± 0.26 | 0.36 ± 0.34 | 0.41 ± 0.34 | 0.0033a |
Glycoside | 29 (20) | 15 (21) | 15 (26) | 0.5996b |
Aspirin | 117 (79) | 58 (78) | 41 (71) | 0.4189b |
Nitrate | 74 (50) | 41 (55) | 31 (54) | 0.7307b |
Antiarrhythmic agent | 19 (13) | 10 (14) | 13 (22) | 0.2048b |
Statin | 62 (42) | 27 (37) | 25 (43) | 0.6804b |
Prognostic Scores | | | | |
SHFM, Mean (SD) | 0.67 ± 0.45 | 1.4 ± 0.31 | 0.60 ± 0.36 | < .0001a |
FRS, Mean (SD) | 20.5 ± 4.3 | 19.5 ± 3.7 | 21.8 ± 3.8 | 0.0392a |
MAGGIC, Mean (SD) | 21.3 ± 4.0 | 28.3 ± 3.3 | 21.3 ± 4.6 | < .0001a |
CLP, n (%) | | | | < .0001b |
0 | 31 (94) | 2 (6) | 0 (0) | |
1 | 105 (88) | 14 (12) | 0 (0) | |
2 | 10 (44) | 9 (39) | 4 (17) | |
3 | 2 (2) | 40 (47) | 44 (51) | |
4 | 0 (0) | 9 (47) | 10 (53) | |
Caption: |
Cohort characteristics and prognostic score distribution across risk clusters. The prognostic scores used for clustering were: SHFM (Seattle Heart Failure Model), FRS (Framingham Risk Score), and MAGGIC (Meta-analysis Global Group in Chronic Heart Failure), and Cardiac Lipid Panel Risk Score (CLP). Each prognostic score was standardized to the same scale (mean = 0; SD = 1). Ward’s minimum variance method was used for clustering. |
Abbreviations: |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CE 18:2, triacylglycerol 18:1/18:0/18:0; COPD, chronic obstructive pulmonary disease; E/A, ratio of the early (E) to late (A) ventricular filling velocities; E/e', ratio between early mitral inflow velocity and mitral annular early diastolic velocity; LAes, left atrial end systole; LDL, low-density lipoprotein; NYHA, New York Heart Association; HDL, high-density lipoprotein; LVDed, left ventricular diameter end diastole; LVDes, left ventricular diameter end systole; LVVed, left ventricular volume end diastole; LVEF, left ventricular ejection fraction; LVVes, left ventricular volume end systole; mg/kg, milligrams per kilograms; NTpro-BNP, N-terminal pro–B-type natriuretic; PC 16:0/18:2, phosphatidylcholine 16:0/18:2; SM d18:1/23:1, SM d18:2/23:0, SM d17:1/24:1, the sum of the 3 isobaric sphingomyelin species SM d18:1/23:1, SM d18:2/23:0, and SM d17:1/24:1 |
aWilcoxon rank sum test, bPearson’s chi-square test, cMantel-Haenszel chi-square. |
*Imputed using the median, 31%, of the normal range 20–40% |
† Median (Interquartile Range) |
The correlation of the CLP biomarkers TAG, PC, and SM were most correlated with the clinical characteristics triglycerides (r = 0.531, p < 0.001), total cholesterol (r = 0.431, p < 0.001), and LDL (r=, 0.502, p < 0.001), respectively (Supplemental Fig. 3).