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Recent findings Hypertension is invariably diagnosed along with multiple comorbidities, particularly diabetes mellitus, obesity, chronic kidney disease, coronary artery disease, and heart failure. Evidence pertinent to prevalence, incidence, and temporal trends is reported, with an emphasis on differences according to age, gender, and race/ethnicity.

Summary The clustering of these conditions requires a thorough —and often multidisciplinary —approach in the evaluation and management of individuals with hypertension. Populations with higher risk include the elderly, women, and racial/ethnic groups.

Keywords comorbidity, epidemiology, hypertension INTRODUCTION Following the definition of hypertension (HTN) as a systolic blood pressure (SBP) of 140 mmHg or a diastolic blood pressure (DBP) of 90 mmHg, or the current use of antihypertensive medication, or being told by a healthcare professional at least twice that one has high blood pressure (BP), the American Heart Association’s (AHA) Heart Disease and Stroke Statistics 2016 Update reported that approximately 80 million US adults more than 20 years old have HTN (i.e., 32.6% prevalence) [1 &&]. With reference to age, 2.9 and 3.7% of male and female adolescents aged 12 – 19 years, respectively, were found to have poor BP [2]. Based on National Health and Nutrition Examination Survey (NHANES) data, the prevalence of HTN rises in direct proportion with the age of the population: 7.3, 32.4, and 65% among individuals aged 18 – 39 years, 40 – 59 years, and 60 years, respectively [3]. For US adults 80 years or older, 76.5% had HTN [4]. With respect to gender, more men than women have HTN until 45 years of age. The prevalence becomes similar from 45 to 64 years of age, whereas more women than men aged 65 or older have HTN according to NHANES data. Classified by race/ ethnicity, the prevalence of HTN among US blacks (42.1%) surpassed that of whites (28%), Hispanics (24.7%), and Asians (24.7%) [3]. Age-adjusted aware- ness of HTN, however, was similar among blacks, whites, and Hispanics, and lowest in Asians. This review will present contemporary evidence relevant to the epidemiology of comorbidities among individuals with HTN, specifically diabetes mellitus, obesity, chronic kidney disease (CKD), coronary artery disease (CAD), and heart failure. Differences pertinent to age, gender, and race/ethnicity will be discussed based upon available data.

DIABETES MELLITUS HTN and diabetes mellitus are often co-existent. By itself, diabetes mellitus is a major risk factor for CAD; as a comorbidity in patients with HTN, the risk is amplified. HTN and diabetes mellitus may be Community Heart and Vascular Hospital, Indianapolis, Indiana, USA Correspondence to Rey P. Vivo, MD, FACC, Advanced Heart Failure Program, Community Heart and Vascular Hospital, 8075 N. Shadeland Avenue, Suite 310, Indianapolis, IN 46250, USA. Tel: +1 317 6218500;fax: +1 317 6218501; e-mail: [email protected] Curr Opin Cardiol 2016, 31:376 – 380 DOI:10.1097/HCO.0000000000000298 www.co-cardiology.com Volume 31 Number 4 July 2016 REVIEW Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. diagnosed at the same time, but frequent cases of HTN preceding the onset of diabetes mellitus may suggest that it occurs independently or develops as part of the metabolic syndrome [5]. In type 1 dia- betes mellitus, the lifetime risk of HTN is estimated at 60%, and the presence of microalbuminuria accel- erates the risk [6,7]. Furthermore, approximately 75% of individuals with Type 2 diabetes mellitus are hypertensive. Hypertensive individuals have a 2.5 times higher risk of developing diabetes mellitus than matched patients with normal BP [8]. The relationship between these two conditions has been found to be mediated by interrelated physio- logic abnormalities, including impaired circadian BP cycle, dysregulation of the renin – angiotensin – aldosterone system, and micro-vascular and macro- vascular damage, among others [5,9]. An estimated 21.1 million adults in the United States have diagnosed diabetes mellitus, of whom 90 – 95% have type 2 diabetes mellitus [1 &&,10 &&]. An additional 8.1 million adults have undiagnosed diabetes mellitus, and 80.8 million adults have pre- diabetes. The prevalence of type 2 diabetes mellitus is generally similar across genders. However, there are several observed differences in the cardiovascu- lar consequences of diabetes mellitus between men and women [11 &]. On incidence, 1.7 million new cases of diabetes mellitus (type 1 or type 2) were diagnosed in US adults of at least 20 years of age in 2012 [10 &&]. It is projected that the total prevalence of diabetes mellitus in the United States will more than double from 2005 to 2050 (i.e., from 5.6 to 12.0%) across all populations, whereas more marked increases are expected among the oldest age groups (e.g., 220% increase among ages 65 – 74 years; 449% among ages 75 years), non-Hispanic blacks older than 75 years (606%), and Hispanics (127%) [12]. An inordinate burden of diabetes mellitus exists among racial/ethnic groups. Compared with non-Hispanic whites (7.6%), the age-adjusted pre- valence of its diagnosis is higher for American Indians/Alaska Natives (15.9%), non-Hispanic blacks (13.2%), Hispanics (12.8%), and Asian Americans (9.0%) [10 &&]. Data from the Multi-Ethnic Study of Atherosclerosis (MESA) [13] showed that over 5 years of follow-up, the incidence of diabetes mellitus was highest among Hispanics (11.3%), non-Hispanic blacks (9.5%), and Chinese Americans (7.7%), and lowest in non-Hispanic whites (6.3%).

Findings from one study [14] demonstrated that among treated type 2 diabetes mellitus patients, non-Hispanic blacks and Mexican Americans were less likely to achieve glycemic control (hemoglobin A1C <7%) as compared with non-Hispanic whites. OBESITY It is established that excessive weight increases the risk of having elevated BP. Obesity (i.e., BMI 30 kg/ m2) confers a 3.5-fold higher likelihood of developing HTN [15]. Moreover, approximately 60 – 70% of HTN in adults is ascribable to adiposity, particularly centrally located body fat [16]. The following physio- logic abnormalities have been implicated in obesity- related HTN: sympathetic overdrive, renin – angio- tensin – aldosterone system activation, brain melano- cortinergic system abnormalities, adipocyte-derived hormonal dysregulation, insulin resistance, renal impairment, and vascular alterations [16,17 &]. Overweight and obesity have reached epidemic proportions globally. In the United States, the 2016 AHA Statistics revealed that 69 and 35% of adults are overweight and obese, respectively [1 &&]. Although the temporal trend in prevalence of obesity has been reported as stable among adults between 2003 – 2004 and 2011 – 2012, there has been an increase in preva- lence among women aged 60 years from 31.5 to 38.1% during the aforementioned time periods [18 &,19]. Among older people, rates of obesity have increased as a result of both the rise in the elderly population and the proportion of that population that is obese [20]. Between 1991 and 2000, the prevalence of obesity in the age group 60 – 69 years and greater than 70 years increased by 56 and 36%, respectively [21,22]. Hispanic men are more likely to be overweight (80%) than non-Hispanic white (73%) or black (69%) men. Non-Hispanic black (82%) and Hispanic (76%) women are more likely to be overweight than non- Hispanic white (61%) women. Hispanic and non- Hispanic black men and women are more likely to be obese than non-Hispanic white counterparts [1 &&]. CHRONIC KIDNEY DISEASE HTN is reported to occur in as many as greater than 85% of patients with CKD [23]. Elevated BP KEY POINTS HTN is often diagnosed with diabetes mellitus and obesity, and is a major risk factor for the development of CKD, CAD, and heart failure.

The prevalence of obesity is higher among older people, whereas both diabetes mellitus and obesity disproportionately affect more Hispanic and non- Hispanic black than non-Hispanic white Americans.

Similarly, the elderly and racial/ethnic minorities are more at risk for CKD, CAD, and heart failure. Epidemiology of comorbidities in hypertensive patients Shrestha et al. 0268-4705 Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. www.co-cardiology.com 377 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. is considered a leading cause for CKD; indeed, CKD is more prevalent (31.0%) in persons with HTN compared with those without it [1 &&]. HTN can result in elevated intraglomerular pressure, leading to impaired glomerular filtration [24]. Conversely, worsening CKD can make BP difficult to control because of increased intravascular volume and systemic vascular resistance [25 &]. In addition, resist- ant HTN (i.e., uncontrolled BP despite adherence to three optimally dosed antihypertensive medi- cations including a diuretic) is twice as high in patients with CKD as in those without [26 &]. Results from one study [27] demonstrated that 42% of patients with CKD had resistant HTN. CKD is defined as either kidney damage for 3 months, as confirmed by kidney biopsy or biomarkers of kidney damage, with or without a decrease in glomerular filtration rate (GFR), or GFR <60 for 3 months, with or without kidney damage [28]. According to the US Renal Data System 2014 annual report, the prevalence of CKD from 2007 to 2012 was estimated to be 13.6%. Stratified by stage, the prevalence of stages 1, 2, and 3 is 4.2, 3.0, and 5.9%, respectively. The combined preva- lence of stages 4 and 5 is 0.6%. End-stage renal disease (ESRD) is diagnosed when patients receive chronic renal replacement treatment such as hemodialysis, peritoneal dialysis, or kidney trans- plantation. Current estimates showed that ESRD is prevalent in more than 600 000 individuals, reflect- ing a four-fold increase from the 1970s through 2006 [29 &&]. The prevalence of CKD increases in direct proportion to aging: 5.7% in those 20 – 39 years, 8.9% in those 40 – 59 years, and 33.2% for those of at least 60 years of age [29 &&]. In the elderly ( 80 years old), the prevalence of CKD increased through time from 40.5% from 1988 – 1994 to 51.2% in 2005 – 2010 [30]. Women have been reported to be less aware of having impaired kidney function, despite a higher prevalence of CKD among them than in men. Although the incidence of ESRD in non-Hispanic blacks is four-fold higher than in non- Hispanic whites, both groups have paradoxically the same prevalence of CKD, with rates higher than those of Mexican Americans [31].

CORONARY ARTERY DISEASE HTN is an established independent risk factor for CAD in all populations and accounts for approxi- mately 47% of ischemic events [32]. The pathophy- siologic associations between HTN and CAD are impacted by neurohumoral activation (i.e., sympathetic nervous and renin – angiotensin – aldosterone systems); increased myocardial oxygen demand; endothelial dysfunction and vascular stiff- ening; and upregulation of oxidative stress, inflam- mation, and atherogenesis [33 &&]. The clustering of other risk factors including aging, diabetes mellitus, dyslipidemia, cigarette smoking, and left ventricular hypertrophy amplifies the likelihood of developing CAD [34]. Of note, antihypertensive management can reduce CAD risk. Recent data from the Standard Blood Pressure Intervention Trial (SPRINT) study [35 &] provided evidence that intensive (targeting SBP <120 mmHg) rather than standard (targeting SBP <140 mmHg) treatment resulted in lower rates of fatal and nonfatal major cardiovascular events (including acute coronary syndrome and decom- pensated heart failure) and death from any cause. According to data from the AHA, an estimated 15.5 million Americans 20 years old have CAD [1&&]. The total prevalence is projected to rise from approximately 6% to approximately 18% by 2030.

The annual incidence of myocardial infarction (MI) is estimated at 550 000 new coronary events and 200 000 recurrent events. CAD comprises more than half of all cardiovascular events among individuals less than 75 years of age [1 &&]. Incremental rises in BP throughout middle and old age are significantly and directly related to CAD mortality rates. A meta- analysis of 1 million adults in 61 prospective studies found that between the ages 40 – 69 years, each 20 mmHg increase in SBP or 10 mmHg increase in DBP is associated with a two-fold higher risk for a fatal coronary event [36]. The annual absolute differences in risk are even greater in older age. Data from the Framingham Heart Study [37] revealed that whereas DBP is a more important risk predictor for CAD before 50 years of age, SBP and pulse pressure are more relevant for people older than 60 years. In the United States, CAD prevalence is 7.6% for men and 5.0% for women. Comparing temporal trends among middle-aged persons between the 1988 – 1994 and 1999 – 2004 periods, the prevalence of MI was significantly greater in men than in women in both periods, but showed a downtrend in men and an uptrend in women [38]. For incidence, the rates of total CAD for women lag behind men by 10 years, and by 20 years for MI and sudden death [1 &&]. However, the incidence of CAD rises sharply among women after menopause, with rates triple those of age-matched women who are still premenopausal [39]. After HTN onset, the most common first major cardiovascular event was CAD among men and stroke in women [40]. Broken down by race/ethnicity, CAD prevalence is as follows: non-Hispanic white men: 7.8% and women: 4.6%; non-Hispanic black men: 7.2% and women: 7.0%; Hispanic men: 6.7% and women:

5.9%; Asians: 3.3% [1 &&]. Based on a cohort of diverse Hypertension 378 www.co-cardiology.com Volume 31 Number 4 July 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. patients (i.e., white, black, Hispanic, Native American, and Asian) with stable angina and acute coronary syndromes in the American College of Cardiology – National Cardiovascular Data Registry, non-Hispanic black women had the lowest risk- adjusted odds for significant CAD [41]. Non- Hispanic white women presenting with stable angina had a 1.34-fold higher in-hospital mortality compared with other groups. An analysis of MESA examined the distribution of coronary artery calcium on the basis of race/ethnicity [42]. Among women, non-Hispanic whites had the highest percentiles whereas Hispanics had the lowest.

Among men, non-Hispanic whites had the highest calcium levels, non-Hispanic blacks had the lowest at younger ages, and Chinese the lowest at the older ages.

HEART FAILURE Like HTN, heart failure is a major public health burden. HTN plays a key role in the pathogenesis of asymptomatic left ventricular hypertrophy transitioning into symptomatic heart failure with either preserved or reduced ejection fraction [43 – 45]. In response to high BP, left ventricular geometry undergoes remodeling, and this process is in turn impacted by demographic, genetic, and comorbid factors; pressure and volume load; and neurohormonal alterations [43]. Among hyperten- sive patients, the progression from hypertrophy to clinical heart failure may or may not be mediated by ischemic heart disease. Nearly 6 million people in the United States older than 20 years have heart failure, and the prevalence is projected to increase to over 8 million in 2030. Although CAD is the most common clinical cardiac disease that occurs in individuals with HTN, HTN is the strongest major risk factor among patients with heart failure [46]. About 75% of patients with heart failure have pre-existing HTN.

The lifetime risk of heart failure for individuals with BP greater than 160/90 mmHg is double that of those with BP greater than 140/90 mmHg [1 &&]. A study [47] of the Framingham cohort reported that men and women at 40 years old have a 20% lifetime risk for developing new heart failure. The remaining lifetime risk remains approximately the same at age 80, even in the context of shorter life expectancy. Evidence also indicates that the annual rates of new heart failure events double with each 10-year age increase from 65 to 85 years and triple for women between ages 65 to 74 and 75 to 84 years. Based on data from MESA, non-Hispanic blacks have the highest risk of developing heart failure, followed by Hispanics, non-Hispanic whites, and Chinese Americans [48]. Findings from the Atherosclerosis Risk in Communities study [49] demonstrated that the 5-year case fatality rate after heart failure hospitalization was greater in non- Hispanic blacks than non-Hispanic whites. Differ- ences in heart failure clinical risk factors exist across racial/ethnic groups. The Health, Aging, and Body Composition Study [50] documented that HTN and CAD had the highest population attributable risk among non-Hispanic white and black persons; non-Hispanic blacks had a higher proportion of HTN, left ventricular hypertrophy and other mod- ifiable risk features. In contrast, Hispanic Americans have an inordinate cardiometabolic risk burden accounted for by higher rates of diabetes mellitus, obesity, and metabolic syndrome [51].

CONCLUSION To conclude, HTN frequently occurs with multiple comorbidities that may amplify the cardiovascular risk of an affected individual or a specific popu- lation. Therefore, a diagnosis of HTN should spur a thorough assessment and multidisciplinary man- agement of co-existing risk factors and/or clinical sequelae. Special attention should be given to more at-risk groups such as the elderly, women, and racial/ethnic populations.

Acknowledgements None.

Financial support and sponsorship None.

Conflicts of interest There are no conflicts of interest.

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