Telomere length and outcome in heart failure

Figures & data

Figure 1. Telomere length, expressed as the telomere-to-single-reference-gene (T/S) ratio, is plotted as a function of age. Telomere length decreases with age at a mean yearly rate of 0.005 ± 0.001 in T/S ratio (P = 2.21 × 10−9). Shaded is the 95% confidence interval of the mean.

Table I. Base-line characteristics.

	Quartile of telomere length
Characteristics of the patients ^a	Quartile 1 (n = 222)	Quartile 2 (n = 223)	Quartile 3 (n = 223)	Quartile 4 (n = 222)	P-value	Total population n = 890
Telomere length ratio	0.52 [0.48–0.56]	0.64 [0.62–0.66]	0.77 [0.73–0.81]	1.02 [0.92–1.15]	Defining criterion	0.69 [0.59–0.86]
Natural log-transformed telomere length ratio	−0.67 ± 0.12	−0.45 ± 0.04	−0.26 ± 0.05	0.05 ± 0.17	Defining criterion	−0.33 ± 0.29
Age, yr	76 [68–81]	75 [66–80]	70 [62–78]	69 [59–78]	<0.001	73 [64–79]
Female sex, n (%)	76 (34)	86 (39)	91 (41)	91 (41)	0.43	344 (39)
COACH randomization	67/73/82 (30/33/37)	64/44/82 (29/35/37)	76/77/70 (34/35/31)	81/69/72 (36/31/32)	0.56	288/296/306 (32/33/34)
NYHA class, n (%)					0.36
II	104 (47)	114 (52)	120 (54)	109 (51)		447 (51)
III–IV	116 (53)	104 (48)	103 (46)	107 (49)		430 (49)
Age of onset CHF, yr	73 [66–79]	73 [64–78]	67 [58–76]	68 [57–76]	<0.001	70 [61–77]
Left ventricular ejection fraction (%)	34 ± 15	36 ± 14	34 ± 14	32 ± 14	0.07	34 ± 14
Body-mass index	26 [23–29]	26 [24–30]	26 [24–30]	26 [23–29]	0.49	26 [24–30]
Blood pressure, mmHg
Systolic	120 [102–130]	118 [105–130]	115 [105–130]	113 [100–130]	0.13	115 [101–130]
Diastolic	68 [60–73]	68 [60–75]	70 [60–80]	66 [60–75]	0.11	70 [60–76]
Heart rate, beats/min	72 [64–80]	74 [64–82]	74 [64–82]	74 [65–82]	0.56	72 [64–82]
Medical history, n (%)
Myocardial infarction	107 (48)	102 (46)	78 (35)	87 (39)	0.018	374 (42)
Hypertension	91 (41)	90 (40)	105 (47)	87 (39)	0.33	373 (42)
Diabetes	61 (27)	66 (30)	69 (31)	54 (24)	0.43	254 (29)
Atrial fibrillation	104 (47)	95 (43)	100 (45)	97 (44)	0.83	396 (45)
Stroke	26 (12)	15 (7)	28 (13)	21 (10)	0.17	90 (10)
Laboratory measurements
NT-proBNP, pg/dL	2864 [1513–6440]	2451 [900–5284]	2072 [1183–4576]	2856 [1480–5869]	0.15	2529 [1248–5522]
Serum sodium, mmol/L	139 [136–141]	139 [136–141]	139 [136–141]	139 [136–142]	0.94	139 [136–141]
Hemoglobin, mmol/L	8.2 [7.4–9.1]	8.3 [7.7–9.1]	8.5 [7.8–9.3]	8.6 [7.8–9.3]	0.017	8.4 [7.6–9.2]
Estimated GFR, mL/min/1.73m^2	48 [38–63]	54 [40–69]	56 [41–69]	57 [41–71]	0.015	54 [34–68]
Current medication, n (%)
RAS-inhibitors	168 (76)	185 (83)	191 (86)	194 (87)	0.006	738 (83)
Beta-blockers	146 (66)	141 (63)	151 (68)	149 (67)	0.76	587 (66)
Diuretics	215 (97)	215 (96)	215 (96)	208 (94)	0.38	851 (96)
Digoxin	65 (29)	75 (34)	77 (35)	59 (27)	0.23	276 (31)
Statins	82 (37)	84 (38)	91 (41)	85 (38)	0.85	342 (38)

^a Normally distributed data are presented as means ± SD, skewed distributed data as median [interquartile range]. The body-mass index is the weight in kilograms divided by the square of the height in meters. Diuretics includes loop diuretics, thiazides, and aldosterone antagonists.

CHF = chronic heart failure; COACH = Co-ordinating study evaluating outcomes of Advising and Counseling in Heart failure; NYHA = New York Heart Association functional class; CABG = coronary artery by-pass grafting; PCI = percutaneous coronary intervention; NT-proBNP = N-terminal pro-B-type natriuretic peptide; GFR = glomerular filtration rate estimated; RAS-inhibitors = renin-angiotensin system inhibitors (angiotensin-converting enzyme and/or angiotensin-receptor blocker).

Table II. Clinical and biochemical associations with telomere length.

Variable	Univariate (r)	Adjusted for age, age of onset CHF, and gender (Std Beta)
Body mass index	0.026 (P = 0.47)
Systolic blood pressure	−0.068 (P = 0.043)	−0.033 (P = 0.32)
Diastolic blood pressure	0.047 (P = 0.16)
Heart rate	0.023 (P = 0.49)
Left ventricular ejection fraction	−0.097 (P = 0.006)	−0.062 (P = 0.081)
N-terminal pro-B-type natriuretic peptide	−0.006 (P = 0.89)
Serum sodium	−0.023 (P = 0.49)
Hemoglobin	0.118 (P < 0.001)	0.101 (P = 0.003)
Estimated renal function	0.122 (P < 0.001)	0.073 (P = 0.041)

Figure 2. Kaplan-Meier curves for outcome according to quartile of telomere length. The telomere length quartiles were as follows: first quartile, less than 0.59; second quartile 0.59 to 0.69; third quartile 0.69 to 0.86; and fourth quartile, more than 0.86. P = 0.009 by the log-rank test for the overall comparison among groups.

Figure 3. Hazard ratios per unit decrease in telomere length ratio for outcome. The (adjusted) hazard ratio and 95% confidence intervals (CI) are shown for the primary outcome for telomere length ratio univariately (model 1), after adjustment for age, age of CHF onset, and gender (model 2), the model after adjustment for the covariates selected by forward and backward stepwise conditional selection (model 3), the model after adjustment for the covariates selected by the multivariable fractional polynominal closed-test algorithm (model 4), and the model after adjustment for the covariates selected by the Royston and Altman model selection algorithm (model 5). CHF = chronic heart failure; NT-proBNP = N-terminal pro-B-type natriuretic peptide; Hb = hemoglobin; EGFR = estimated renal function; CVA = history of cerebrovascular accident.

Figure 4. Distribution of telomere length and associated hazard ratio. The green bars represent the histogram of the untransformed telomere length ratio (horizontal axis versus percentage on left vertical axis). The red line represents the estimated hazard ratio for the primary end-point (total mortality and hospitalization for heart failure) after multivariable adjustment for age of onset, gender, estimated renal function, N-terminal pro-B-type natriuretic peptide, hemoglobin, a history of atrial fibrillation, and diabetes (model 3).