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Background Isolated systolic hypertension (ISH) in middle-aged and elderly is associated with high cardiovascular risk, but no randomised controlled trial has assessed the effect of antihypertensive treatment in ISH using today’s definition, i.e. systolic blood pressure (SBP) ≥140 mmHg and diastolic blood pressure (DBP)

Aim: While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion. Methods: We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%. Results: During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001). Conclusions: In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Aim: The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial. Methods: Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated. Results: Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028). Conclusions: Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).

Aim: Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH. Methods: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up. Results: Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001). Conclusions: These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Aim: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study. Methods: Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging. Results: Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P < 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P < 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports. Conclusions: In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).

Background Measurement of serum concentrations of drugs is a novelty found useful in detecting poor drug adherence in patients taking ≥2 antihypertensive agents. Regarding patients with treatment‐resistant hypertension, we previously based our assessment on directly observed therapy. The present study aimed to investigate whether serum drug measurements in patients with resistant hypertension offer additional information regarding drug adherence, beyond that of initial assessment with directly observed therapy. Methods and Results Nineteen patients assumed to have true treatment‐resistant hypertension and adherence to antihypertensive drugs based on directly observed therapy were investigated repeatedly through 7 years. Serum concentrations of antihypertensive drugs were measured by ultra‐high‐performance liquid chromatography–tandem mass spectrometry from blood samples taken at baseline, 6‐month, 3‐year, and 7‐year visits. Cytochrome P450 polymorphisms, self‐reported adherence and beliefs about medicine were performed as supplement investigations. Seven patients (37%) were redefined as nonadherent based on their serum concentrations during follow‐up. All patients reported high adherence to medications. Nonadherent patients expressed lower necessity and higher concerns regarding intake of antihypertensive medication (P=0.003). Cytochrome P450 polymorphisms affecting metabolism of antihypertensive drugs were found in 16 patients (84%), 21% were poor metabolizers, and none were ultra‐rapid metabolizers. Six of 7 patients redefined as nonadherent had cytochrome P450 polymorphisms, however, not explaining the low serum drug concentrations measured in these patients. Conclusions Our data suggest that repeated measurements of serum concentrations of antihypertensive drugs revealed nonadherence in one‐third of patients previously evaluated as adherent and treatment resistant by directly observed therapy, thereby improving the accuracy of adherence evaluation. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT01673516.

Purpose Event-based clinical outcome trials have shown limited evidence to support guidelines recommendations to lower blood pressure (BP) to

Purpose Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to

Purpose The Hypertension Optimal Treatment (HOT) Study investigated the relationship between target office diastolic blood pressure (BP) ≤80, ≤85 or ≤90 mmHg and cardiovascular morbidity and mortality in 18,790 patients aged 50–80 years. The home BP sub-study enrolled 926 patients and the aim was to clarify whether the separation into the BP target groups in the office prevailed in the out-of-office setting. The present study aimed to identify variables that characterised masked uncontrolled hypertension (MUCH) and white coat uncontrolled hypertension (WUCH). Material and Methods The sub-study participants took their home BP when office BP had been up titrated. The cut-off for normal or high BP was set to ≥135/85 mmHg at home and ≥140/90 mmHg in the office. We analysed data by using multivariate and stepwise multivariate logistic regression with home and office BP combinations as the dependent variables. Results WUCH was associated with lower body mass index (BMI) (odds ratio (OR) 0.92, 95% confident intervals (CIs) 0.88–0.96, p

Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined. Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels. Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90–1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16–2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78–1.31). Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF. Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1

Aims: Atrial fibrillation (AF) is associated with increased cardiovascular risk and the incidence increases with age, hypertension and left ventricular hypertrophy (LVH). Reducing in-treatment systolic blood pressure (SBP) prevents new-onset AF but has previously not been studied in patients with isolated systolic hypertension (ISH). We aimed to investigate the effect on preventing new-onset AF by decreased in-treatment SBP in patients with ISH compared to patients with non-ISH. Methods and results: Double-blind, randomized, parallel-group study of 1320 patients with ISH and electrocardiographic (ECG) LVH, included among the 9193 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Annual ECGs were Minnesota coded centrally, and new-onset AF was evaluated in 1248 ISH patients and compared with 7583 non-ISH patients during mean 4.8 ± 0.9 years follow-up. Cox regression analyses were used to assess the effect of reduced in-treatment SBP. New-onset AF occurred in 61 (4.9%) ISH patients and 292 (3.9%) non-ISH patients. In multivariate analysis lower in-treatment SBP was associated with 17% risk reduction (p = 0.008) for new-onset AF in ISH patients and 9% risk reduction (p = 0.006) in non-ISH patients per 10 mmHg decrease in in-treatment SBP, independent of treatment modality, baseline risk factors, baseline SBP and in-treatment heart rate and ECG-LVH. There was a significant interaction (p = 0.041) in favor of SBP reduction and AF prevention in ISH vs. non-ISH patients. Conclusion: Our data suggest that the effect of in-treatment SBP reduction in preventing new-onset AF is stronger in ISH compared to non-ISH patients with hypertension and ECG-LVH. However, the principal findings were the same in ISH and non-ISH patients.

Aims: We aimed to investigate whether left bundle branch block (LBBB) is related to new-onset left ventricle (LV) wall motion abnormalities during treatment in hypertensive patients with electrocardiographic (ECG) defined left ventricular hypertrophy (LVH). Methods and results: 960 patients with essential hypertension and ECG-LVH participating in the LIFE Echo Sub-study were investigated at baseline and annually with echocardiography, during randomized antihypertensive therapy. After excluding patients with LV wall motion abnormalities at baseline and patients developing new-onset LBBB during study time, we investigated 784 patients. The participants with (n = 32) and without (n = 752) LBBB were similar regarding most baseline variables. Logistic regression models controlling for LV mass index, Framingham risk score, and randomized treatment assignment were used to assess the odds ratio of developing new-onset abnormal LV wall motion on annual follow-up echocardiograms. The likelihood of developing new global LV wall motion abnormalities in patients with LBBB was not higher compared to those without LBBB except at year 5 (p = .002). The likelihood of developing new segmental LV wall motion abnormalities in patients with LBBB was however higher compared to patients without LBBB after 1 year (OR = 3.1, 95% CI = 0.7–14.2, p = .173); 2 years (OR = 6.9, 2.1–22.4, p = .003); 3 years (OR = 5.3, 2.0–14.3, p

Background: Available nomograms to predict aortic root (AoR) diameter for body surface area have limitations. The purpose of this study was to evaluate the use of a new multivariate predictive model to identify AoR dilatation in hypertensive patients with left ventricular hypertrophy. Methods: 943 of 961 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic sub-study had the necessary baseline characteristics and echocardiographic 2D measurements of AoR size to be included. Results: Predicted AoR (Sinus of Valsalva) diameter was 1.519 + (age [years] × 0.010) + (height [cm] × 0.010) – (gender [1 = M, 2 = F] × 0.247), and a measured AoR diameter exceeding the 97.5-percentile of this estimate was considered dilated. Measured AoR diameter was larger in men than in women (3.75 vs. 3.48 cm, p < 0.001) and AoR diameter predicted by the model was larger than predicted by nomogram (3.52 vs. 3.28 cm, p < 0.001). Using the multivariate model to identify patients with AoR dilatation, the prevalence was 13.7% in men and 12.3% in women (p = 0.537). There was consensus of AoR phenotype (normal/dilated) between model and nomogram in 92.8% of the patients. In multivariate logistic regression, AoR dilatation by model definition was predicted by presence of aortic regurgitation (OR 2.67, p < 0.001) and SD increase in age (OR 0.75, p = 0.023), pulse pressure (OR 0.64, p < 0.001), left ventricular mass index (OR 1.36, p = 0.08) and stroke volume (OR 1.45, p = 0.002), but not by body weight. Conclusions: Using the proposed model the prevalence of AoR dilatation was equal in men and women and the model seems to address the effects of gender, age and body size on AoR size. Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00338260.

Objective: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. Methods: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age

Background: Studies of renal denervation (RDN) in patients with apparent treatment resistant hypertension have been hampered by a number of patient and physician related confounders on blood pressure (BP) including poor drug adherence. It remains uncertain whether RDN lowers BP. We aimed to investigate whether the use of sham control is essential in RDN studies or whether systematic use of 24-hour ambulatory BP provides enough information thereby making an invasive sham control redundant. Methods: We meta-analyzed randomized controlled trials of the BP response to RDN on top of continued or optimized antihypertensive drugs in patients with resistant hypertension. On top of the randomized trials reviewed earlier, we additionally included three studies, one conducted in Spain (24 patients, RDN vs. spironolactone), one conducted in Denmark (69 patients, sham controlled) and one conducted in Netherlands (139 patients, RDN vs. continued treatment). We analyzed 24-hour ambulatory BP in 3 sham controlled studies vs. 7 no sham controlled studies. Results: The updated meta-analysis of 10 studies showed 3.6 mmHg (p = .45) and 1.0 mmHg (p = .54) reductions in office and in 24-hour systolic BP, respectively. Meta-analysis of 24-hour systolic BP in the 3 sham-controlled studies showed a reduction of 2.18 mmHg (95% confidence intervals (CIs) −4.70 to 0.33 mmHg, n = 396 vs. 230, p = .07). For the 7 no sham controlled studies there was no difference in 24-hour systolic BP (+0.38 mmHg; 95% CIs −5.29 to 6.04 mmHg, n = 215 vs. 245, p = .90). The test for sub-group heterogeneity showed no significant interaction (p = .69). Removing one trial at a time produced confirmatory results. Conclusion: The overall meta-analysis of 10 randomized and controlled studies showed no significant effect on BP of RDN in resistant hypertension. Moreover, our analysis does not support the use of sham control but rather suggests extensive use of 24-hour ambulatory BP in studies of RDN in resistant hypertension

Objective: There is an association between exercise systolic blood pressure (SBP) and cardiovascular disease and mortality. The aim of this study was to investigate this association, with 35 years of follow-up. Methods: Through 1972–75, 2014 healthy, middle-aged men underwent thorough medical examination and a bicycle exercise test. 1999 participants completed six minutes at 100 W. SBP was measured manually, both before the test and every two minutes during the test. Highest SBP measured during the first six minutes (SBP100W) was used in further analyses. Results: Participants were divided into quartiles (Q) based on their SBP100W; Q1: 100–160 mm Hg (n = 457), Q2: 165–175 mm Hg (n = 508), Q3: 180–195 mm Hg (n = 545) and Q4: 200–275 mm Hg (n = 489). After 35-years follow-up, there was a significant association between exercise SBP at baseline and cardiovascular disease and mortality. In the multivariate analysis adjusting for resting SBP, age, smoking status, total serum cholesterol and family history of coronary heart disease, as well as physical fitness, there is a 1.39-fold (CI: 1.00–1.93, p = 0.05) increased risk of cardiovascular mortality in Q4 compared to Q1. When not adjusting for physical fitness, there is a 1.29-fold (CI: 1.03–1.61, p = 0.02) increase in risk of cardiovascular disease between Q1 and Q4. Conclusions: The results of this study suggest that the association between exercise SBP at moderate workload and cardiovascular disease and mortality in middle-aged men extends through as long as 35 years and into old ages.

Background: Abnormal P-wave terminal force in lead V1 (PTF-V1) is an ECG marker of increased left atrial (LA) volume, elevated LA filling pressures and/or LA systolic dysfunction. Because left ventricular (LV) diastolic dysfunction is one of the potential mechanisms driving LA remodelling, we hypothesized that PTF-V1 might be an additional ECG marker of diastolic dysfunction. Methods: LV diastolic function after 3 years’ systematic antihypertensive treatment was examined in relation to baseline PTF-V1 in 431 hypertensive patients undergoing protocol-driven blood pressure reduction who had baseline and year-3 ECG and echocardiographic data and a preserved LV ejection fraction (EF >45%) at year-3. Abnormal diastolic function was defined by the tenth or 90th percentile values from 405 normotensive, non-obese and non-diabetic adults without overt cardiovascular disease. Abnormal PTF-V1, defined by the presence of a negative terminal P-wave in lead V1 ≥ 4000 μV·ms, was present in 167 patients (38.7%). Results: Abnormal PTF-V1 was associated with worse year-3 mean diastolic first third filling time (0.43 ± 0.08 vs 0.40 ± 0.07 sec, p = 0.039), first half filling time (0.55 ± 0.07 vs 0.53 ± 0.07 sec, p = 0.041), mitral valve A velocity (86 ± 27 vs 76 ± 19 cm/sec, p = 0.009) and mitral valve E/A ratio (0.85 ± 0.22 vs 0.94 ± 0.27, p = 0.007) after adjusting for other potential predictors of diastolic dysfunction including race, and heart rate, systolic blood pressure and severity of ECG LVH by Cornell product criteria at baseline. In parallel multivariate logistic regression analysis, abnormal PTF-V1 was associated with significantly increased odds of abnormal mitral valve E/A ratio (OR 1.55, 95%CI 1.04–2.32 p = 0.032), and a trend toward higher odds of abnormal half filling time (OR 1.42, 95%CI 0.94–2.15, p = 0.098) at year-3 of follow-up. Conclusions: Abnormal P-wave terminal force in lead V1 is associated with worse diastolic function and predicts abnormal LV diastolic behaviour in patients with preserved EF after 3 years of blood pressure reductive therapy.

BackgroundPatients with hypertension with ECG left ventricular hypertrophy (LVH) have higher cardiovascular morbidity and mortality, but single ECG criteria may underestimate risk. Whether continued presence or new development of ECG LVH by 2 criteria can further concentrate risk during blood pressure lowering is unclear. Methods and ResultsIncident stroke, myocardial infarction, cardiovascular death, the composite of these outcomes, and all‐cause mortality were examined in relation to the presence of on‐treatment ECG LVH by Cornell product and/or Sokolow‐Lyon voltage during a mean of 4.8±0.9 years follow‐up in 9193 patients with hypertension randomized to losartan‐ or atenolol‐based regimens. Patients were categorized into 4 groups according to the presence or absence of ECG LVH by each criterion at baseline and yearly during the study. At baseline, LVH by both criteria was present in 960 patients (10.4%). Compared with the absence of ECG LVH by both criteria, persistence or development of ECG LVH by both criteria entered as a time‐varying covariate was associated with >3‐fold increased risks of events in multivariable Cox analyses adjusting for randomized treatment, baseline risk factors, and on‐treatment heart rate and systolic and diastolic blood pressures. Patients with ECG LVH by either Cornell product or Sokolow‐Lyon voltage had 45% to 140% higher risks of all end points. ConclusionsPersistence or development of ECG LVH by both Cornell product and Sokolow‐Lyon voltage criteria during antihypertensive therapy is associated with markedly increased risks of cardiovascular end points and all‐cause mortality. Further study is indicated to determine whether additional therapy in these patients can reduce their risk. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260.

BackgroundChronotropic index is a standardized measure of heart rate (HR) increment during exercise that reflects the combined effects of age, resting HR, and physical fitness. Low chronotropic index has been reported to predict disease and death. We tested whether temporal change in chronotropic index over 7 years influenced risk of cardiovascular death through up to 28 years. Methods and ResultsChronotropic index was calculated ([achieved maximal HR−resting HR]/[age‐predicted maximal HR−resting HR]) after a symptom‐limited bicycle ECG exercise test in 1420 healthy men at 2 examinations 7 years apart, in 1972 and 1979. Events of cardiovascular death were registered by manual scrutiny of all participants’ hospital charts and the Norwegian Cause of Death Registry. The participants were divided into quartiles of temporal change in chronotropic index, with quartile one having the most negative value. Cox proportional hazard regression models were used to estimate risks and adjusted for classical cardiovascular risk factors. Incidence of cardiovascular death was 310 (22%) during median of 21 years of follow‐up. After multivariable adjustment, and comparison with quartile four (mean +0.11), quartiles one (−0.16), two (−0.04), and three (+0.02) were associated with hazard ratios 1.50 (95% CI 1.10–2.05), 1.10 (0.79–1.53), and 1.04 (0.74–1.45) for cardiovascular death. Results remained robust also after exclusion of 31 participants with exercise ECG‐induced signs of coronary ischemia. ConclusionsTemporal reduction in chronotropic index was associated with increased long‐term risk of cardiovascular death and might be a clinically important predictor when assessing risk in healthy individuals over a longer time.