Metabolic hypertension: concept and practice

Abstract

Hypertension is a serious public health problem worldwide. More than 60% of the risk factors for hypertension are associated with metabolic disturbances. Metabolic abnormalities increase the risk for hypertension and cause high blood pressure. Improving metabolic disturbances is beneficial for hypertension treatment. Due to the importance of metabolic abnormalities in the pathogenesis of hypertension, we propose a concept of metabolic hypertension. In this review, we discuss and review the clinical types, pathogenesis, risk evaluation and management of metabolic hypertension. Elucidation of the mechanism of metabolic hypertension should facilitate the design of novel pharmacotherapeutics and dedicated antihypertensive manipulations.

Keywords

hypertension / cardiometabolic risk factors / metabolic abnormalities

Concept of metabolic hypertension

Greater than 60% of the risk factors for hypertension are metabolic, although genetic and secondary etiology plays an important role in the development of hypertension [1]. Thus, hypertension can be considered a hypertensive syndrome caused by multiple cardiometabolic risk factors. Currently, the risk stratification of hypertension is mainly based on metabolic risk factors in the domestic and international guidelines for hypertension. Treatments for hypertension should control both blood pressure and metabolic disturbances. Due to the importance of metabolic abnormalities in the pathogenesis, risk assessment and treatment of hypertension, we propose a new classification of the etiology of hypertension and introduce the concept of metabolic hypertension [2]. Metabolic hypertension may be defined as high blood pressure that is caused by metabolic disturbances but not other classic secondary factors, such as endocrine disorders, kidney diseases, Takayasu’s arteritis or pregnancy, and can be ameliorated by the correction of these metabolic abnormalities [3,4]. According to the criteria of high blood pressure in the diagnosis of metabolic syndrome [5], the blood pressure value for metabolic hypertension is defined as greater than or equal to 130/85 mmHg. Because there is a cause-and-effect relationship between metabolic abnormalities and high blood pressure, metabolic hypertension should be classified as secondary hypertension. Importantly, the definition of metabolic hypertension should be further investigated.

Clinical types of metabolic hypertension

Traditionally, hypertension has been classified into primary and secondary hypertension, which account for 90% and 10% of total hypertension, respectively. The common secondary etiologies include Takayasu’s arteritis, kidney diseases, endocrine disorders, cardiovascular diseases, brain lesions, pregnancy, polycythaemia and certain drugs. Obesity, diabetes, dyslipidaemia, high salt intake, hyperuricaemia and hyperhomocysteinaemia are major metabolic risk factors for hypertension. However, numerous studies in recent years have shown that metabolic abnormalities alone can contribute to the pathogenesis of hypertension. According to reports from the Shanghai Institute of Hypertension and the Chongqing Institute of Hypertension, more than 80% of hypertensive patients are complicated with different forms of metabolic abnormalities, while only 20% of hypertensive patients are not complicated with metabolic disturbances [6,7].

The common clinical types of metabolic hypertension include obesity-related hypertension, diabetes-induced hypertension [8], familial dyslipidaemia-associated hypertension, metabolic syndrome [9], hypertension with hyperhomocysteinaemia, hypertension with hyperuricaemia [10] and salt-sensitive hypertension. Among these metabolic related hypertensions, some of them are caused by the metabolic abnormalities, but some of them raise blood pressure first, and then develop the metabolic abnormalities. If there is a clear cause-and-effect relationship between metabolic abnormalities and hypertension without other secondary factors, it is reasonable to diagnosis as metabolic hypertension, while the others should be called hypertension concomitant with metabolic abnormalities. However, it is sometimes difficult to distinguish a cause-and-effect relationship between metabolic abnormalities and high blood pressure in clinical practice.

Role of metabolic risk factors in the evaluation of hypertension risk

Metabolic risk factors play an important role in the risk stratification of hypertension [11]. For example, the ESC/ESH guidelines for the management of arterial hypertension have emphasized the role of abdominal obesity, lowered the cut-off points for total cholesterol and LDL-cholesterol concentrations and added new metabolic risk factors, such as hypertriglyceridaemia, impaired fasting glucose and glucose tolerance. Metabolic syndrome is now considered to be an independent risk factor for hypertension. Hypertensive patients with diabetes or metabolic syndrome are now stratified into high risk or very high risk of cardiovascular disease even if their blood pressure is not high [12,13]. Clinical studies have demonstrated that metabolic disorders significantly increase the risk of vascular diseases as an independent risk factor. Hyperuricaemia is related to reduced renal blood flow and increased renal vascular resistance in hypertension [14]. The Framingham Heart Study indicated that obesity is an independent risk factor for cardiovascular disease [15]. Diabetes is strongly associated with both microvascular and macrovascular complications and causes target organ damage in approximately one-third to one-half of people with diabetes [16]. Therefore, the assessment of the risk for hypertension should be based on blood pressure levels and the amount and severity of the combined metabolic risk factors [17–19] because metabolic risk factors can modulate the risk stratification of hypertension [20,21]. The Framingham Heart Study reported that the cardiovascular risk in patients with abnormal glucose tolerance or other metabolic risk factors will be significantly increased [22]. The INTERHEART study showed that the risk of myocardial infarction increases linearly with increasing cardiometabolic risk factors [23]. An elevation in the body mass index or waist circumference can increase the cardiovascular risk by 2–3 times, and the treatment of obesity-related hypertension is refractory [24,25].

The mechanisms underlying metabolic hypertension

Hypertension is characterized by the hyperreactivity and remodelling of small resistance arteries. However, many studies show that hypertensive patients with metabolic abnormalities also suffer from macrovascular lesions, which cause declines in vascular compliance, endothelial dysfunction and atherosclerosis [26]. The form of vascular lesions is dependent on the types of metabolic risk factors. Dyslipidaemia leads to macrovascular atherosclerosis, which causes monocyte adhesion and migration to the subendothelium, the uptake of oxidised low-density lipoprotein (LDL)-cholesterol by monocytes and vascular smooth muscle cells to form the foam cells, further development of fatty plaque, fibrosis and calcification, endothelial dysfunction and decreased vascular compliance. Hyperglycaemia destroys the endothelium [27] and causes microvascular injury in the retina and kidney, although other mechanisms, such as activation of the cellular polyol pathway, protein kinase C and hexosamine pathway and the formation of advanced glycation end products, could also be involved [28–31]. The mechanisms responsible for obesity-induced vascular damage include endothelial dysfunction, insulin resistance, obstructive sleep apnoea, impaired baroreflex sensitivity, and the activation of the renin-angiotensin-aldosterone and sympathetic nervous systems [32]. Genetic loci implicated in metabolic abnormalities also contribute to metabolic hypertension. Common variants in a number of candidate genes influencing fat and glucose metabolism can, together with environmental factors, increase susceptibility to metabolic syndrome [33,34]. Large-scale, genome-wide association studies (GWAS) showed that certain genetic variants and loci are responsible for some of the variation in the components of metabolic syndrome including adiposity traits, serum HDL and triglycerides, blood pressure, and glycaemic traits [35,36].

In recent years, damaged fat tissue has been shown to produce a variety of adipokines, inflammatory factors and vasoactive peptides, which also have important implications for vascular dysfunction. The common pathway of metabolic risk factors leading to high blood pressure includes increased vascular inflammation and oxidative stress, dysregulation of neurohumoral factors, vascular lesions and renal dysfunction. Recent studies have shown that the gastrointestinal tract also contributes to metabolic dysfunction by modulating gut hormones and microbiota [37–39]. The gastrointestinal tract is involved in the absorption of salt-, fat- and carbohydrate-rich diets, which target the cardiovascular and metabolic system. Thus, the gastrointestinal tract can be regarded as initiating organ for metabolic hypertension (Fig. 1).

The management of metabolic hypertension

The treatment of metabolic hypertension should emphasize lowering blood pressure and improving metabolic disturbances [40–42]. The treatment strategies include therapeutic lifestyle changes (TLC) and drug therapy. A healthy diet and regular exercise are important for weight loss, lipid reduction, glucose control and salt restriction [43]. Our recent studies have shown that activation of the transient receptor potential vanilloid 1 (TRPV1, capsaicin receptor) by dietary capsaicin and transient receptor potential subfamily M member 8 (TRPM8, cold-sensitive channel) by dietary menthol significantly reduced both body weight and blood pressure, which are suitable for the dietary intervention of obesity-related hypertension [44–59]. However, a meta-analysis showed that a one-year TLC intervention caused 1 kg of weight loss and a 1-mmHg drop in blood pressure, while a two-year treatment only induced 1 kg of weight loss and a 0.5-mmHg drop in blood pressure. Therefore, the long-term effect of TLC intervention is limited to obesity-related hypertension, especially in hypertensive patients with multiple risk factors, target organ damage or cardiovascular diseases. Currently, initiation of drug therapy is recommended as soon as possible if the TLC intervention is not effective [47]. Several antihypertensive drugs are recommended to treat hypertensive patients with metabolic disturbances in the hypertension management guideline [48]. Dihydropyridine calcium channel blockers can be used to treat hypertensive patients with atherosclerosis, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are suggested to treat hypertensive patients with metabolic syndrome or diabetic nephropathy [49–51]. Recently, we confirmed that combination metformin hydrochloride (0.5 g/d) and calcium antagonists or angiotensin II receptor blockers can effectively reduce visceral fat and blood pressure in non-diabetic obesity-related hypertensive patients without type 2 diabetes through a randomized, double-blind, controlled trial [52]. In recent years, the fixed-dose combination of statins with calcium channel blockers is used to treat hypertensive patients with dyslipidaemia. Earlier interventions for metabolic hypertension may reduce the amount of target organ damage and cardiovascular events. A previous study showed that early anti-diabetic treatments (less than 10 years) can effectively prevent the development of the metabolic memory effect of hyperglycaemia later in life [53,54]. In addition to pharmacotherapeutics, metabolic surgery has demonstrated a unique benefit in the treatment of diabetic patients with obesity-related hypertension [55]. Several gastrointestinal operations designed to promote weight loss can greatly ameliorate type 2 diabetes mellitus, obesity and hypertension. Although hypertension is traditionally regarded as a chronic disease in which prevention of end-organ complications is the major treatment goal, metabolic surgery offers a novel endpoint: complete disease remission [56–58]. Clinical studies have shown that gastric bypass surgery can significantly decrease weight, improve or cure diabetes and promote effective blood pressure control in 70% of patients with hypertension [55]. Although the mechanism of metabolic surgery is not understood, its promising long-term efficacy has raised its potential in clinical practice.

In summary, metabolic hypertension is now considered to be a clinical syndrome rather than a theoretical concept. Mounting evidence indicates the characteristics of metabolic hypertension beyond the classical view of primary hypertension. There are distinct differences in the concept, diagnostic criteria, pathogenesis and treatment between metabolic hypertension and primary or genetic hypertension (Table 1). Research to elucidate its mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antihypertensive manipulations.

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