A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension (aTRH) and risk of cardiovascular disease (CVD).

To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association.

We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants (n = 25516) from 625 primary care settings throughout the United States, Canada, Puerto Rico, and United States Virgin Islands, aged 55 and older with hypertension and at least one additional risk factor for heart disease. aTRH was assessed from the year 2 visit. CVD event was defined as one of the following from the year 2 follow-up visit: Fatal or non-fatal myocardial infarction, coronary revascularization, angina, stroke, heart failure, or peripheral artery disease. Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk. Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction.

Of the total study participants (n = 25516), 5030 experienced a CVD event during a mean of 4.7 years follow-up. aTRH was associated with a 30% increase in risk of CVD compared to non-aTRH [hazards ratio (HR) = 1.3, 95%CI: 1.19-1.42]. Sex and age modified this relationship on both multiplicative and additive scales independently. Stratified by sex, aTRH was associated with a 64% increase in risk of CVD (HR = 1.64, 95%CI: 1.43–1.88) in women, and a 13% increase in risk of CVD (HR = 1.13, 95%CI: 1.01–1.27) in men. Stratified by age, aTRH had a stronger impact on the risk of CVD in participants aged < 65 (HR = 1.53, 95%CI: 1.32–1.77) than it did in those aged ≥ 65 (HR = 1.18, 95%CI: 1.05–1.32). Significant two-way interactions of sex and aTRH, and age and aTRH on risk of CVD were observed (P < 0.05). The observed joint effect of aTRH and ages ≥ 65 years (HR = 1.85, 95%CI: 1.22–2.48) in males was less than what was expected for both additive and multiplicative models (HR = 4.10, 95%CI: 3.63–4.57 and 4.88, 95%CI: 3.66–6.31), although three-way interaction of sex, age, and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance (P > 0.05).

aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age. Further studies are warranted to test these mechanisms.

• Apparent treatment resistant hypertension
• Cardiovascular disease outcomes
• Chronic kidney disease
• Sex
• Age

Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P < 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120–129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17–3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.

• APOE
• hypertension
• intracerebral haemorrhage

• Aged
• Antihypertensive Agents/therapeutic use
• Blood Pressure Determination/statistics & numerical data
• Cerebral Hemorrhage/epidemiology
• Cerebral Hemorrhage/ethnology
• Cerebral Hemorrhage/etiology
• Cerebral Hemorrhage/pathology
• Female
• Humans
• Hypertension/complications
• Hypertension/ethnology
• Hypertension/prevention & control
• Male
• Middle Aged
• Multivariate Analysis
• Recurrence
• Risk
• Secondary Prevention/methods
• Statistics, Nonparametric
• Survivors
• Time Factors

• AG26484 NIA NIH HHS
• K23NS086873 NINDS NIH HHS
• U10NS077360 NINDS NIH HHS
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• R01NS073344 NINDS NIH HHS
• U01NS069208 NINDS NIH HHS
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• K23 NS086873 NINDS NIH HHS
• P50 AG005134 NIA NIH HHS
• P50 NS051343 NINDS NIH HHS
• U01 NS069763 NINDS NIH HHS
• U01 NS069208 NINDS NIH HHS
• U10 NS077360 NINDS NIH HHS
• R01 AG047975 NIA NIH HHS
• R01 NS063925 NINDS NIH HHS