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Background: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. the primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 mu m/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 mu m/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: the extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials., Austrian Science Fund (FWF)Austrian Science Fund (FWF) [P 32488]; Dr-Johannes-and-Hertha-Tuba Foundation; German Research FoundationGerman Research Foundation (DFG) [DFG Lo 1569/2-1, DFG Lo 1569/2-3]; excellence initiative "Competence Centers for Excellent Technologies" (COMET) of the Austrian Research Promotion Agency (FFG) "Research Center of Excellence in Vascular Ageing: Tyrol, VAS-Cage" - Bundesministerium fur Verkehr, Innovation und Technologie (B [843536]; Bundesministerium fur Bildung, Wissenschaft und Forschung (BMWFW); Wirtschaftsagentur Wien; Standortagentur Tirol, This work was supported by the Austrian Science Fund (FWF; P 32488); the Dr-Johannes-and-Hertha-Tuba Foundation; the German Research Foundation (DFG Lo 1569/2-1 and DFG Lo 1569/2-3); and the excellence initiative "Competence Centers for Excellent Technologies" (COMET) of the Austrian Research Promotion Agency (FFG) "Research Center of Excellence in Vascular Ageing: Tyrol, VAS-Cage" (K-Project No. 843536), funded by Bundesministerium fur Verkehr, Innovation und Technologie (BMVIT), Bundesministerium fur Bildung, Wissenschaft und Forschung (BMWFW), Wirtschaftsagentur Wien, and Standortagentur Tirol.

Background: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular (CV) disease and CV mortality. A recent large, population-based study suggested that COPD is associated with an increased risk of sudden cardiac death (SCD). However, whether COPD predicts SCD in hypertensive patients during aggressive blood pressure (BP) lowering has not been examined. Methods: Risk of SCD was examined in relation to a history of COPD in 9193 hypertensive patients with ECG left ventricular hypertrophy (LVH) who were randomly assigned to losartan- or atenolol-based treatment. A history of COPD was present in 385 patients (4.2%). SCD, a prespecified secondary endpoint in LIFE, was defined as death that was sudden and unexpected, including observed arrhythmic deaths and those not attributable to myocardial infarction (MI), intractable heart failure (HF) or other identifiable cause, occurring within 24 hours of symptom onset or when the subject was last seen alive if unwitnessed SCD. Results: During mean follow-up of 4.8±0.9 years, 178 patients (2.4%) had SCD, with a higher incidence rate per 1000 person-years in those with COPD: 9.0; 95% CI, 6.1-11.9 vs 3.8; 95% CI, 3.4-4.2; p=0.001. In a univariate Cox model, COPD was associated with a > 2-fold increased risk of SCD (HR 2.36, 95% CI 1.42-3.95, p=0.001). In a multivariable Cox regression model that adjusted for other predictors of SCD in this population (randomized treatment, age, gender, race, history of atrial fibrillation, stroke or transient ischemic attack, baseline serum creatinine and glucose entered as standard covariates and incident MI, incident HF and in-treatment diastolic pressure, heart rate, QRS duration, HDL cholesterol, and use of hydrochlorothiazide or a statin entered as time-varying covariates), COPD remained associated with a nearly 2-fold increased risk of SCD (HR, 1.82; 95% CI, 1.04-3.18, p=0.035). Conclusions: COPD is associated with an increased risk of SCD in hypertensive patients. The higher SCD risk in COPD patients persists after adjusting for the higher prevalence of risk factors in COPD patients, in-treatment blood pressure, incident MI and HF, and the established predictive value of in-treatment ECG LVH and heart rate for SCD in this population.

Background: Recent findings in population-based studies suggest that abnormal P-wave terminal force in lead V 1 (PTFV 1 ), a marker of left atrial (LA) abnormalities such as fibrosis, dilatation and elevated filling pressures, is associated with incident ischemic stroke, even in the absence of atrial fibrillation (AF). However, whether PTFV 1 predicts incident stroke in hypertensive patients during aggressive blood pressure (BP) lowering has not been examined. Methods: Risk of incident stroke was examined in relation to abnormal PTFV 1 on a baseline ECG in 1879 hypertensive patients aged 60 or younger with ECG left ventricular hypertrophy (LVH), no history of AF, in sinus rhythm on their baseline ECG with no incident AF during follow-up, who were randomly assigned to losartan- or atenolol-based treatment. Patients >60 years old were not included because of a highly significant interaction between PTFV 1 and age in Cox analyses. Abnormal PTFV 1 was defined by the presence of a negative terminal P wave in lead V 1 with amplitude x duration ≥4000 V*ms. Results: During mean follow-up of 4.8±0.9 years, 45 patients (2.4%) experienced a definite stroke. A higher incidence of stroke occurred in those with abnormal than normal baseline PTFV 1 : incidence rate per 1000 person-years, 7.8, 95% CI, 5.2-11.4 vs 3.4; 95% CI, 2.2-5.2; p=0.004. In univariate Cox models, abnormal PTFV 1 was associated with a > 2-fold increased risk of incident stroke (HR 2.31, 95% CI 1.28-4.16, p=0.005). In multivariable Cox regression models that adjusted for other significant predictors of incident stroke in this population (gender, history of stroke or transient ischemic attack, ischemic heart disease or diabetes, baseline creatinine and in-treatment systolic BP), abnormal PTFV 1 remained associated with a > 2-fold increased risk of incident stroke (HR, 2.06; 95% CI, 1.14-3.74, p=0.017). Conclusions: Abnormal PTFV 1, a marker of LA abnormality, was strongly associated with incident stroke in hypertensive patients, independent of in-treatment systolic BP and other predictors of incident stroke. This association, in the absence of detectable AF, suggests that an underlying atrial cardiopathy may cause LA thromboembolism and a subsequent stroke without necessarily manifesting with AF.

Background— The presence of the ECG strain pattern of lateral ST depression and T-wave inversion at baseline has been associated with an increased risk of cardiovascular morbidity and mortality; however, the independent predictive value for cardiovascular outcomes of regression versus persistence versus development of new ECG strain during antihypertensive therapy is unclear. Methods and Results— ECG strain was evaluated at baseline and after 1 year of therapy in 7409 hypertensive patients in the LIFE study (Losartan Intervention For End-point reduction in hypertension) treated in a blinded manner with atenolol- or losartan-based regimens. During 3.8±0.8 years of follow-up after the year 1 ECG, cardiovascular death occurred in 236 patients (3.2%), myocardial infarction in 198 (2.7%), stroke in 313 (4.2%), the LIFE composite end point of these 3 events in 600 (8.1%), sudden death in 92 (1.2%), and death due to any cause in 486 (6.6%). Strain was absent on both baseline and year 1 ECGs in 6323 patients (85.3%), regressed from baseline to year 1 in 245 (3.3%), persisted on both ECGs in 549 (7.4%), and was absent at baseline but developed by year 1 in 292 patients (3.9%). Compared with absence of strain on both ECGs, development of new ECG strain was associated with 2.8- to 4.7-fold higher event rates; patients with regression or persistence of strain had intermediate event rates. In Cox multivariable analyses with adjustment for the known predictive value of in-treatment ECG left ventricular hypertrophy by Cornell product and Sokolow-Lyon voltage, in-treatment systolic and diastolic pressure, randomized treatment, and standard cardiovascular risk factors, development of new ECG strain was independently associated with increased risks of cardiovascular death (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.56 to 3.76), myocardial infarction (HR 1.95, 95% CI 1.11 to 3.44), stroke (HR 1.98, 95% CI 1.30 to 3.01), the LIFE composite end point (HR 2.05, 95% CI 1.51 to 2.78), sudden cardiac death (HR 2.19, 95% CI 1.06 to 4.53), and all-cause mortality (HR 1.92, 95% CI 1.37 to 2.69), whereas the risk associated with regression or persistence of strain was attenuated. Conclusions— Development of new ECG strain is associated with an increased risk of cardiovascular morbidity and mortality and of all-cause mortality in the setting of antihypertensive therapy and regression of ECG left ventricular hypertrophy.

Background— Sudden cardiac death (SCD) occurs more often in patients with ECG left ventricular (LV) hypertrophy. However, whether LV hypertrophy regression is associated with a reduced risk of SCD remains unclear. Methods and Results— The Losartan Intervention for End Point Reduction in Hypertension (LIFE) study included 9193 patients 55 to 80 years of age with essential hypertension and ECG LV hypertrophy by gender-adjusted Cornell product (CP) (RaVL+SV 3 [+6 mm in women]) · QRS duration>2440 mm · ms) and/or Sokolow-Lyon voltage (SLV) (SV 1 +RV 5/6 >38 mm). During follow-up (mean, 4.8 years), 190 patients (2%) experienced SCD. In time-dependent Cox analyses, absence of in-treatment LV hypertrophy was associated with a decreased risk of SCD: every 1-SD-lower in-treatment CP (1050 mm · ms) was associated with a 28% lower risk of SCD (hazard ratio [HR], 0.72; 95% CI, 0.66 to 0.79) and 1-SD-lower SLV (10.5 mm) with a 26% lower risk (HR, 0.74; 95% CI, 0.65 to 0.84). After adjustment for time-varying systolic and diastolic blood pressures, treatment allocation, age, gender, baseline Framingham risk score, ECG strain, heart rate, urine albumin/creatinine ratio, smoking, diabetes, congestive heart failure, coronary heart disease, atrial fibrillation, and occurrence of myocardial infarction, atrial fibrillation, heart failure, and noncardiovascular death, both in-treatment CP and SLV remained predictive of SCD: each 1-SD-lower CP was associated with a 19% lower risk of SCD (HR, 0.81; 95% CI, 0.73 to 0.90) and 1-SD-lower SLV with an 18% lower risk (HR, 0.82; 95% CI, 0.70 to 0.98). Absence of in-treatment LV hypertrophy by both SLV and CP was associated with a 30% lower risk of SCD (HR, 0.70; 95% CI, 0.54 to 0.92). Conclusions— Absence of in-treatment ECG LV hypertrophy is associated with reduced risk of SCD independently of treatment modality, blood pressure reduction, prevalent coronary heart disease, and other cardiovascular risk factors in hypertensive patients with LV hypertrophy.

Background— The ECG strain pattern of ST depression and T-wave inversion is strongly associated with left ventricular hypertrophy (LVH) independently of coronary heart disease and with an increased risk of cardiovascular morbidity and mortality in hypertensive patients. However, whether ECG strain is an independent predictor of new-onset congestive heart failure (CHF) in the setting of aggressive antihypertensive therapy in unclear. Methods and Results— The relationship of ECG strain at study baseline to the development of CHF was examined in 8696 patients with no history of CHF who were enrolled in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. All patients had ECG LVH by Cornell product and/or Sokolow-Lyon voltage criteria on a screening ECG, were treated in a blinded manner with atenolol- or losartan-based regimens, and were followed up for a mean of 4.7±1.1 years. Strain was defined as a downsloping convex ST segment with inverted asymmetrical T-wave opposite the QRS axis in lead V 5 or V 6 . ECG strain was present in 923 patients (10.6%), and new-onset CHF occurred in 265 patients (3.0%), 26 of whom had a CHF-related death. Compared with patients who did not develop CHF, hypertensive patients who developed CHF were older; were more likely to be black, current smokers, and diabetic; were more like to have a history of myocardial infarction, ischemic heart disease, stroke, or peripheral vascular disease; and had greater baseline severity of LVH by Cornell product and Sokolow-Lyon voltage, higher baseline body mass indexes, higher serum glucose levels and albuminuria, similar baseline systolic and diastolic pressures, and reductions in diastolic pressure with treatment but greater reductions in systolic pressure. In univariate Cox analyses, ECG strain was a significant predictor of new-onset CHF (hazard ratio [HR], 3.27; 95% CI, 2.49 to 4.29) and CHF mortality (HR, 4.74; 95% CI, 2.11 to 10.64). In Cox multivariable analyses adjusting for baseline differences between patients with and without new-onset CHF, in-treatment differences in systolic and diastolic pressures, Sokolow-Lyon voltage, and Cornell product, and the impact of treatment with losartan versus atenolol on outcomes, ECG strain remained a significant predictor of incident CHF (HR, 1.80; 95% CI, 1.30 to 2.48) and CHF-related death (HR, 2.78; 95% CI, 1.02 to 7.63). Conclusions— ECG strain identifies hypertensive patients at increased risk of developing CHF and dying as a result of CHF, even in the setting of aggressive blood pressure lowering.

Background— Obesity may independently increase the risk of adverse events in hypertension with target-organ damage. We investigated whether body build was independently associated with higher cardiovascular risk and whether treatment with losartan relative to atenolol influenced the impact of body build on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and on cardiovascular death in patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Methods and Results— The population of 9079 patients was divided as follows: thin (body mass index [BMI] 2 , 2%), normal weight (BMI 20 to 24.9, 24%), overweight (BMI 25 to 29.9, 45%), and obese (class I: BMI 30 to 34.9, 21%; class II: BMI 35 to 39.9, 6%; class III: BMI ≥40, 2%). Incident diabetes increased progressively with BMI and was somewhat higher in the atenolol arm. Differences in gender and race were detected among the body build groups. Rates (Cox proportional hazard analysis) of the primary composite end point did not differ among body build groups after adjustment for age, gender, race, smoking habit, prevalent cardiovascular disease, and left ventricular hypertrophy. Cardiovascular death was more frequent among thin ( P P Conclusions— In the LIFE study, stratification for classes of body build identified increased risk of cardiovascular mortality in both thin and moderately-to-severely obese individuals. This risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan-based treatment as opposed to atenolol-based treatment.

Background— Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. Methods and Results— Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months’ follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, −200 versus −69 mm · ms, P P P Conclusions— After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.

Background : Whether aortic regurgitation (AI) is associated with higher cardiovascular (CV) morbidity and mortality in hypertension with electrocardiographic (ECG) left ventricular hypertrophy (LVH) is unknown. Methods : Hypertensive patients with ECG-LVH were randomized to losartan- or atenolol-based treatment and followed for 4.8 years in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. In the LIFE echo substudy, echocardiograms were used to detect AI. Baseline clinical, echocardiographic variables and cardiovascular endpoints data were used in current analyses. Results: The presence of AI was detected in 132 participants (68 women; 68.4 ± 7.3 years). AI was associated with older age (p < 0.001) but not gender. After adjustment for age, AI was associated with significantly increased LV mass indexed by body surface area (BSA) and height 2.7 (both p < 0.005), echocardiographic eccentric LVH (p < 0.05) but not concentric left ventricular (LV) geometry (p < 0.05). After adjusting for significant confounders including history of CV disease, Framingham risk score, randomized antihypertensive therapy, LV eccentric geometry, LV mass indexed by BSA and height 2.7 , multivariate Cox regression analyses showed that AI was independently associated with 2.83-fold more CV death (95% confidence interval [CI] 1.12 to 7.13), 2.24-fold more all-cause mortality (95% CI 1.17 to 4.28) (both p < 0.05). Conclusion : In hypertensive patients with ECG-LVH, AI independently identifies patients at increased risk of CV and all-course mortality.

We hypothesize that some levels of CPR generated low-flow may in fact worsen myocardial recovery compared with no-flow of similar duration. To test this hypothesis we determined the effect of low-flow reperfusion simulating CPR, on myocardial ROS production, cellular redox changes and recovery of contractile function in the whole heart. Methods: Isolated perfused male Sprague Dawley rat hearts were subjected to either 20 minutes of global ischemia followed by full reperfusion with 85 mm Hg perfusion (Control) or 3 minutes of global ischemia followed by 17 minutes of low-flow with perfusion pressure of 20 mm Hg before full reperfusion at 20 minutes (CPR model). Full reperfusion was for 30 minutes in all hearts. A fiberoptic spectrometer measured fluorescence on the left ventricular wall. Hearts were preloaded with 2 probes, dihydrofluorescein (an intracellular probe) and amplex red (an extracellular probe), both of which are oxidized and fluoresce in the presence of reactive oxygen species (ROS). NADH autofluorescence, a measure of cellular redox state, and LV contractile function were continuously measured. Changes in fluorescence and function were normalized to baseline and compared between groups using ANOVA. Results: At the end of the 30 minute reperfusion period, rate pressure product (RPP in mmHg/min) was significantly reduced in CPR modeled hearts (RPP = 6,733 ± 3,720) (p Conclusions: It is well understood that under CPR conditions, the level of low-flow can be quite variable. However, at some level of low-flow, recovery of myocardial function may be worse than recovery following a similar duration of no-flow. This depressed myocardial function may be ROS mediated, as this level of low-flow alters the compartmentalizded ROS burst seen at full reperfusion.

Background— Diabetes mellitus is associated with increased cardiovascular (CV) morbidity and mortality and with greater ECG left ventricular hypertrophy (LVH); however, it is unclear whether diabetes attenuates regression of hypertensive LVH and whether regression of ECG LVH has similar prognostic value in diabetic and nondiabetic hypertensive individuals. Methods and Results— A total of 9193 hypertensive patients (1195 with diabetes) in the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study were treated with losartan- or atenolol-based regimens and followed up with serial ECG and blood pressure determinations at baseline and 6 months and then yearly until death or study end. ECG LVH was defined with gender-adjusted Cornell voltage-duration product (CP) criteria >2440 mm · ms. After a mean follow-up of 4.8±0.9 years, patients with diabetes had less regression of CP LVH (−138±866 versus −204±854 mm · ms, P P Conclusions— Hypertensive patients with diabetes have less regression of CP LVH in response to antihypertensive therapy than patients without diabetes, and regression of ECG LVH is less useful as a surrogate marker of outcomes in hypertensive patients with diabetes. These findings may in part explain the higher CV morbidity and mortality in hypertensive patients with diabetes, and the absence of a demonstrable improvement in prognosis in diabetic patients in response to regression of ECG LVH suggests a more complex interrelation between underlying LV structural and functional abnormalities and outcome in these patients.