AIMS Despite evidence-based therapeutic approaches, target blood pressure is obtained by less than half of patients with hypertension. Hypertension is associated with a significant risk for heart failure (HF), in particular HF with preserved left ventricular (LV) ejection fraction (HFpEF). Although treatment is suggested to be given early after hypertension diagnosis, there is still no evidence-based medical treatment for HFpEF. We aim to study the underlying mechanisms behind the transition from uncomplicated hypertension to hypertensive heart disease (HHD) and HFpEF. To this end, we will combine cardiac imaging techniques and measurements of circulating fibrosis markers to longitudinally monitor fibrosis development in patients with hypertension.

METHODS In a prospective cohort study, 250 patients with primary hypertension and 60 healthy controls, will be characterized at inclusion, and after 1 and 6 years. Doppler-echocardiography, cardiac magnetic resonance imaging (CMR) and ECG will be used for measures of cardiac structure and function over time. Blood biomarkers reflecting myocardial fibrosis, inflammation and endothelial dysfunction will be analysed. As a proxy for HFpEF development, the primary endpoint is to measure echocardiographic changes in LV function and structure (E/e´ and LAVI) and to relate these measures of LV filling to blood pressure, biomarkers, ECG and CMR.

CONCLUSION We aim to study the timeline and transition from uncomplicated hypertension to HHD and HFpEF. In order to identify subjects prone to develop HHD and HFpEF, we want to find biomarkers and cardiac imaging variables to explain disease progression. Ultimately, we aim at finding new pathways to prevent HFpEF.

INTRODUCTION Hypertension is common with a prevalence of approximately one third of the adult Swedish population and similar figures reported world wide. It is associated to cardiac structural- and functional changes as well as vascular dysfunction which all can be delayed or reversed by appropriate antihypertensive treatment. Although blood pressure (BP) control is improving, target BP is still reached by less than half of the treated patients. Hypertension is the single risk factor with the greatest attributable risk for incident heart failure (HF) and is considerably more common in HF with preserved left ventricular (LV) ejection fraction (HFpEF) than in HF with reduced EF (HFrEF). In patients with established HFpEF hypertension is very common, ranging between 50-70%. However, the exact mechanisms for the transition from hypertension to hypertensive heart disease and HFpEF are less well understood. In contrast, pathophysiology and progression of HFrEF is better elucidated and may successfully be reversed by 7-8 evidence-based treatments.

The evolution of myocardial fibrosis may be one early important mechanism in the transition from hypertension to HHD, and subsequent heart failure. This can be studied through the recent development of cardiac imaging with advanced Doppler-echocardiography, cardiac magnetic resonance (CMR) imaging, and assessment of circulating biomarkers reflecting myocardial fibrosis turnover, inflammation and endothelial dysfunction. Indeed, echocardiographic left chamber longitudinal strain and extracellular volume measured by CMR have recently been demonstrated to be useful to discriminate between healthy controls, patients with hypertension and patients with HFpEF. Also circulating plasma biomarkers reflecting altered myocardial tissue turnover can differentiate patients with left ventricular hypertrophy (LVH) from patients with LVH and HFpEF. In addition, biomarkers may identify phenotypes of high collagen cross-linking which has been suggested to have impact on the response to medical treatment in HFpEF.

An increased understanding of these mechanisms allows the development of specific treatments, guided by cardiac imaging and/or biomarker assessments, to delay or prevent the transition from hypertension to HF. This may have considerable clinical implications in reducing cardiovascular complications to hypertension. Thus, the aim of the present study is to characterize and study the timeline and the transition from uncomplicated hypertension to HHD and HFpEF in subjects with primary hypertension using advanced cardiac imaging techniques and bioinformatics, Table 1. Furthermore, we aim to compare changes of HFpEF variables and biomarkers in this study to patients with new onset symptomatic HFpEF in the Stockholm PREFERS Heart failure study, see below.

Table 1.

HYPOTHESES:

1. Hypertension with normal left atrial/ventricular function deteriorates over time, starting with increasing filling pressure, left atrial enlargement followed by reduced global longitudinal strain with LVEF>50% and heart failure symptoms (HFpEF)
2. Circulating biomarkers reflecting myocardial fibrosis, inflammation and endothelial dysfunction reflects the transition from hypertension to hypertensive heart disease and HFpEF

As a proxy for HFpEF development our OVERALL AIM is to investigate:

if change in diastolic cardiac function E/e' or left atrial volume index (LAVI) after one year is associated to blood pressure at baseline.

SPECIFIC AIMS:

1. to study if change in diastolic cardiac function measured with E/e' or LAVI after one year is associated to change in blood pressure from baseline to one year.
2. to assess if blood pressure control at baseline (according to guidelines and age adjusted) is associated to diastolic cardiac function measured with E/e' or LAVI after one year.
3. to investigate if blood pressure control after one year (according to guidelines and age adjusted) is associated to diastolic cardiac function measured with E/e' or LAVI after one year.
4. to study the temporal evolution (baseline, one year, six years) of the diastolic function measured with E/e' or LAVI.
5. to investigate gender aspects on the temporal evolution (baseline, one year, six years) of the diastolic function measured with E/e' or LAVI.
6. to study the temporal evolution (baseline, one year, six years) of the diastolic function measured with echocardiography and CMR.
7. to assess if temporal changes (baseline, one year, six years) in circulating levels of biomarkers reflecting myocardial fibrosis, inflammation and endothelial dysfunction are associated with changes in blood pressure.
8. to assess if temporal changes (baseline, one year, six years) in circulating levels of biomarkers reflecting myocardial fibrosis, inflammation and endothelial dysfunction are associated with changes in diastolic function.

METHODS

STUDY DESIGN The study PREFERS Hypertension, is the last part of the PREFERS (Preserved and Reduced Ejection Fraction Epidemiological Regional Study in Stockholm, Clin trial NCT03671122), a clinical trial first aiming at describing underlying pathophysiological mechanisms in new onset HF, either HFpEF or HFrEF with approximately 600 patients. PREFERS Hypertension study is a single-centre, prospective clinical cohort study performed in collaboration between the Department of Cardiology at Danderyd Hospital and the Primary Health Care Services in Stockholm, Sweden. The study will recruit patients with a diagnosis of primary hypertension with an ongoing antihypertensive drug treatment as well as healthy control subjects, for comparison as previously described. For inclusion and exclusion criteria, see below. All subjects will be assessed at the Cardiovascular Research Laboratory, which is part of the Clinical Research Centre at Danderyd University Hospital.

Primary hypertension is defined as a diagnosis documented in primary care at some time point within the last 24 months and ongoing antihypertensive drug treatment (maximum up to 2-3 drugs). The currently recommended definition of hypertension as a systolic office BP >140 mmHg and/or diastolic BP >90 mmHg(19) is widely adapted in primary health care. Exclusion of secondary hypertension is at the discretion of the primary health care physician or may be excluded at the inclusion visit. Controlled hypertension is defined as <140/90 mm Hg.

RECRUITMENT OF STUDY PARTICIPANTS AND TIMELINE Hypertension in Sweden is usually managed at primary health care centers. Through a collaboration between hospital and primary care, the patients will be recruited from health care centers in various socioeconomic areas in Stockholm (approximately 10 care centers, total catchment area of 100 000 inhabitants). To include 250 patients and with an expected response rate of 25-30%, each health care center will identify and randomly select and invite 100 patients, gender 1:1 using the software MedRave4 (Medrave Software AB, Stockholm, Sweden). Patients will be characterized at baseline, after 1 and 6 years per standardized protocol, and they will have their medication optimized at baseline and follow-ups, according to ESC/ESH 2018 guidelines. Parallel with patient recruitment, healthy control subjects, matched in age and gender will be recruited by advertisement in local newspapers. Inclusion will be performed following a telephone interview, confirming they are apparently healthy and have no daily medication. Control subjects will follow the same study protocol as the patients but planned to be examined at inclusion only. The study protocol has been approved by the regional Ethics committee and the Stockholm Health Care services, and all study participants will give their written informed consent.

MEASUREMENTS All study data will be collected into electronic case report forms (eCRF) using the Research Electronic Data Capture (REDCap).

BLOOD PRESSURE MEASUREMENTS AND PULSE WAVE VELOCITY Seated BP measurements will be made in accordance to current ESC/ESH 2018 guidelines. Three consecutive BP measurements are recorded, 1-2 min apart, using an oscillometry device (Omron M3 Comfort, OMROM Healthcare Co., Ltd. Kyoto, Japan). BP will also be measured 1 min and 3 min after standing from a seated position, to assess orthostatic hypotension. To screen for lower extremity artery disease an ankle-brachial index will be recorded, using continuous wave Doppler.

Ambulatory blood pressure monitoring (ABPM) during 24 h will be assessed by a Spacelabs ABP monitoring 90217A device (Spacelabs Healthcare, Snoqualmie, WA, US), programmed to record BP at 20 min intervals to provide an average BP value for day-time, night-time and 24h. A diary of the patients´ activities and sleep-time will be recorded. A minimum of 70% useable BP recordings are required for a valid ABPM session. The diagnostic threshold for hypertension is according to ESC/EHS 2018 guidelines. The carotid-femoral pulse wave velocity (PWV) is assessed by the SphygmoCor XCEL device (AtCor Medical, Sydney, Australia), which allows for non-invasive assessment of the central arterial pressure waveform and measures of aortic stiffness.

ELECTROCARDIOGRAM 12 lead ECG data will be stored digitally (EC store version 4.1; Cardiolex Medical AB, Stockholm, Sweden). In harmony with the PREFERS HF study, LVH will be assessed according to the Sokolov Lyon index. In addition, beside a conventional 12-lead ECG we will analyse a resting 12-lead ECG that combines advanced and conventional ECG parameters within computerized ECG-scores which have been demonstrated to increase the detection accuracy of concentric LVH and in screening for LV systolic dysfunction.

ECHOCARDIOGRAPHIC AND CMR MEASUREMENTS We will follow current recommendations for echocardiography to record two-dimensional echocardiographic and Doppler variables, and perform Doppler tissue imaging similar to those measured in the PREFERS HF study. All measurements will be presented as mean values of three cardiac cycles. A Vivid E9 (GE, Waukesha, Wisconsin, USA) Ultrasound System will be used. To reduce interobserver variability only two sonographers will perform the investigations, which will be stored on a digital server, and will be analyzed offline.

For CMR, a Siemens Aera system (Siemens Healthcare, Erlangen, Germany) will be used to deliver standard measurements of chamber dimensions and function, and signs of tissue scars of ischemic and non-ischemic origin. Myocardial extracellular matrix and signs of fibrosis will be examined by T1 mapping. Fully automated quantitative perfusion mapping during rest and adenosine stress will give a quantitative measurement for perfusion in mL/min/g, which will be used to search for perfusion defects; both focal defects due to obstructive coronary artery disease and defects in the global myocardial perfusion reserve due to coronary microvascular disease.

MEASUREMENTS QUESTIONNAIRES Quality of life measurements are to be assessed with validated instruments; the EuroQol-5 dimensions (EQ-5D), the Kansas City cardiomyopathy questionnaire (KCCQ-12) and the Minnesota living with heart failure questionnaire (MLHFQ). To screen for excessive daytime sleepiness, we will use the Epworth Sleepiness Scale (ESS) version 1.0.

SCREENING FOR OBSTRUCTIVE SLEEP APNEA Screening for sleep disorders and obstructive sleep apnea (OSA) is performed at inclusion by the Somnocheck micro CARDIO (Weinman, Hamburg, Germany), self-applied by the study participants at home before bedtime. The ambulatory overnight cardio-respiratory polygraphy recording will measure apnea/hypopnea-, desaturation- and arousal indices.

PERIPHERAL VENOUS BLOOD- AND URINE SAMPLING Peripheral blood and urine will be collected after overnight fasting with no ingestion of caffeine or nicotine within at least 12h. Clinical routine analyses of plasma and urine will be performed directly, but for future analysis of biomarkers and DNA extraction, aliquots of whole blood, plasma and serum will be stored at -80 degrees C in the Stockholm Medical Biobank until further analysis. This ensures a standardized handling of biomaterial with high security and traceability also for long-term storage. In the PREFERS Hypertension study we plan to analyze the same panel of biomarkers as for the PREFERS HF study(17), which will enable a comparison between the two cohorts. Here, we focus on biomarkers indicative of various pathophysiological mechanisms relevant to HFpEF, including those reflecting myocardial fibrosis, inflammation and endothelial dysfunction. Fibrosis i.e: Collagen split products PICP, CITP-I, sST2, Galectin-3, MMPs and IGFBP2; Inflammation i.e: HsCRP, IL-6, E-selectin, TNF-alfa, YLK-40, GDF15; Endothelial dysfunction i.e: ICAM-1, VCAM-1, Allantoin, SDMA, ADMA, Calprotectin, Arginin, von Willebrand factor, EMPs.

OUTCOME MEASURES Mortality data outside hospital and incident admission to hospital due to heart failure will be obtained by merging the Swedish cause of death register and the Swedish national inpatient register. The unique personal identification number of all Swedish citizens will ascertain complete follow-up.

PRIMARY ENDPOINT AND STATISTICAL POWER As a proxy for HFpEF development our overall aim is to investigate if change in diastolic cardiac function E/e' or left atrial volume index (LAVI) after one year is associated to blood pressure at baseline. Therefore, the primary endpoint in this study is, either mean change of E/e' of 2 or more, or mean change of LAVI of 4 mL/m2 or more after one year. These assumptions are based on a cross-sectional analysis of a big cohort from Olmsted County, Minnesota, where clear-cut differences were shown for these echocardiographic variables in patients with hypertension, HFpEF and healthy controls. To reach 80% power at a 2-sided level of significance of 0.05 the present study is planned to recruit 250 patients and 60 healthy controls, including 20% drop outs.

Inclusion Criteria:

• Primary hypertension
• Age ≥ 18 years
• Preserved cognitive function and expected longevity 1 year
• Written informed consent

Exclusion Criteria:

• Heart failure and/or reduced LVEF
• Valvular heart disease of hemodynamic importance
• Resistant hypertension
• Pregnancy
• Renal failure, GFR <30 mL/min/1,73 m2

Patients with primary hypertension will be recruited from health care centers in various socioeconomic areas in Stockholm. To include 250 patients and with an expected response rate of 25-30%, each health care center will identify and randomly select and invite 100 patients, gender 1:1. Patients will be characterized at baseline, after 1 and 6 years per standardized protocol and they will have their medication optimized at baseline and follow-ups, according to guidelines. Parallel with patient recruitment, healthy control subjects, matched in age and gender will be recruited by advertisement in local newspapers. Inclusion will be performed following a telephone interview, confirming they are apparently healthy and have no daily medication. Control subjects will follow the same study protocol as the patients but planned to be examined at inclusion only.

The regional ethics committee has not approved any sharing of individual participant data. If this question comes up later we have to write a new application för ethical approval but still, all data has to be coded and pseudonymized.