Clinical Trial. Left Ventricular Wall Stress Mass Heart Rate Product and Cardiovascular Events in Treated Hypertensive Patients.

Clinical Trial Left Ventricular Wall Stress Mass Heart Rate Product and Cardiovascular Events in Treated Hypertensive Patients LIFE Study Richard B. Devereux, Casper N. Bang, Mary J. Roman, Vittorio Palmieri, Kurt Boman, Eva Gerdts, Markku S. Nieminen, Vasilios Papademetriou, Kristian Wachtell, Darcy A. Hille, Björn Dahlöf Abstract In the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, 4.8 years losartan- versus atenolol-based antihypertensive treatment reduced left ventricular hypertrophy and cardiovascular end points, including cardiovascular death and stroke. However, there was no difference in myocardial infarction (MI), possibly related to greater reduction in myocardial oxygen demand by atenolol-based treatment. Myocardial oxygen demand was assessed indirectly by the left ventricular mass wall stress heart rate (triple product) in 905 LIFE participants. The triple product was included as time-varying covariate in Cox models assessing predictors of the LIFE primary composite end point (cardiovascular death, MI, or stroke), its individual components, and all-cause mortality. At baseline, the triple product in both treatment groups was, compared with normal adults, elevated in 70% of patients. During randomized treatment, the triple product was reduced more by atenolol, with prevalences of elevated triple product of 39% versus 51% on losartan (both P 0.001). In Cox regression analyses adjusting for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure, 1 SD lower triple product was associated with 23% (95% confidence interval 13% 32%) fewer composite end points, 31% (18% 41%) less cardiovascular mortality, 30% (15% 41%) lower MI, and 22% (11% 33%) lower all-cause mortality (all P 0.001), without association with stroke (P=0.34). Although losartan-based therapy reduced ventricular mass more, greater heart rate reduction with atenolol resulted in larger reduction of the triple product. Lower triple product during antihypertensive treatment was strongly, independently associated with lower rates of the LIFE primary composite end point, cardiovascular death, and MI, but not stroke. (Hypertension. 2015;66:945-953. DOI: 10.1161/ HYPERTENSIONAHA.114.05582.) Key Words: hypertension hypertrophy myocardial infarction oxygen prognosis Left ventricular (LV) hypertrophy (LVH) is a cardinal manifestation of preclinical cardiovascular disease 1 that strongly predicts myocardial infarction (MI), stroke, and cardiovascular death in patients with hypertension, 2,3 members of the general population, 4,5 and patients with or without coronary artery disease at cardiac catheterization. 6 8 In the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study, 9,10 losartan-based antihypertensive treatment, compared with an atenolol-based regimen, led to a lower rate of cardiovascular events, especially stroke, 11 and greater regression of LVH, 12,13 which was in turn associated with reduced rates of cardiovascular events. 14,15 In view of the greater effect of losartan-based therapy on LVH and the known association between LVH and MI, an unexpected result of the LIFE study was the lack of a lower rate of MI in losartan-treated patients. 11 Animal experiments have identified an important role of increased myocardial oxygen demand in sensitizing the hypertrophied LV in hypertension to greater size of infarction, as well as arrhythmia, when coronary arterial blood flow is reduced. 16 18 These studies are in accord with earlier experiments demonstrating a close relation between the myocardial tension time index and oxygen consumption per gram of myocardium. 19 The finding that rapid normalization of blood pressure (BP) before reversal of LVH, which would have reduced wall stress and O 2 consumption per gram of myocardium, reduced infarct size and prevalence after a standardized coronary artery ligation supports the concept that these adverse effects are related to the product of LV mass, wall stress, and heart rate. 20 We have previously shown that the LV mass wall stress heart rate product is substantially elevated in hypertensive patients with LVH, 21 but the relation of this noninvasive index of myocardial oxygen demand to cardiovascular events has not been evaluated. Furthermore, it is unknown whether the greater effect of losartan-based therapy Received April 28, 2015; first decision May 11, 2015; revision accepted August 24, 2015. From the Department of Medicine, Weill Medical College of Cornell University, New York, NY (R.B.D., C.N.B., M.J.R., V.P.); Research Unit, Department of Medicine Skellefteå, Umeå University, Skellefteå, Sweden (K.B.); Department of Clinical Science, University of Bergen, Bergen, Norway (E.G.); Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland (M.S.N.); Division of Cardiology, A.O.S.G. Moscati, Avellino, Italy (V.P.); Department of Medicine, Glostrup University Hospital, Glostrup, Denmark (K.W.); Section on Biostatistics, Merck Research Laboratories, North Wales, PA (D.A.H.); and Department of Medicine, Sahlgrenska University Hospital, Östra, Sweden (B.D.). Correspondence to Richard B. Devereux, Division of Cardiology, Box 222, 525 E 68th St, New York, NY 10065. E-mail rbdevere@med.cornell.edu 2015 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.05582 945

946 Hypertension November 2015 on LV mass or the greater reduction of heart rate with atenolol-based therapy in LIFE resulted in differential reduction of the LV mass wall stress heart rate product between treatment arms. Accordingly, the present study was undertaken to determine the relative effects of losartan- versus atenololbased antihypertensive treatment on determinants of myocardial oxygen demand, including the LV mass stress heart rate product, and the relation of this triple product during antihypertensive treatment to cardiovascular events in hypertensive patients with ECG LVH enrolled in the LIFE echocardiography substudy. 22 Methods Study Design As previously described, 10 patients aged 55 to 80 with mean seated BP 160 to 200/95 to 115 mm Hg after 1 to 2 weeks on placebo treatment who had not suffered a MI or stroke within 6 months and did not have a clinical requirement for treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor or β-blocker were recruited into the LIFE study if they had electrocardiographic LVH by the product of QRS duration times the Cornell voltage combination (RaVL+SV 3, 23,24 with 6 mm added in women) >2440 mm ms or Sokolow Lyon voltage (SV 1 +RV 5-6 ) >38 mm. Patients were treated with losartan- or atenololbased antihypertensive treatment with addition of hydrochlorothiazide, increase in dose of the randomized medication, and addition of other antihypertensive agents to reduce BP to <140/90 mm Hg. The LIFE study, which took place between 1995 and 2001, was approved by institutional review committees, and subjects gave informed consent. Subjects were provided with losartan and atenolol, as well as hydrochlorothiazide, when needed by Merck & Co, North Wales, PA. Echocardiographic Methods Echocardiograms were performed at baseline and annually thereafter as previously described. 12,14,21,22 LV internal dimension and wall thicknesses were measured at end-diastole and end-systole following American Society of Echocardiography recommendations. 25,26 Arterial BP was measured, using the first and fifth phases of the Korotkoff sounds, at the end of the echocardiogram with the patient in the supine position on the examining table. End-diastolic LV dimensions were used to calculate LV mass by an anatomically validated formula. 27 End-systolic LV circumferential wall stress was calculated by an invasively validated method. 28 End Points The LIFE study used a composite end point of cardiovascular death, MI, or stroke. 9,11 End points were ascertained by systematic surveillance at regular outpatient visits and investigator contact of patients and verified by an End Point Committee 9,11 ; members of the End Point Committee were blinded to echocardiographic LV mass measurements. Survival status in patients otherwise lost to follow-up was ascertained using professional patient locators, the US National Death Index and Central Person Registers in Nordic countries. Statistical Analyses Data are expressed as mean+standard deviation (SD) or as proportions. Differences between losartan- and atenolol-treated groups were assessed by independent samples t tests, and within-group differences from baseline were assessed by 1-sample t tests. To place findings concerning the LV mass stress heart rate product in LIFE patients in context, reference values were obtained in 366 normotensive adults without evident cardiovascular disease from a previously reported population. 29,30 In this reference group, the LV mass stress heart rate product was 1.23±0.46 10 6 g kdyne/cm 2 bpm; the upper limit of the 95% confidence interval (CI) in this reference population (2.13 10 6 g kdyne/cm 2 bpm) was used as a partition value to identify elevated levels of the triple product. To test the hypothesis that lower LV mass wall stress heart rate during antihypertensive therapy results in reduction in clinical events, independent of antihypertensive treatment type and degree of BP lowering, the effect of the in-treatment triple product on risk of clinical end points was analyzed by the intention-to-treat principle following all randomized patients with baseline LV mass wall stress heart rate values for end points for the entire duration of the study, regardless of protocol violations or discontinuation of study medication. To determine whether the triple product improved prediction of the composite end point, we used SAS 9.2 to calculate C-statistics for each component of the triple product separately, for a multivariate model, including the 3 individual components, and for a second multivariable model adding the triple product to its components. The effect of the in-treatment triple product on the risk of clinical end points, expressed as the hazard ratio and its 95% CI per SD of the baseline triple product (1.38 10 6 g kdyne/cm 2 bpm), was analyzed using multivariable Cox regression models. In the primary model, the baseline triple product and treatment group indicator were standard covariates, and triple products at annual evaluations were time-varying covariates carried forward until the next evaluation. Additional Cox models considered the components of the LV mass wall stress heart rate product separately and the double product of systolic blood pressure (SBP) heart rate as time-varying predictors of the composite end point and components thereof. The effects of treatment type on the relation between the LV mass wall stress heart rate product as a time-varying covariate and end points was assessed by inclusion of an interaction term between the treatment group and the triple product, with similar tests for interaction with other patient characteristics. To account for the impact of all-cause mortality as a competing end point, odds ratios (OR) were determined by logit link model for competing risks, where a regression analysis of the cumulative incidence probabilities was calculated for each of the end points stroke, cardiovascular death, and MI. 31 To place in context the degree to which the LV mass wall stress heart rate product and components thereof were normalized by treatment, values in female and male LIFE patients were compared with those in women and men from groups of 366 apparently normal adults from a previously described population 29,30 studied in New York by similar echocardiographic methods. Results Patient Characteristics A total of 905 participants in the LIFE echocardiography substudy had echocardiographic and end-echo BP measurements needed for the present study. As shown in Table 1, patients randomized to losartan- versus atenolol-based therapy did not differ in mean age, BP, heart rate, body mass index, or the proportions who were black or had histories of diabetes mellitus, previous MI, or previous stroke, whereas more atenololtreated patients had previous peripheral vascular disease. As previously reported, 22 the LIFE echo substudy included higher proportions of men and black patients but otherwise was similar to the entire LIFE study population. Changes in BP, Heart Rate, and LV Mass and Wall Stress SBP and diastolic BP both fell substantially during the first year in LIFE and decreased slightly thereafter in both treatment groups (Table 2). Heart rate fell by 8 to 9 bpm at all intervals of follow-up in atenolol-treated patients versus 1 to 2 bpm in losartan-treated patients. End-systolic LV wall stress fell during the first 2 years of treatment in both patient groups, returned to baseline values after 3 years, and rose slightly above baseline levels at fourth and fifth year follow-ups. LV mass decreased markedly from baseline to 12 months and

Devereux et al Myocardial O 2 Demand and Prognosis in HTN 947 Table 1. Characteristics of Patients Randomized to Losartan- Based versus Atenolol-Based Treatment Variable Losartan-Treated (n=456) Atenolol-Treated (n=449) P Value Age, y 66±7 66±7 NS Women, % 42 41 NS Black, % 14 15 NS Blood pressure, mm Hg 173±14/98±9 174±14/96±9 NS Heart rate, bpm 72±11 72±11 NS Body mass index, kg/m 2 27.4±4.3 27.1±4.5 NS Diabetes mellitus, % 14 13 NS Previous myocardial 5 7 NS infarction, % Previous stroke, % 3 6 NS Prior peripheral vascular disease, % 8 3 0.003 NS indicates nonsignificant. significantly between 12 and 24 months, with small further decrements throughout the 60-month follow-up, with greater decreases in losartan- than in atenolol-treated patients, as previously reported. 12 As a result of these changes in primary measures of LV mass, LV wall stress, and heart rate, LV mass wall stress heart rate fell substantially in losartan-treated patients (Figure 1) by a mean of 16% after 1 year, 24% after 2 years, 21% after 3 years, 20% after 4 years, and 15% after 5 years of treatment (all P<0.001). Even greater reductions of the triple product occurred in atenolol-treated patients by means of 27% after 1 year, 31% after 2 years, 28% after 3 years, 25% after 4 years, and 22% after 5 years (all P<0.001). At each interval of follow-up, the proportion of patients with elevated levels (above the 95% CI in normal adults) of LV mass wall stress heart rate remained lower (all P<0.02) in atenolol- than in losartan-treated patients (Figure 2). Despite substantial decreases in response to treatment in LIFE, mean values remained substantially higher than those observed in 366 normal adults for LV mass (146 g), circumferential end-systolic wall stress (124 kdynes/cm 2, upper limit of the 95% CI, 171 kdynes/cm 2 ) and LV mass wall stress heart rate (1.22 10 6 g dynes/cm 2 bpm, upper limit of 95% CI, 2.10 10 6 g dynes/cm 2 bpm). Clinical End Points Primary events occurred in 103 patients during mean followup of 4.9±0.3 years (23.2/1000 patient-years). Cardiovascular death occurred in 33 patients, MI in 38, stroke in 59, and allcause mortality in 73 patients. A test for interaction between losartan treatment and the LV mass wall stress heart rate product on the composite cardiovascular end point was not significant (P=0.83). The results of Cox multivariable proportional hazards analyses considering time-varying LV mass wall stress heart rate product as a continuous variable are summarized in Table 3. After adjusting for baseline triple product and study treatment, lower in-treatment LV mass wall stress heart rate was strongly associated (all P<0.0001) with reduced risk for the composite end point, cardiovascular death, MI, and the secondary end point of all-cause mortality. In a similar analysis, lower LV mass stress heart rate product as a time-varying covariate was more weakly, but significantly, associated with a lower risk of stroke. After further adjustment for age, smoking, diabetes mellitus, prior stroke, prior MI, and heart failure, the reductions in rates of the composite end point, Table 2. Change in Blood Pressure, Heart Rate, and Left Ventricular End-Systolic Stress and Mass in Losartan-Treated or Atenolol-Treated Patients Variable Baseline (456/449) 12 Months (416/402) 24 Months (384/372) 36 Months (361/343) 48 Months (337/339) 60 Months (172/164) Systolic BP, mm Hg Losartan-treated 174±21 151±19* 148±19* 146±19* 145±19* 144±20* Atenolol-treated 173±21 150±20* 150±20* 148±20* 147±18* 148±19* Diastolic BP, mm Hg Losartan-treated 96±12 85±11* 84±10* 83±10* 82±10* 81±9* Atenolol-treated 95±12 83±10* 83±9* 82±10* 81±10* 82±10* Heart rate, bpm Losartan-treated 69±11 68±11 68±12 67±16 67±11 68±13 Atenolol-treated 67±12 58±11* 58±11* 58±11* 59±11* 59±11* End-systolic stress, kdyne/cm 2 Losartan-treated 184±53 176±53* 169±43* 181±50 187±51* 196±51* Atenolol-treated 183±46 174±43* 168±37* 182±43 191±48* 200±50* LV mass, g Losartan-treated 236±57 207±51* 194±43* 193±46* 188±47* 187±47* Atenolol-treated 231±54 206±49* 195±45* 193±45* 190±44* 187±43* BP indicates blood pressure; and LV, left ventricular. Statistical significance versus baseline: *P<0.001. Statistical difference, change from baseline, losartan- vs atenolol-treated patients: P<0.001 and P<0.05.

948 Hypertension November 2015 Figure 1. Left ventricular mass wall stress heart rate product in losartan and atenolol-treated patients at baseline and annual re-evaluations during the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study. cardiovascular death, MI, and all-cause mortality associated with lower in-treatment LV mass stress heart rate remained highly significant, whereas the association of lower timevarying triple product with reduced rate of stroke became nonsignificant. In time-varying competing risk calculations with all-cause mortality as a competing event, 1 SD lower triple product was independently associated with cardiovascular death (OR 0.70 [0.54 0.92], P=0.007) and the composite end point (OR 0.72 [0.57 0.91], P=0.006), but not with stroke (OR 2.44 [0.70 1.33], P=0.854) or MI (OR 0.93 [0.62 1.41], P=0.742). Additional Cox models assessing the presence or absence of LV mass stress heart rate values above the upper limit of the 95% CIs in the reference population are also summarized in Table 2. Absence versus presence of high mass stress heart rate as a time-varying covariate during follow-up was associated with significantly lower rates of cardiovascular or allcause mortality with a trend toward reduced composite end points (Table 2). Relation of Clinical Events to Wall Stress and Heart Rate During Antihypertensive Treatment Results of Cox multivariable proportional hazards analyses considering time-varying LV wall stress and heart rate product as separate continuous variables are summarized in Tables 4 and 5. After adjusting for baseline wall stress and study treatment, lower LV wall stress was weakly associated with reduced risk for the composite end point and cardiovascular death, strongly (P<0.0001) associated with lower rate of MI, but bore no relation to stroke or all-cause mortality. The reduction in rate of MI with lower time-varying wall stress remained significant, whereas associations with other end points did not with further adjustment for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure. There was no association of normal versus elevated end-systolic stress as a timevarying categorical variable with lower rate of any end point (data not shown). In time-varying competing risk calculations with all-cause mortality as competing event, 1 SD lower LV wall stress was significantly associated with the composite end point (OR 1.20 [1.02 1.43], P=0.023), stroke (OR 2.44 [1.28 4.76], P=0.006), MI (OR 1.45 [1.04 2.04], P=0.023) but not cardiovascular death (OR 0.91 [0.76 1.10], P=0.316). After adjusting for baseline heart rate and study treatment, lower time-varying heart rate was strongly associated with reduced risk for cardiovascular death and all-cause mortality, with a weak trend toward association with fewer composite end points but no relation with the rates of MI or stroke. The reduction in rates of cardiovascular death and all-cause mortality with lower time-varying heart rate remained virtually unchanged, as did the lack of significant associations of timevarying heart rate with other end points, with further adjustment for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure. Too few study participants had elevated heart rate during antihypertensive treatment in the LIFE study to permit analyses of normal versus elevated heart rate as a time-varying categorical variable (data not shown). In timevarying competing risk calculations with all-cause mortality as competing event, 1 SD lower time-varying heart rate was associated with less cardiovascular death (OR 0.71 [0.52 0.97] P=0.03) but not associated with any of the other end points (All P>0.05, data not shown). C-statistics for prediction of the composite end point of the LIFE study was calculated for the component parts of the triple product (LV mass [c=0.624], end-systolic stress Figure 2. The proportion of patients with high left ventricular (LV) mass wall stress heart rate product (vertical axis) was similar in both treatment groups at baseline, but was significantly lower in atenolol-treated than in losartan-treated patients at each year of follow-up during the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study.

Devereux et al Myocardial O 2 Demand and Prognosis in HTN 949 Table 3. Association of In-Treatment LV Mass Wall Stress Heart Rate With Risk of Cardiovascular Events and All-Cause Mortality: Results of Cox Multivariable Proportional Hazards Analyses In-Treatment LV Mass Wall Stress Heart Rate Measure and End Point Adjustments HR (95% CI) P Value Higher by 1 SD (1.38 10 6 g kdynes/cm 2 bpm) Composite Treatment 1.25 (1.07 1.1.46) 0.0054 Cardiovascular death Same 1.41 (1.23 1.62) <0.0001 Myocardial infarction Same 1.26 (1.06 1.49) 0.0090 Stroke Same 1.40 (1.21 1.61) <0.0001 All-cause mortality Same 1.40 (1.19 1.65) <0.0001 Higher by 1 SD (1.38 10 6 g kdynes/cm 2 bpm) Composite Add age, smoking, diabetes mellitus, 1.17 (1.00 1.37) 0.0446 prior stroke, prior MI, heart failure Cardiovascular death Same 1.30 (1.13 1.50) 0.0002 Myocardial infarction Same 1.17 (0.99 1.39) 0.0670 Stroke Same 1.29 (1.11 1.49) 0.0007 All-cause mortality Same 1.29 (1.09 1.52) 0.0035 Presence versus absence of high mass stress heart rate Composite Treatment, BP lowering 1.07 (0.70 1.64) 0.7455 Cardiovascular death Same 1.52 (0.99 2.33) 0.0537 Myocardial infarction Same 1.11 (0.73 1.70) 0.6227 Stroke Same 1.41 (0.92 2.17) 0.1128 All-cause mortality Same 1.85 (1.10 3.12) 0.0202 BP indicates blood pressure; CI, confidence interval; HR, hazard ratio; LV, left ventricle; MI, myocardial infarction; and SD, standard deviation. [c=0.568], and heart rate [c=0.536]). A first multivariate model incorporating LV mass, end-systolic stress, and heart rate yielded a C-statistic of 0.629, whereas a second multivariate model adding the triple product as a predictor raised the C-statistic to 0.697 (P<0.0009 compared with the first multivariate model). After adjusting for baseline heart rate BP product and study treatment, lower time-varying heart rate SBP was strongly associated with reduced risk for the composite end point, cardiovascular death, stroke, and all-cause mortality, without association with risk of MI (Table 6). The reduction in rates of these outcomes with lower time-varying heart rate SBP remained virtually unchanged, as did the lack of significant association with MI, with further adjustment for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure. Elevated heart rate SBP product during antihypertensive treatment in the LIFE study was associated with higher risk of the composite end point and of cardiovascular and all-cause death. In competing risk models with all-cause mortality as competing event, 1 SD higher time-varying rate pressure product was associated with higher risk of cardiovascular disease (OR 2.20 [95% CI 1.57 3.06], P=0.019) and the composite end point (OR 1.74 [95% CI 1.39 2.19], P=0.0165) but not MI (P=0.383) or stroke (P=0.106). Outcomes in Subsets of the Population Associations between lower in-treatment LV mass stress heart rate and lower rate of the composite end point were also seen in women and men (HR=0.77 and 0.67 per 1.38 10 6 g kdynes/cm 2 bpm), patients older versus younger than 65 years (HR=0.73 and 0.70), diabetic and nondiabetic patients (HR=0.65 and 0.74), patients assigned to losartan- or atenololbased treatment (HR=0.76 and 0.64), and in nonblack patients (HR=0.69, all P<0.01; P for interaction between groups all >0.50), but not in black participants (HR=0.98, P=0.95; P for interaction versus nonblack participants 0.18). Discussion The present study provides the first evidence, from a large population of hypertensive patients, that reduction during antihypertensive treatment of an indirect index of myocardial oxygen demand (the LV mass stress heart rate product) is associated with reduced rates of morbidity and mortality. We detected significantly reduced rates of cardiovascular events and all-cause mortality in association with lower LV mass wall stress heart rate products in a population of hypertensive patients with ECG LVH who had not only increased LV mass but also increased substantially supranormal wall stresses and even more markedly elevated triple products. 21 The triple product was reduced more in patients randomized to β-blocker-based group versus losartan group. Thus, this analysis provides direct evidence of a cardio-protective effect of β-blockers on the triple product, which is an indirect measure of oxygen consumption in the heart. This result provides indirect support for the conclusion that the known reduction of morbidity and mortality in survivors of MI by β-blocker treatment 32 is due, at least in part, to reduction of myocardial oxygen demand because of lower BP, heart rate, and myocardial inotropic state. The present evidence of a major demand-side

950 Hypertension November 2015 Table 4. Association of In-Treatment End-Systolic Stress With Risk of Cardiovascular Events and All-Cause Mortality: Results of Cox Multivariable Proportional Hazards Analyses On-Treatment End-Systolic Stress and End point Adjustments HR (95% CI) P Value Higher by 1 SD (24.1 kdynes/cm 2 ) Composite Treatment 0.94 (0.85 1.05) 0.2618 Cardiovascular death Same 1.10 (1.02 1.20) 0.0140 Myocardial infarction Same 0.97 (0.88 1.08) 0.5766 Stroke Same 1.07 (0.98 1.17) 0.1475 All-cause mortality Same 1.03 (0.93 1.14) 0.6166 Higher by 1 SD (24.1 kdynes/cm 2 ) Composite Add age, smoking, diabetes 0.94 (0.85 1.04) 0.2132 mellitus, prior stroke, prior MI, heart failure Cardiovascular death Same 1.07 (0.99 1.16) 0.0732 Myocardial infarction Same 0.97 (0.88 1.06) 0.4508 Stroke Same 1.04 (0.96 1.13) 0.3459 All-cause mortality Same 1.01 (0.92 1.11) 0.8124 CI indicates confidence interval; HR, hazard ratio; LV, left ventricle; MI, myocardial infarction; and SD, standard deviation. predisposition to clinical events because of myocardial ischemia in the presence of hypertensive LVH raises the possibility that this may also occur in patients who have increased LV mass and wall stresses because of cardiomyopathy, valvular heart disease, or other conditions. Role of Myocardial Hypertrophy and Oxygen Demand in Cardiovascular Events A series of studies in dogs with experimental hypertension subjected to standardized coronary artery ligation showed that greater LVH was associated with larger size 16 and more rapid spread 17 of MI and higher rates of ventricular arrhythmias. 18 The initial interpretation that these were direct deleterious consequences of higher myocardial mass was challenged, however, by a subsequent experiment 20 in which acute reduction of arterial pressure by reversal of renal artery stenosis resulted in nearnormalization of myocardial infarct size, despite persistence of substantial LVH. Because acute normalization of arterial pressure before there was time for regression of LVH would reduce LV wall stresses to subnormal levels, the LV mass stress product would have been reduced to nearly normal levels in the experiment of Inoue et al, 20 suggesting that it was myocardial oxygen demand rather than the level of LV mass that was the principal determinant of infarct size. The fact that the associations of the LV mass wall stress heart rate product with cardiovascular events and all-cause mortality shown in Table 3 were stronger than those we previously reported for LV mass alone 14 is consistent with the concept that excess myocardial oxygen demand may be the most immediate contributor to excess rates of cardiovascular events, with contributions to high LV mass, wall stresses, and heart rate. Of note, the predictive values for adverse outcomes of the SBP heart rate product were somewhat lower than those for the triple product, consistent with the known adverse prognostic significance of LVH. Table 5. Association of Lower In-Treatment Heart Rate With Risk of Cardiovascular Events and All-Cause Mortality: Results of Cox Multivariable Proportional Hazards Analyses In-Treatment Heart Rate and End Point Adjustments HR (95% CI) P Value Higher by 1 SD (11.9 bpm) Composite Treatment 1.04 (0.82 1.30) 0.7607 Cardiovascular death Same 0.97 (0.77 1.23) 0.8259 Myocardial infarction Same 0.96 (0.76 1.22) 0.7463 Stroke Same 1.00 (0.80 1.27) 0.9700 All-cause mortality Same 1.42 (1.12 1.82) 0.0046 Higher by 1 SD (11.9 bpm) Composite Add age, smoking, diabetes mellitus, 1.02 (0.81 1.28) 0.8591 prior stroke, prior MI, heart failure Cardiovascular death Same 0.96 (0.76 1.21) 0.6994 Myocardial infarction Same 0.95 (0.75 1.19) 0.6455 Stroke Same 0.99 (0.79 1.25) 0.9562 All-cause mortality Same 1.40 (1.19 1.79) 0.0082 CI indicates confidence interval; HR, hazard ratio; MI, myocardial infarction; LV, left ventricle; and SD, standard deviation.

Devereux et al Myocardial O 2 Demand and Prognosis in HTN 951 Table 6. Association of In-Treatment Systolic Blood Pressure Heart Rate With Risk of Cardiovascular Events, and All-Cause Mortality: Results of Cox Multivariable Proportional Hazards Analyses In-Treatment Systolic Blood Pressure Heart Rate Measure and End point Adjustments HR (95% CI) P Value Higher by 1 SD (2212 mm Hg bpm) Composite Treatment 1.32 (1.08 1.62) 0.0062 Cardiovascular death Same 1.55 (1.11 2.15) 0.0099 Myocardial infarction Same 1.05 (0.98 1.13) 0.1600 Stroke Same 1.36 (1.05 1.77) 0.0205 All-cause mortality Same 1.40 (1.13 1.74) 0.0074 Higher by 1 SD (2212 mm Hg bpm) Composite Add age, smoking, diabetes mellitus, 1.32 (1.08 1.61) 0.0076 prior stroke, prior MI, heart failure Cardiovascular death Same 1.70 (1.21 1.38) 0.0020 Myocardial infarction Same 1.05 (0.98 1.13) 0.1792 Stroke Same 1.36 (1.05 1.77) 0.0194 All-cause mortality Same 1.31 (1.05 1.63) 0.0151 Presence versus absence of high systolic blood pressure heart rate Composite Treatment 1.69 (1.08 2.63) 0.0214 Cardiovascular death Same 2.52 (1.21 5.27) 0.0137 Myocardial infarction Same 1.08 (0.91 1.28) 0.3981 Stroke Same 1.45 (0.79 2.66) 0.2292 All-cause mortality Same 2.24 (1.37 3.66) 0.0014 CI indicates confidence interval; HR, hazard ratio; MI, myocardial infarction; LV, left ventricle; and SD, standard deviation. Association of the Left Ventricular Mass Stress Heart Rate Product With Specific Events In univariate Cox models, the LV mass wall stress heart rate product during antihypertensive treatment as a timevarying covariate was strongly related to first occurrence of the composite end point of the LIFE study, 2 of its components (first occurrence of cardiovascular death or MI), and all-cause mortality, but it was only weakly related to the risk of stroke. When the associations between in-treatment mass stress heart rate and adverse events were further adjusted for established cardiovascular risk factors and prevalent cardiovascular diseases, the triple product maintained strong associations with cardiovascular death, MI, and allcause mortality, consistent with a major role of excessive myocardial energy demand in the pathogenesis of cardiac events but not with cerebrovascular events. One interesting result of the present study is that in time-varying competing risk calculations with all-cause mortality as competing event, lower LV wall stress was associated with higher risks of the LIFE composite end point, stroke, and MI. These findings are consistent with the recent observation of particularly high event rates in LIFE patients with persistence of ECG LVH, despite especially good reduction of SBP. 33 Additional analyses using the commonly calculated product of systolic pressure heart rate as a time-varying covariate revealed associations with specific end points that paralleled, but with generally lesser statistical significance, those obtained with the triple product. Reduction of Left Ventricular Mass Stress Heart Rate During Antihypertensive Therapy A notable result of the present study is that aggressive antihypertensive therapy was less successful in reducing the LV mass wall stress heart rate product into the normal range than had been the case for LV mass alone. 14 This was somewhat more true in patients randomized to losartan- than to atenolol-based treatment (Figure 2). Taken together with evidence from the present report that lower in-treatment LV mass stress heart rate is associated with lower rates of cardiovascular events and all-cause mortality, these results raise the possibility that a combination of losartan with verapamil or another heart rate slowing calcium channel blocker might further improve cardiovascular protection by providing both the prognostic benefits of losartan-based therapy documented in the LIFE study 11 and additional benefit from reduction of the heart rate component of the LV mass wall stress heart rate triple product. Impact of Other Patient Characteristics Subgroup analyses showed no difference in the association between LV mass wall stress heart rate and the likelihood of cardiovascular events or all-cause mortality between women and men, between patients with or without diabetes mellitus, between those older versus younger than 65 years, or between patients assigned to losartan- versus atenolol-based treatment. The reduction in the composite end point per SD lower intreatment LV mass stress heart rate triple product attained statistical significance in nonblack patients but not in black

952 Hypertension November 2015 participants. However, a formal test for interaction between black and nonblack patients was not significant (P=0.18), making it uncertain whether the apparent discordance between black and nonblack patients is a real finding. Limitations of the Study The present study was undertaken in patients selected for the combination of moderately severe hypertension and electrocardiographic LVH and thereby may not be directly applicable to hypertensive patients without LVH or nonhypertensive patients treated with these agents for other conditions, including post-mi care or heart failure. However, the number of adults meeting entry criteria for the LIFE study has been estimated at 7.8 million in the first 15 member states of the European Union, 34 with nearly as many in either the United States or Eastern Europe. Furthermore, it is unknown whether these findings are applicable to nonhypertensive subjects treated with losartan or with β-blockers as secondary prevention treatment for MI survivors. Of note, results of the present study were consistent across most subgroups. Perspectives International guidelines recognize the role of imbalance between myocardial oxygen supply and demand in causation of MI, 35 but little information is available on the potential association between elevated myocardial oxygen demand and subsequent risk of MI or other adverse outcomes. Initial evidence from the present study of high-risk hypertensive patients shows that reduction during antihypertensive treatment of an indirect index of myocardial oxygen demand (the LV mass stress heart rate product) is associated with reduced rates of cardiovascular events and all-cause mortality. These results require replication in other populations and with use of 3D imaging methods in patients with distorted LV geometry. With further verification, indirect evidence of high myocardial oxygen demand may identify individuals at increased risk of clinical events because of myocardial ischemia and as a marker of risk of other cardiovascular events in patients who have increased LV mass and wall stresses because of a spectrum of cardiovascular conditions. Sources of Funding Supported in part by grant COZ-368 from Merck and Co, Inc, West Point, PA, and by grants HL18323 and HL47540 from the National Heart, Lung and Blood Institute, Bethesda, MD. Disclosures Drs Devereux, Gerdts, and Wachtell received grant support from Merck & Co. Inc. Dr Dahlöf receives grant support from Boehringer- Ingelheim, Novartis, and Pfizer; receives honoraria from Merck & Co, Inc, Novartis, Boehringer-Ingelheim, and Pfizer; and serves as a consultant for Merck & Co. Inc, Novartis and Boehringer-Engelheim. Dr Devereux consults for Merck & Co. Inc. and General Electric Medical Systems. The other authors report no conflicts. 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