Abstract
Pulse pressure (PP) is affected by arterial stiffness and is a predictor of cardiovascular events. However, value and utility of PP assessment in patients with acute myocardial infarction (AMI) remain less clear. We aimed to evaluate the association between PP and cardiovascular events in surviving patients with AMI at discharge. A total of 11 944 surviving patients with AMI at discharge from a Korean nationwide registry were included. Blood pressure was checked just before discharge. Noncardiac death and major adverse cardiovascular events (MACEs) including cardiac death, AMI, and stroke after discharge were analyzed. The median follow‐up duration was 368 (IQR 339, 388) days. The rate of MACEs and cardiac death was higher in groups with the lowest PP (PP < 20 mm Hg) and highest PP (PP ≥ 71 mm Hg) and lowest in the group with PP of 31‐40 mm Hg. With PP of 31‐40 mm Hg as reference, univariate analysis showed a U‐shaped association between the risk of MACEs (PP ≤ 20 mm Hg: hazard ratio [HR] 2.3; PP ≥ 71 mm Hg: HR 2.7) or cardiac death (PP ≤ 20 mm Hg: HR 2.6; PP ≥ 71 mm Hg: HR 3.1) and PP. In multivariate analysis, the curve changed from being U‐shaped to J‐shaped, and HR for PP ≥ 71 mm Hg (1.2 for MACEs and 1.4 cardiac death) decreased and HR for PP < 20 (2.1 for MACEs and 2.4 for cardiac death) did not significantly decrease after adjustment for cardiovascular risk factors. Our findings indicate that PP is a strong independent prognostic factor of MACEs and cardiac death in surviving patients with AMI. Low PP is a more significant independent predictor of MACEs and cardiac death than high PP in surviving patients after AMI.
Keywords: acute myocardial infarction, cardiac death, major adverse cardiovascular events, pulse pressure
1. INTRODUCTION
Acute myocardial infarction (AMI) is a major cause of death and disability worldwide.1 Several studies have suggested several predictive markers for clinical outcomes in patients with AMI.
Pulse pressure (PP) refers to the difference between the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and is affected by atrial stiffness and the summation of a forward wave originating from the heart and propagating at a given speed (pulse wave velocity) and a backward wave returning to the heart. Therefore, an increase in PP leads to vascular component damage and increased cardiac stress, which can result in heart disease.2, 3 For example, increased PP results in fatigue and an increased fracture rate in the elastic components of the vessel wall, thereby increasing the risk of atherosclerosis. Increased PP is also associated with increased stress on the left ventricle. Elevated systolic pressure raises the myocardial oxygen requirement, and lower diastolic pressure may affect coronary perfusion.4 In the Framingham Heart study, each 10 mm Hg increase in PP was associated with an increase in the risk for development of coronary heart disease by about 23 percent.5 According to Roman et al,6 PP predicts adverse cardiovascular outcomes and may serve as a target in intervention strategies. The Strong Heart Study showed that PP was more strongly associated with vascular hypertrophy and atherosclerosis than SBP.7 Previous studies also reported that PP was associated with mortality in the general population or older patients with hypertension.8, 9
However, PP was inversely associated with adverse cardiovascular outcomes in patients with heart failure.10, 11 Laskey et al12 showed the nonlinear association between PP at hospital discharge and 1‐year outcomes in patients with heart failure.
Limited studies have assessed the relationship between PP and clinical outcomes in patients with AMI. A sub‐study of the Survival and Ventricular Enlargement (SAVE) trial showed that PP was an independent predictor of all‐cause mortality and recurrent AMI.13
The value and utility of PP assessment in patients with AMI remain less clear. Therefore, this study aimed to evaluate the association between PP and cardiovascular events in surviving patients with AMI at discharge.
2. METHODS
2.1. Study design and population
In Korea, efforts have been exerted to collect nationwide data and standardize clinical practice with respect to AMI management. We selected consecutive patients with AMI from the database of Korea Acute Myocardial Infarction Registry‐Korean National Institutes of Health (KAMIR‐KNIH). KAMIR‐KNIH is a prospective, multicenter, web‐based observational cohort study that aims to develop a prognostic and surveillance index for Korean patients with AMI. KAMIR‐KNIH was initiated in November 2011, with the participation of 15 centers in Korea; eventually, 20 centers participated in total. This prospective registry received grant support from the Korea Centers for Disease Control and Prevention. Patients with a diagnosis of AMI at presentation to a hospital have been enrolled and followed up continuously. The study is expected to complete the scheduled enrollment of approximately 13 000 patients in October 2015, and the follow‐up duration is up to 5 years for each patient. The aims and protocols of the registries have been published elsewhere.14, 15
The protocol of the present study was reviewed and approved by the institutional review board at each participating center of KAMIR‐KNIH. Data on demographics, procedures, medical/surgical history, medications and vital signs at admission/discharge, serum laboratory test results, in‐hospital outcomes and discharge status, and clinical outcomes were collected from the KAMIR‐KNIH database. All data were entered onto the database by well‐trained coordinators. Invalid or incomplete data were excluded from the present analysis.
We selected 13 104 patients with AMI from the database and included 11 944 patients with AMI in the study after excluding patients in whom in‐hospital death occurred and other diagnoses were established (n = 504) and in whom blood pressure was not checked before discharge (n = 656). Choice of treatment (percutaneous coronary intervention [PCI], coronary artery bypass grafting, or medications) was based on physician’s discretion. Coronary angiography and PCI were performed using standard techniques.16 Multivessel disease was defined as ≥70% stenosis in at least two major epicardial coronary arteries or ≥50% stenosis in the left main coronary artery. All patients underwent treatments after discharge according to current guidelines. Baseline characteristics of patients from all 20 centers were somewhat heterogenous (Table S1).
Electronic case report forms for data collection were developed and managed using Internet‐based clinical research and trial management system, a data management system established by the Korea Centers for Disease Control and Prevention with support from the Ministry of Health and Welfare.
2.2. Pulse pressure measurement
In accordance with the protocol of KAMIR‐KNIH, blood pressure of patients was measured at discharge. PP was defined as SBP minus DBP.
The protocol recommended that trained and quality‐controlled examiners manually measured BP using a mercury sphygmomanometer while the subject was seated. The subjects were asked to refrain from smoking for 30 minutes before the measurement and rested for 5 minutes before the measurements. Three measurements were obtained at 30‐second intervals. The average of the second and third measurements was used as the mean SBP or DBP value. PP was obtained by subtracting DBP from SBP.
2.3. Clinical outcomes
All deaths were considered cardiac deaths unless a noncardiac origin was documented. Recurrent AMI was defined as recurrent AMI symptoms with new ST segment elevation or re‐elevation in cardiac marker level to at least twice the upper normal limit. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiac death, recurrent AMI, and cerebrovascular accident.
2.4. Statistical analysis
All statistical analyses were performed using SPSS version 20.0 (IBM Corp., Armonk, NY). Baseline data are expressed as frequencies or mean and 95% confidence interval (95% CI). Continuous variables were compared using an ANOVA test, and categorical variables were compared using the chi‐square test. Patients were stratified into seven groups according to PP (PP ≤ 20 mm Hg [range, 10‐20 mm Hg], 21‐30 mm Hg, 31‐40 mm Hg [reference group], 41‐50 mm Hg, 51‐60 mm Hg, 61‐70 mm Hg, and ≥71 mm Hg). The PP category with the lowest MACE risk was used as the reference group. Cox proportional hazards models were used to evaluate the association between PP at discharge and MACEs and cardiac death. Analyses were adjusted for the following covariates: old age (>60 years); male sex; body mass index (>24 kg/m2); history of hypertension, diabetes, and dyslipidemia; renal failure (creatinine level > 2.0 mg/dL); left ventricular (LV) dysfunction, characterized by an LV ejection fraction of <50%; current smoking; multivessel disease or LM disease; STEMI vs NSTEMI; poor Killip classification, characterized by Killip ≥3; and medications (beta‐blocker, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, statin). Patients lost to follow‐up were considered at risk until the date of last contact, at which point their data were censored. Results of risk analyses are provided as hazard ratio (HR) with 95% confidence interval (95% CI).
3. RESULTS
3.1. Baseline characteristics
The median follow‐up duration was 368 days (range, 0‐826 days). Patients were classified into seven groups according to PP. As PP increased, SBP increased and DBP decreased. A history of diabetes, hypertension, CVA, angina, myocardial infarction, renal dysfunction and multivessel disease, and NSTEMI were more frequent in older patients in the high PP groups. Conversely, patients in the lower PP groups tended to have higher levels of current smoking, lower BMI, and LV dysfunction (Table 1). MACEs occurred in 710 patients. Patients with MACEs were older; had higher creatinine, brain natriuretic peptide, and high‐sensitivity C‐reactive protein levels, lower ejection fraction and body mass index, and poorer Killip class; and were less likely to have underwent PCI or used beta‐blocker, renin‐angiotensin‐aldosterone system blocker, and statin. PP and SBP were higher (both P < 0.001), and DBP was lower (P = 0.041) in patients with MACEs than in those without MACEs (Table 2).
Table 1.
Baseline characteristics according to discharge pulse pressure
| PP group (mm Hg) |
>‐20 n = 87 |
21‐30 n = 1323 |
31‐40 n = 4781 |
41‐50 n = 3270 |
51‐60 n = 1621 |
61‐70 n = 575 |
71‐< n = 287 |
P‐Value |
|---|---|---|---|---|---|---|---|---|
| Age, y | 62.9 (60.3‐65.5) | 61.8 (61.1‐62.4) | 63.0 (62.7‐62.4) | 63.0 (62.5‐63.4) | 64.9 (64.3‐65.5) | 68.4 (67.4‐69.3) | 70.9 (69.6‐72.2) | <0.001 |
| Men, n (%) | 65 (94.7) | 985 (74.5) | 3592 (75.1) | 2491 (76.2) | 1187 (73.2) | 394 (68.5) | 174 (60.6) | <0.001 |
| SBP at discharge, mm Hg | 95.0 (92.7‐97.4) | 96.6 (96.2‐97.1) | 107.0 (106.7‐107.2) | 116.5 (116.1‐116.9) | 125.6 (125.1‐126.2) | 134.5 (133.6‐135.5) | 147.6 (146.0‐149.3) | <0.001 |
| DBP at discharge, mm Hg | 76.3(73.8‐78.8) | 67.0 (66.5‐67.5) | 67.7 (67.4‐67.9) | 68.6 (68.2‐68.9) | 68.6 (68.1‐69.9) | 68.4 (65.8‐66.4) | 66.7 (79.8‐82.1) | <0.001 |
| PP at discharge, mm Hg | 18.7 (18.0‐19.4) | 29.6 (29.5‐29.7) | 39.3 (39.2‐39.3) | 47.9 (47.8‐48.0) | 57.0 (56.8‐57.1) | 66.1 (65.8‐66.4) | 80.9 (79.8‐82.1) | <0.001 |
| STEMI, n (%) | 51 (58.6) | 768 (58.0) | 2389 (50.0) | 1531 (46.8) | 671 (41.4) | 199 (34.6) | 76 (26.5) | <0.001 |
| NSTEMI, n (%) | 36 (41.4) | 555 (42.0) | 2392 (50.0) | 1739 (53.2) | 950 (58.6) | 376 (65.4) | 211 (73.5) | <0.001 |
| Medical history, n (%) | ||||||||
| Hypertension | 37 (42.5) | 531 (40.1) | 2197 (46.0) | 1702 (52.0) | 988 (61.0) | 390 (67.8) | 218 (76.0) | <0.001 |
| Diabetes | 18 (20.7) | 280 (21.2) | 1272 (26.6) | 892 (27.3) | 527 (32.5) | 223 (38.8) | 145 (50.5) | <0.001 |
| Dyslipidemia | 3 (3.4) | 128 (9.7) | 506 (10.6) | 412 (12.6) | 208 (12.8) | 77 (13.4) | 36 (12.5) | <0.001 |
| Current smoking | 34 (39.1) | 604 (45.7) | 1972 (41.2) | 1315 (40.2) | 589 (36.3) | 158 (27.5) | 74 (25.8) | <0.001 |
| CVA | 8 (9.2) | 68 (5.1) | 304 (6.4) | 185 (5.7) | 111 (6.8) | 60 (10.4) | 40 (13.9) | <0.001 |
| Prior angina | 4 (4.6) | 113 (8.5) | 411 (8.6) | 293 (9.0) | 183 (11.3) | 85 (14.8) | 50 (17.4) | <0.001 |
| Prior myocardial infarction | 12 (13.8) | 99 (7.5) | 355 (7.4) | 234 (7.2) | 148 (9.1) | 52 (9.0) | 28 (9.8) | 0.042 |
| Laboratory finding | ||||||||
| Glucose, mg/dL | 152.4 (139.5‐165.4) | 163.4 (159.4‐167.5) | 165.3 (163.1‐167.5) | 166.2 (163.4‐169.0) | 168.7 (164.6‐172.7) | 169.9 (163.5‐176.3) | 198.8 (185.8‐211.8) | <0.001 |
| Creatinine, mg/dL | 1.03 (0.84‐1.21) | 0.94 (0.90‐0.98) | 1.00 (0.97‐1.02) | 1.10 (1.06‐1.14) | 1.26 (1.19‐1.14) | 1.42 (1.28‐1.56) | 2.02 (1.78‐2.28) | <0.001 |
| LDL‐cholesterol, mg/dL | 112.2 (101.3‐123.0) | 115.6 (113.3‐117.9) | 113.5 (112.3‐114.7) | 113.4 (111.9‐114.8) | 108.7 (106.8‐110.8) | 104.5 (101.2‐107.8) | 100.3 (95.3‐105.2) | <0.001 |
| Peak CK‐MB, ng/mL | 132.1 (104.2‐160.0) | 140.1 (131.8‐148.5) | 118.8 (114.1‐123.4) | 106.2 (100.3‐112.0) | 78.4 (71.8‐84.9) | 60.7 (51.8‐69.6) | 42.6 (34.2‐51.1) | <0.001 |
| Peak Troponin I, ng/mL | 38.2 (26.8‐49.6) | 55.0 (49.9‐60.6) | 44.8 (41.8‐47.8) | 47.6 (43.1‐52.0) | 39.2 (35.1‐43.2) | 29.9 (24.1‐35.6) | 18.4 (1406‐22.1) | <0.001 |
| NT‐pro BNP, pg/dL | 2158.5 (576.6‐3740.3) | 1768.8 (1448.2‐2089.5) | 1843.7 (1643.9‐2043.6) | 2241.4 (1838.1‐2644.7) | 3486.4 (2795.9‐4176.9) | 3818.8 (3060.7‐4576.9) | 6495.1 (4994.1‐7996.2) | <0.001 |
| hs‐CRP, mg/L | 0.92 (0.15‐1.70) | 1.46 (1.20‐1.73) | 1.64 (1.36‐1.91) | 1.21 (0.99‐1.44) | 1.23 (1.05‐1.42) | 1.81 (0.76‐2.85) | 2.14 (1.22‐3.06) | 0.115 |
| BMI, kg/m2 | 23.4 (22.7‐24.1) | 23.7 (23.5‐23.9) | 23.9 (23.8‐24.1) | 24.3 (24.2‐24.4) | 24.2 (23.9‐24.3) | 24.0 (23.7‐24.3) | 23.5 (23.1‐23.9) | <0.001 |
| Renal dysfunction (Cr > 2.0 mg/dL) | 2 (2.3) | 27 (2.0) | 153 (3.2) | 142 (4.3) | 124 (7.6) | 62 (10.8) | 76 (26.5) | <0.001 |
| EF, % | 51.7 ± 11.9 | 50.6 ± 11.0 | 52.1 ± 11.0 | 52.8 ± 10.6 | 52.9 ± 11.0 | 53.1 ± 11.1 | 51.4 ± 12.4 | <0.001 |
| LVEF < 50%, n (%) | 36 (42.4) | 590 (45.3) | 1814 (38.9) | 1088 (34.5) | 525 (33.6) | 192 (34.7) | 97 (35.7) | <0.001 |
| Killip class III, IV, n (%) | 15 (17.2) | 171 (12.9) | 488 (10.2) | 324 (9.9) | 202 (12.5) | 79 (13.7) | 59 (20.6) | 0.004 |
| Angiographic finding | ||||||||
| Multivessel disease, n (%) | 35 (40.7) | 558 (42.5) | 2243 (47.2) | 1582 (49.0) | 860 (54.1) | 311 (56.0) | 151 (54.9) | <0.001 |
| Culprit vessel, n (%) | ||||||||
| LM | 3 (3.9) | 17 (1.4) | 88 (2.0) | 59 (2.0) | 28 (2.0) | 15 (3.1) | 3 (1.4) | 0.002 |
| LAD | 33 (43.4) | 622 (50.7) | 2105 (48.0) | 1331 (45.1) | 617 (43.2) | 203 (41.6) | 102 (46.4) | 0.002 |
| LCX | 15 (19.7) | 201 (16.4) | 750 (17.1) | 545 (18.5) | 265 (18.5) | 81 (16.6) | 42 (19.1) | 0.002 |
| RCA | 25 (32.9) | 387 (31.5) | 1446 (32.9) | 1015 (34.4) | 519 (36.3) | 189 (38.7) | 73 (33.2) | 0.002 |
| Initial TIMI flow 0, n (%) | 46 (60.5) | 834 (68.0) | 2601 (59.3) | 1658 (56.2) | 721 (50.5) | 222 (45.5) | 101 (45.9) | <0.001 |
| Post‐TIMI flow < 3, n (%) | 3(3.9) | 51 (4.2) | 125 (2.8) | 102 (3.5) | 32 (2.2) | 8 (1.6) | 7 (3.2) | 0.026 |
| PCI, n, (%) | 76 (87.4) | 1226 (92.7) | 4383 (91.7) | 2945 (90.1) | 1425 (87.9) | 487 (84.7) | 219 (76.3) | <0.001 |
| At discharge medication, n (%) | ||||||||
| Aspirin | 87 (100) | 1320 (99.8) | 4766 (99.7) | 3261 (99.7) | 1615 (99.6) | 574 (99.8) | 283 (98.6) | 0.095 |
| P2Y12 inhibitor | 87 (100) | 1312 (99.2) | 4749 (99.3) | 3249 (99.4) | 1608 (99.2) | 573 (99.7) | 281 (97.9) | 0.353 |
| CCB | 9 (10.3) | 59 (4.5) | 285 (6.0) | 296 (9.1) | 203 (12.5) | 91 (15.8) | 68 (23.7) | <0.001 |
| Beta‐blocker | 66 (75.9) | 1096 (82.8) | 4033 (84.4) | 2734 (83.6) | 1374 (84.8) | 480 (83.5) | 236 (82.2) | 0.295 |
| RAAS blocker | 62 (71.3) | 1021 (77.2) | 3863 (80.8) | 2600 (79.5) | 1296 (80.0) | 461 (80.2) | 223 (77.7) | 0.035 |
| Statin | 82 (94.3) | 1241 (93.8) | 4469 (93.5) | 3076 (94.1) | 1519 (93.7) | 533 (92.7) | 248 (86.4) | 0.002 |
Data given as number (%) or mean (95% confidence interval).
Abbreviations: BMI, body mass index; CCB, calcium channel blocker; CVA, cerebrovascular attack; DBP, diastolic blood pressure; EF, ejection fraction; hs‐CRP, high‐sensitivity C‐reactive protein; LAD, left anterior descending artery; LCX, left circumflex artery; LDL‐C, low‐density lipoprotein cholesterol; LM, left main; (N)STEMI, (non)‐ST elevation myocardial infarction; PCI, percutaneous coronary intervention; PP, pulse pressure; RAAS, renin‐aldosterone‐angiotensin system; RCA, right coronary artery; SBP, systolic blood pressure; TIMI, thrombolysis in myocardial infarction.
Table 2.
Baseline characteristics according to major cardiovascular events
| MACEs (−) n = 11 234 | MACEs (+) n = 710 | P‐Value | |
|---|---|---|---|
| Age, y | 63.0 (62.8‐63.3) | 71.2 (70.4‐72.1) | <0.001 |
| Male sex, n, (%) | 7977 (75.6) | 911 (65.7) | <0.001 |
| SBP at discharge, mm Hg | 113.0 (112.8‐113.3) | 114.7 (113.6‐116.2) | 0.002 |
| DBP at discharge, mm Hg | 68.1 (67.9‐68.3) | 67.6 (66.6‐68.1) | 0.041 |
| PP at discharge, mm Hg | 45.0 (44.8‐45.2) | 47.5 (46.5‐48.5) | <0.001 |
| STEMI, n (%) | 5103 (48.3) | 582 (42.0) | <0.001 |
| NSTEMI, n (%) | 5455 (51.7) | 804 (58.0) | <0.001 |
| Medical history, n (%) | |||
| Hypertension | 5187 (49.1) | 876 (63.2) | <0.001 |
| Diabetes | 2832 (26.8) | 525 (37.9) | <0.001 |
| Dyslipidemia | 1231 (11.7) | 139 (10.0) | 0.073 |
| Current smoking | 4314 (40.9) | 4.2 (31.2) | <0.001 |
| CVA | 647 (6.1) | 129 (9.3) | <0.001 |
| Prior angina | 946 (9.0) | 193 (13.9) | <0.001 |
| Prior myocardial infarction | 763 (7.2) | 165 (11.9) | <0.001 |
| Laboratory finding | |||
| Glucose, mg/dL | 164.9 (164.2‐167.1) | 184.2 (177.2‐191.1) | <0.001 |
| Creatinine, mg/dL | 1.07 (1.05‐1.09) | 1.55 (1.43‐2.67) | <0.001 |
| LDL‐cholesterol, mg/dL | 113.1 (112.3‐113.8) | 99.8 (96.6‐103.8) | <0.001 |
| Peak CK‐MB, ng/mL | 109.3 (106.3‐112.2) | 82.1 (71.9‐92.3) | <0.001 |
| Peak troponin I, ng/mL | 44.8 (42.8‐46.8) | 37.5 (32.2‐42.8) | 0.064 |
| NT‐proBNP, pg/mL | 2026.0 (1854.4‐2197.7) | 7932.8 (6745.4‐9120.3) | <0.001 |
| hs‐CRP, mg/L | 1.40 (1.25‐1.54) | 2.54 (2.08‐2.99) | <0.001 |
| BMI (kg/m2) | 24.1 (24.1‐24.1) | 22.9 (22.7‐23.2) | <0.001 |
| EF (%) | 52.6 (52.3‐52.8) | 47.7 (46.6‐48.7) | <0.001 |
| LVEF <50%, n (%) | 3674 (35.8) | 668 (50.2) | <0.001 |
| Killip class III or IV, n (%) | 1042 (9.9) | 296 (21.4) | <0.001 |
| Angiographic finding, n (%) | |||
| Multivessel disease | 4881 (46.6) | 859 (64.6) | <0.001 |
| Culprit vessel (%) | |||
| LM | 162 (1.7) | 51 (4.3) | <0.001 |
| LAD | 4482 (46.7) | 531 (45.0) | <0.001 |
| LCX | 1709 (17.8) | 190 (16.1) | <0.001 |
| RCA | 3246 (33.8) | 408 (34.6) | <0.001 |
| Initial TIMI flow grade 0/1, n (%) | 5552 (57.8) | 631 (53.5) | 0.004 |
| Post‐TIMI flow grade <3, n (%) | 281 (2.9) | 47 (4.0) | 0.046 |
| PCI, n (%) | 9584 (90.8) | 1177 (84.9) | <0.001 |
| Medication at discharge, n (%) | |||
| Aspirin | 10528 (99.7) | 1378 (99.4) | 0.069 |
| P2Y12 inhibitor | 10487 (99.3) | 1372 (99.0) | 0.16 |
| Calcium channel blocker | 911 (8.6) | 100 (7.2) | 0.075 |
| Beta‐blocker | 8925 (84.5) | 1094 (78.9) | <0.001 |
| RAAS blocker | 8485 (80.4) | 1041 (75.1) | <0.001 |
| Statin | 9949 (94.2) | 1219 (88.0) | <0.001 |
Data given as number (%) or mean (95% confidence interval).
Abbreviations: BMI, body mass index; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CK‐MB, creatine kinase‐MB; CVA, cerebrovascular accident; DBP, diastolic blood pressure; EF, ejection fraction; hs‐CRP, high‐sensitivity C‐reactive protein; LAD, left anterior descending; LCX, left circumflex; LDL, low‐density lipoprotein; LM, left main; LVEF, left ventricular ejection fraction; MACEs, major adverse cardiovascular events; NSTEMI, non‐ST segment elevation myocardial infarction; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; PCI, percutaneous coronary intervention; PP, pulse pressure; RAAS, renin‐angiotensin‐aldosterone system; RCA, right coronary artery; SBP, systolic blood pressure; STEMI, ST segment elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction.
3.2. Relationship with pulse pressure based on blood pressure, sex, and age
Pulse pressure and SBP increased with increasing age, whereas DBP decreased with increasing age, with both sexes showing a similar pattern (Figure 1). Creatinine (r = 0.167, P < 0.001) and brain natriuretic peptide (r = 0.125, P < 0.001) levels positively correlated to PP.
Figure 1.
Trends in systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) according to age and sex
3.3. Clinical outcomes
The rate of MACEs and cardiac death was highest in the groups with the lowest and highest PP and lowest in the group with PP of 31‐40 mm Hg. In groups with PP > 40 mm Hg and <40 mm Hg, the rate of MACEs and cardiac death increased and decreased, respectively, as increased PP. Moreover, the rate of noncardiac death and AMI was high in the groups with the lowest and highest PP, albeit without statistical significance. Rate of stroke did not show statistically change with increased PP (Table 3).
Table 3.
Clinical outcomes according to pulse pressure
| <20 mm Hg n = 87 | 21‐30 mm Hg n = 1323 | 31‐40 mm Hg n = 4781 | 41‐50 mm Hg n = 3270 | 51‐60 mm Hg n = 1621 | 61‐70 mm Hg n = 575 | >71 mm Hg n = 287 | P trend | |
|---|---|---|---|---|---|---|---|---|
| MACEs, n, (%) | 10 (11.5) | 74 (5.6) | 244 (5.1) | 182 (5.6) | 116 (7.2) | 44 (7.7) | 40 (13.9) | <0.001 |
| CD, n, (%) | 6 (6.9) | 39 (2.9) | 119 (2.5) | 92 (2.8) | 63 (3.9) | 26 (4.5) | 36 (12.5) | <0.001 |
| AMI, n, (%) | 5 (5.7) | 28 (2.1) | 87 (1.8) | 64 (2.0) | 35 (2.2) | 14 (2.4) | 11 (3.8) | 0.243 |
| Stroke, n, (%) | 1 (1.1) | 15 (1.1) | 55 (1.2) | 36 (1.1) | 22 (1.4) | 7 (1.2) | 4 (1.4) | 0.579 |
| NCD, n, (%) | 2 (2.3) | 23 (1.7) | 70 (1.5) | 45 (1.4) | 28 (1.7) | 12 (2.1) | 9 (3.1) | 0.384 |
Data given as number (%).
Abbreviations: AMI, acute myocardial infarction; CD, cardiac death; MACEs, major adverse cardiovascular events; NCD, noncardiac death.
Kaplan‐Meier curves showed that the cumulative rate of MACEs and cardiac death was higher in the group with PP ≤ 20 mm Hg or PP ≥ 70 mm Hg than in other groups (log‐rank P < 0.001). (Figure 2)
Figure 2.
Kaplan‐Meier curves according to pulse pressure. Cumulative rates of (A) major adverse cardiovascular events (MACEs) and (B) cardiac death according to pulse pressure
3.4. Association between pulse pressure and outcomes in patients with acute myocardial infarction
Univariate and multivariate analyses were performed to evaluate the risk of PP for MACEs and cardiac death. In the univariate analysis, old age, male sex, hypertension, diabetes, dyslipidemia, BMI, LV function, use of b‐blocker, RAAS blocker, and statin were predictors of MACE and cardiac death. Old age, male sex, hypertension, diabetes, BMI, LV function, and use of b‐blockers and statins were independent predictors of MACE and cardiac death in the multivariate analysis (Tables 4, 5 and 4, 5). Univariate analysis showed a U‐shaped association between the risk (HR) of MACEs (PP ≤ 20 mm Hg: HR 2.2; PP ≥ 71 mm Hg: HR 2.9; reference: PP 31‐40 mm Hg) or cardiac death (PP ≤ 20 mm Hg: HR 2.4; PP ≥ 71 mm Hg: HR 3.3; reference: PP 31‐40 mm Hg) and PP. In multivariate analysis, the curve changed from being U‐shaped to J‐shaped, and HR for PP ≥ 71 mm Hg (1.3 for MACEs and 1.5 for cardiac death) decreased after adjustment for cardiovascular risk factors (Figure 3).
Table 4.
Univariate analysis and multivariate analysis for major cardiovascular events
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P Value | HR | 95% CI | P Value | |
| Old age (>60 y) | 3.13 | 2.59‐3.77 | <0.001 | 2.21 | 1.77‐2.78 | <0.001 |
| Male gender | 0.56 | 0.48‐0.65 | <0.001 | 0.82 | 0.69‐0.99 | 0.036 |
| Hypertension | 1.83 | 1.57‐2.14 | <0.001 | 1.29 | 1.08‐1.54 | 0.006 |
| Diabetes mellitus | 1.99 | 1.71‐2.31 | <0.001 | 1.38 | 1.16‐1.65 | <0.001 |
| Dyslipidemia | 0.77 | 0.59‐0.99 | 0.045 | 0.83 | 0.63‐1.10 | 0.197 |
| Body mass index (>24 kg/m2) | 0.62 | 0.53‐0.73 | <0.001 | 0.80 | 0.68‐0.95 | <0.001 |
| LV dysfunction (EF < 50%) | 1.80 | 1.55‐2.09 | <0.001 | 1.37 | 1.60‐1.63 | <0.001 |
| Renal failure (Cr > 2.0 mg/dL) | 4.40 | 3.62‐5.34 | <0.001 | 2.37 | 1.86‐3.03 | <0.001 |
| Current smoking | 0.57 | 0.49‐0.68 | <0.001 | 1.08 | 0.88‐1.32 | 0.466 |
| Multivessel disease & LM disease | 1.53 | 1.31‐1.79 | <0.001 | 1.22 | 1.03‐1.43 | 0.021 |
| STEMI vs NSTEMI | 0.60 | 0.51‐0.70 | <0.001 | 0.69 | 0.59‐0.83 | <0.001 |
| Killip class >2 | 2.57 | 2.16‐3.06 | <0.001 | 1.48 | 1.21‐1.82 | <0.001 |
| Medication use | ||||||
| beta‐blocker | 0.65 | 0.54‐0.77 | <0.001 | 0.83 | 0.67‐1.02 | 0.078 |
| ACEI or ARB | 0.70 | 0.59‐0.83 | <0.001 | 0.95 | 0.78‐1.16 | 0.588 |
| Statin | 0.38 | 0.31‐0.47 | <0.001 | 0.66 | 0.51‐0.86 | 0.002 |
| PP group (mm Hg) | ||||||
| >‐20 | 2.34 | 1.24‐4.40 | 0.008 | 2.14 | 1.06‐4.35 | 0.035 |
| 21‐30 | 1.11 | 0.86‐1.44 | 0.419 | 1.20 | 0.91‐1.59 | 0.195 |
| 31‐40 | Reference | Reference | ||||
| 41‐50 | 1.08 | 0.89‐1.31 | 0.415 | 1.02 | 0.83‐1.25 | 0.887 |
| 51‐60 | 1.41 | 1.13‐1.76 | 0.002 | 0.08 | 0.85‐1.38 | 0.521 |
| 61‐70 | 1.50 | 1.09‐2.07 | 0.014 | 0.87 | 0.60‐1.27 | 0.475 |
| 71‐< | 2.72 | 1.95‐3.80 | <0.001 | 1.21 | 0.83‐1.77 | 0.328 |
Abbreviations: CI, confidence interval; EF, ejection fraction; HR, hazard ratio; LM, left main; (N)STEMI, (non)‐ST elevation myocardial infarction; PP, pulse pressure; RAAS, renin‐aldosterone‐angiotensin system.
Table 5.
Univariate analysis and multivariate analysis for cardiac death
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P Value | HR | 95% CI | P Value | |
| Old age (>60 y) | 3.11 | 2.53‐3.83 | <0.001 | 2.22 | 1.72‐2.85 | <0.001 |
| Male gender | 0.58 | 0.49‐0.69 | <0.001 | 0.86 | 0.70‐1.06 | 0.148 |
| Hypertension | 1.77 | 1.50‐2.09 | <0.001 | 1.24 | 1.01‐1.52 | 0.036 |
| Diabetes mellitus | 1.99 | 1.69‐2.35 | <0.001 | 1.37 | 1.13‐1.66 | 0.002 |
| Dyslipidemia | 0.67 | 0.50‐0.90 | 0.009 | 0.73 | 0.53‐1.01 | 0.060 |
| Body mass index (>24 kg/m2) | 0.64 | 0.54‐0.76 | <0.001 | 0.85 | 0.71‐1.03 | 0.099 |
| LV dysfunction (EF < 50%) | 2.11 | 1.79‐2.50 | <0.001 | 1.58 | 1.30‐1.91 | <0.001 |
| Renal failure (Cr > 2.0 mg/dL) | 4.98 | 4.05‐6.12 | <0.001 | 2.52 | 1.94‐3.29 | <0.001 |
| Current smoking | 0.58 | 0.48‐0.69 | <0.001 | 1.10 | 0.88‐1.37 | 0.422 |
| Multivessel disease & LM disease | 1.55 | 1.31‐1.85 | <0.001 | 1.22 | 1.02‐1.47 | 0.034 |
| STEMI vs NSTEMI | 0.60 | 0.50‐0.70 | <0.001 | 0.67 | 0.56‐0.82 | <0.001 |
| Killip class >2 | 2.98 | 2.47‐3.58 | <0.001 | 1.63 | 1.31‐2.04 | <0.001 |
| Medication use | ||||||
| beta‐blocker | 0.57 | 0.47‐0.69 | <0.001 | 0.76 | 0.61‐0.96 | 0.019 |
| RAAS blocker | 0.63 | 0.52‐0.75 | <0.001 | 0.90 | 0.73‐1.12 | 0.350 |
| Statin | 0.35 | 0.28‐0.44 | <0.001 | 0.68 | 0.51‐0.90 | 0.006 |
| PP group | ||||||
| >‐20 | 2.61 | 1.34‐5.10 | 0.005 | 2.37 | 1.11‐5.05 | 0.026 |
| 21‐30 | 1.14 | 0.86‐1.52 | 0.364 | 1.25 | 0.92‐1.70 | 0.159 |
| 31‐40 | Reference | Reference | ||||
| 41‐50 | 1.11 | 0.90‐1.38 | 0.326 | 1.06 | 0.84‐1.34 | 0.604 |
| 51‐60 | 1.42 | 1.11‐1.82 | 0.005 | 1.08 | 0.82‐1.42 | 0.595 |
| 61‐70 | 1.57 | 1.11‐2.24 | 0.012 | 0.93 | 0.61‐1.41 | 0.737 |
| 71‐80 | 3.06 | 2.14‐4.37 | <0.001 | 1.36 | 0.90‐2.04 | 0.141 |
Abbreviations: CI, confidence interval; EF, ejection fraction; HR, hazard ratio; LM, left main; (N)STEMI, (non)‐ST elevation myocardial infarction; PP, pulse pressure; RAAS, renin‐aldosterone‐angiotensin system.
Figure 3.
Risk of major adverse cardiovascular events (MACEs) and cardiac death vs pulse pressure (PP) at discharge in acute myocardial infarction. U‐shaped association between the risk (hazard ratio [HR]) of MACEs (A) and cardiac death (C) and PP in the univariate analysis and J‐shaped association between the risk of MACEs (B) and cardiac death (D) and PP in the multivariate analysis. CI, confidence interval
In the group with PP < 40 mm Hg, an increase in PP (for every 10 mm Hg) was associated with favorable outcomes with respect to cardiac death (adjusted HR, 0.748; 95% CI, 0.577‐0.970; P = 0.028) and MACEs (adjusted HR, 0.784; 95% CI, 0.620‐0.992; P = 0.043). In the group with PP > 40 mm Hg, the risk of cardiac death (adjusted HR, 1.039; 95% CI, 0.955‐1.130; P = 0.374) or MACE (adjusted HR, 1.017; 95% CI, 0.942‐1.098; P = 0.664) increased as PP increased (for every 10 mm Hg), albeit without statistical significance (Table 6).
Table 6.
Association between pulse pressure at discharge and MACEs and cardiac death in patients with acute myocardial infarction
| Unadjusted HR (95% CI) | P‐Value | Adjusted HR (95% CI) | P‐Value | ||
|---|---|---|---|---|---|
| MACEs | PP (for every 10 mm Hg increase in PP up to 40 mm Hg) | 0.775 (0.610‐0.985) | 0.037 | 0.784 (0.620‐0.992) | 0.043 |
| PP (for every 10 mm Hg increase in PP ≥ 40 mm Hg) | 1.242 (1.157‐1.333) | <0.001 | 1.017 (0.942‐1.098) | 0.664 | |
| Cardiac death | PP (for every 10 mm Hg increase in PP up to 40 mm Hg) | 0.785 (0.605‐1.017) | 0.067 | 0.748 (0.577‐0.970) | 0.028 |
| PP (for every 10 mm Hg increase in PP ≥ 40 mm Hg) | 1.257 (1.166‐1.356) | <0.001 | 1.039 (0.955‐1.130) | 0.374 |
Abbreviations: CI, confidence interval; HR, hazard ratio; MACEs, major adverse cardiovascular events; PP, pulse pressure.
Analyses were adjusted for the following covariates: old age (>60 y); male sex; body mass index (>24 kg/m2); history of hypertension, diabetes, and dyslipidemia; renal failure (creatinine level > 2.0 mg/dL); left ventricular (LV) dysfunction, characterized by LV ejection fraction <50%; current smoking; multivessel disease or LM disease; STEMI vs NSTEMI, poor Killip classification, characterized by Killip ≥3; and medications (beta‐blocker, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, statin).
4. DISCUSSION
In the present study, we evaluated the association between PP and cardiovascular events in surviving patients with AMI at discharge and found that PP at discharge after AMI is significantly associated with adverse events at 1 year. PP increased with increasing age, with both sexes showing a similar pattern. PP was higher in the group with lean body weight or obesity. The rate of MACEs and cardiac death was highest in the groups with the lowest and highest PP and lowest in the group with PP of 31‐40 mm Hg. Univariate analysis showed a U‐shaped association between the risk of MACEs or cardiac death and PP at discharge, and HR was higher in the groups with high and low PP. In multivariate analysis, the curve changed from being U‐shaped to J‐shaped, and HR for high PP decreased after adjustment for cardiovascular risk factors.
Pulse pressure, a surrogate marker of artery stiffness, is simply calculated by subtracting DBP from SBP.17 An increase in PP leads to additional stress in the vessels, resulting in increased damage to elastic vascular components. The vascular intima becomes frail owing to the damage, thereby increasing the risk of atherosclerosis and thrombosis. Further, an increase in PP is associated with increased cardiac stress, which can lead to heart disease.3 The Multiple Risk Factor Intervention Trial showed that the risk of cardiovascular mortality was 22% higher for the highest PP quartile than for the lowest PP quartile, particularly among older individuals.18 Laskey et al12 investigated the association of PP with clinical outcomes in patients with heart failure and reported a significant association between PP and mortality in patients with heart failure and preserved ejection fraction (≥0.40), with risk increasing as PP increased. Limited studies have assessed the relationship between PP and clinical outcomes in patients with AMI. A sub‐study of SAVE trial showed that PP was an independent predictor of all‐cause mortality and recurrent AMI.13 The study population of the present study comprised all patients diagnosed with AMI, particularly surviving patients at discharge. Blood pressure was checked just before discharge. We found that PP is a predictor of MACEs and cardiac death even after adjustment for baseline characteristics.
Pulse pressure is determined by cardiac function and arterial stiffness through wave reflections.19 High PP is associated with arterial stiffness, which is linked to risk factors such as hypertension, aging, diabetes, and renal failure.20, 21 The Rotterdam Study reported a strong positive association between carotid‐femoral pulse wave velocity and carotid intima‐media thickness.22 Further, arterial stiffness may be a useful marker of the extent of atherosclerosis.23 The relationship between PP and mortality paradoxically appears to be reversed in heart failure with reduced ejection fraction; a previous study suggested that a lower PP is not an index of arterial stiffness but represents reduced cardiac function and lower stroke volume.24 Low PP < 45 mm Hg is independently associated with increased mortality in heart failure, whereas elevated natriuretic peptides are significantly correlated to lower PP.11 In our study, the rate of MACEs and cardiac death was highest in the groups with the lowest and highest PP, and the risk of MACEs and cardiac death increased in the groups with low and high PP, with HR for high PP being significantly decreased after adjustment for cardiovascular risk factors.
Patients with AMI not only have atherosclerosis but also have reduced cardiac function. PP reflects a complex interaction between the heart and vascular systems and is affected by cardiac parameters (diastolic filling and contractility) and hemodynamic factors (stroke volume and peak aortic blood flow).24 AMI leads to loss of contractile fibers, which reduces systolic function,25 and progressive LV remodeling, which is associated with long‐term mortality and morbidity,26 and also affects diastolic function. The risk of MACEs decreased after adjustment for high PP, but HR for low PP did not significantly change after adjustment; hence, low PP is more associated with cardiac function than high PP in patients with AMI.
4.1. Study limitations
Our study has several limitations. First, the present study was based on registry data. Although rigorous adjustment analyses were performed, unmeasured hidden biases may have remained, and a large number of patients were excluded as their blood pressure was not checked before discharge. Second, the lost to follow‐up rate was high. Because data collection was voluntarily performed at each participating center, follow‐up data were partially incomplete. Third, we could not obtain the data on follow‐up blood pressure status and maintenance medications. However, the merits of this study include a large sample size, multicenter design, and prospective data collection. Furthermore, blood pressure was simply and easily checked.
4.2. Conclusions
Pulse pressure is well known to be linearly associated with cardiovascular events in the non‐CVD population. High PP is an indicator of increased artery stiffness and is an independent risk factor for cardiovascular mortality. However, PP is also known to be influenced by ventricular function.
Our findings indicated that not only high PP, but also low PP increases the risk of future cardiovascular events in patients with AMI; low PP was shown to more significantly correlate with cardiovascular events in this regard than high PP. However, further studies are needed for understanding the association between hemodynamic changes and PP and ways of modulating the PP in patients with AMI.
CONFLICT OF INTEREST
None.
AUTHOR CONTRIBUTIONS
All authors were involved in developing the study concept and design, data acquisition, data management, and interpretation of results. Data analysis was performed by HWP and JYH. This submission was drafted by HWP; all other authors were involved in editing and review. All authors have approved the final version of this submission.
Supporting information
ACKNOWLEDGMENTS
The authors thank all the KAMIR‐Korean‐NIH participants.
Park HW, Kang MG, Kim K, et al; on behalf of the KAMIR‐Korean‐NIH registry . Association between pulse pressure at discharge and clinical outcomes in patients with acute myocardial infarction: From the KAMIR‐Korean‐NIH registry. J Clin Hypertens. 2019;21:774–785. 10.1111/jch.13534
Funding information
This research was supported by a fund (2016‐ER6304‐00) by Research of Korea Centers for Disease Control and Prevention.
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