Asian Expert Consensus for the Diagnosis and Treatment of Hypertension-Associated Left Ventricular Hypertrophy

Introduction Left ventricular hypertrophy (LVH) is an important manifestation of hypertensive organ damage associated with increased ventricular wall thickness, left ventricle mass, and cardiac remodeling. Neurohumoral and hemodynamic factors play important roles in the development of LVH. The heart is the most vulnerable target organ for hypertension, and >30% of patients with hypertension will undergo LVH. The incidence rate is positively correlated with the severity of hypertension.[1] LVH is an independent risk factor for a number of cardiovascular disorders such as coronary diseases, congestive heart failure, stroke, temporary ischemic heart disease, and sudden death.[2] LVH accompanied with hypertension can increase and the progression of cardiovascular and cerebrovascular diseases, thus, hypertension associated LVH as a contributor to organ damage, should be paid attention to. Asia is a region with a high prevalence of hypertension (20%-30% of the population). The growth rate of the hypertensive population within Asia is higher than in developed countries.[3,4] A Chinese cohort study showed that 64.6% of pre-hypertensive patients developed hypertension 17 years later, with a total mortality rate of 27.9/1000 person/year. The main cause of death was stroke,[5] and hypertension-associated LVH is related to stroke. A higher risk of coronary disease and stroke was found in the Asian populations with increased systolic pressure than in Caucasians.[6] With urbanization, day-to-day stress, obesity, and high-salt/high-fat diets are becoming more prevalent in Asia, and thus an unhealthy lifestyle has become an important risk factor for heart diseases, which is the main cause of hypertension-induced LVH. The dysfunction in cardiac diastole, as well as the rate of symptomatic heart failure, is also increased. A study from Japan reported that >50% of people with high blood pressure having LVH combined with obviously increased cardiovascular events.[7] Effective blood pressure control and regression of LVH significantly decreased the risk of cardiovascular events and death.[8-10] Taking all these into account, health guidelines for the Asian Region all take LVH as an important index for hypertension-induced heart damage, and by consequence, blood pressure control is an important therapeutic strategy for treatment of LVH.[11-13] Because of the importance of LVH in hypertension and cardiovascular diseases, and the insufficient strategy for intervention of LVH, experts in the Asian Region have achieved a consensus regarding diagnosis, classification, and treatment criteria for LVH, as well as clinical guidelines for the diagnosis and management of patients with hypertension combined with LVH (this guideline is only aimed at hypertension-associated hypertension). Epidemiology of Hypertension-Associated Left Ventricular Hypertrophy At present, the diagnosis of LVH for patients with hypertension relies on electrocardiogram (ECG) and echocardiogram (ECHO) readouts. The detectable rate relying on adopted method and the differences are non-ignorable [Table 1].Table 1: Summaries the predictive value, practicability, repeatability and cost effectiveness of electrocardiogram, echocardiogram, and cardiac magnetic resonanceA retrospective analysis of 26 studies shows that the prevalence of ECG-diagnosed LVH (ECG-LVH) is 18.1%-18.9% within hypertensive patients. A sex-based analysis shows that the average prevalence of LVH is 24.2%-24.4% in men and 16.6%-16.8% in women.[14] Under the same diagnostic criteria (Sokolow-Lyon voltage: SV1 + RV5/RV6 ≥3.5 mV), the prevalence of ECG-LVH in Caucasian hypertensives is 8.6%-26.4%.[14] LVH prevalence in Asian hypertensives is also very high. In a Japanese study, the prevalence of ECHO-diagnosed LVH (ECHO-LVH) is as high as 40%.[15] Prevalence of ECHO-LVH in Chinese hypertensive patients varies from 19.2% to 34.3%,[16-18] and a Taiwan study shows that the prevalence of ECHO-LVH is 13%.[19] A retrospective analysis including 30 studies shows that the prevalence of ECG-LVH is 35.6%-40.9% in the hypertensive patients. A sex-based analysis shows that the average prevalence of LVH is 36.3%-43.5% in men and 37.9%-46.2% in women.[1] Under the same diagnostic criteria (Sokolow-Lyon voltage: SV1 + RV5/RV6 ≥3.5 mV), ECG-LVH patients with hypertension Caucasian detection rate is 14.5%-44.8%.[1] In a Japanese study, the prevalence of ECHO-LVH is as high as 58.3%;[7] an Indian study shows that ECHO-LVH is 24.4%.[20] Prevalence of ECHO-LVH in Chinese hypertensive patients varies from 26% to 73.2%,[17,21-23] and women show an obviously higher prevalence of LVH than that of men.[22-24] Mechanisms Driving Hypertension Combined Left Ventricular Hypertrophy and the Harm Mechanisms of hypertension combined left ventricular hypertrophy The development of cardiac hypotrophy can be divided into three stages as follows: progressing period, compensatory stage, and decompensatory stage. Pathological hypotrophy includes eccentric hypotrophy and concentric hypotrophy. In some conditions, eccentric hypotrophy can also be derived from concentric hypotrophy. The mechanisms of hypertension-related LVH have not been completely elucidated; the pathogenic process is related to factors such as (a) hemodynamics, (b) neurohumoral, paracrine, and autocrine secretions in cardiovascular tissue, and (c) genetic background of patients. Both hemodynamic and neurohumoral factors play major roles in the progression of hypertension-related LVH. Hemodynamics factors Systolic phase overload is pressure overload, and diastolic phase overload is volume overload. Hypertensive patients suffer both pressure overload and volume overload. Both of these overloads can increase the volume of cardiac myocytes, enlarge the size of cardiac myocytes and change components of collagen proteins in the extracellular matrix, all of which can finally induce cardiac hypotrophy.[25] Blood pressure is the most important factor for LVH. The Framingham study revealed that left ventricular mass increased by 10.6 g/m2 for male patient and 3.0 g/m2 for female patient per 20 mmHg increases in systolic pressure. The PALEMA study of 2002 enrolled 2050 patients, in which the left ventricular mass is the highest in hypertensive patients without treatment.[26] Neurohumoral factors Neurohumoral factors are the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous, and adrenal system and the endothelin system.[27] In hypertensive patients, the RAAS activity and synthesis of angiotensin II (AngII) and aldosterone are increased. Circulating AngII can efficiently increase blood pressure through vigorously shrinking arterioles, stimulating secretion of aldosterone to increase circulating blood volume, and promoting the release of catecholamine. AngII in local tissue tends to play long term, therapeutic roles. AngII binds with type I receptor, and regulates expression of proto-oncogene and related protein, causing hypotrophy of cardiac myocytes and overexpression of collagen proteins.[28,29] The activity of the sympathetic nervous system for patients with hypertension-related LVH is much higher than that of primary hypertension without LVH.[30] In patients with the active sympathetic system, the concentration of norepinephrine (NE) in circulation is also higher. NE can promote protein expression in cardiac myocytes through activating α1-adrenergic receptor; it can also activate β-adrenergic receptors to enhance the systolic ability of cardiac muscle, increase heart rate as well as the synthesis of glycogen and adenosine phosphate. The increased content of total protein and un-contractile protein in cardiac myocytes leads to cardiac hypotrophy.[31,32] Meanwhile, increased activity of the sympathetic nervous system enhances invasion of inflammatory mediators into the heart, causing cardiac fibrosis, and aggravating cardiac hypotrophy.[33] In summary, neurohumoral factors participate in the formation of hypertension-induced LVH, induce abnormalities in the signaling transduction system of cardiac myocytes (beta-receptor, G-protein, cyclases, calcium channel, phosphokinase, etc.), and influence protein expression of cardiac myocytes. The increased expression of structural proteins will gradually enhance cardiac contractility, but uncontrolled expression of cardiac fibrils will result in cardiac hypotrophy and enlargement of the ventricular chamber. Risk factors Prevalence of LVH and ventricle remodeling in hypertensive patients is influenced by age, body fat, and genetic factors. The prevalence of LVH is correlated with patient age, i.e., older age means a higher risk of LVH.[34] The left ventricular mass index (LVMI) is distinctly higher in obese patients; and like high systolic and diastolic pressure, obesity (high body mass index) during childhood and adult is distinctly related with eccentric and concentric hypotrophy.[35] Moreover, the left ventricle mass (LVM) displays the obvious difference in patients with a similarly increased segment of blood pressure, suggesting that genetic factors are involved in the development of LVH. Gene polymorphisms associated with both the sympathetic nervous system and RAAS system is correlated with the prevalence of LVH and the impairment of cardiac functions. Gene polymorphism in the sympathetic nervous system and RAAS is related with LVH, yet it has not been identified as the cause or consequence of LVH.[27,36] High-salt diet is also involved in LVH; there have been animal experiments which showed that high-salt diets could induce LVH.[37,38] The damage of hypertension-related left ventricular hypertrophy Reducing coronary flow reserve Because the myocardium is totally dependent on aerobic metabolism, an increase in myocardial oxygen consumption requires an increased coronary blood flow, and this is achieved by dilatation. The ability of the heart to autoregulate coronary perfusion in response to metabolic demands is called coronary flow reserve. Some studies find that in hypertension patients with LVH, the CRF is significantly reduced and the risk of ischemic heart diseases is increased. This can easily induce ischemic disease and increase the risk of death.[39-41] Impairing left ventricle functions In hypertensive patients with LVH, left ventricle hypotrophy will further impair left ventricle functions and finally induce development of heart failure regardless of the contractile status with the left ventricle. Compared with patients suffering from left ventricle systolic dysfunction, LVH patients are more inclined to suffer from left ventricular diastolic dysfunction. Studies show that both the increase in LVM and relative wall thickness (RWT) significantly increase the risk of left ventricle diastolic dysfunction in hypertensive patients.[39,42,43] However, about 13% of concentric LVH patients with normal left ventricle systolic function progress to left ventricle systolic dysfunction within 3 years post-follow-up.[44] Increasing risk of arrhythmia A meta-analysis including 12 studies reveals that risk of arrhythmia in patients with hypertensive-induced LVH is 3 times higher than hypertensive patients without LVH.[45] LVH diagnosed by ECG suggests an obvious increase in SCD risk,[46,47] and reversing LVH can prominently reduce the prevalence of SCD.[48] LVH is also a major risk factor for arterial fibrillation (AF).[49,50] For every 1, standard deviation increase in left ventricular mass, the risk of AF was increased by 1.20 times.[51,52] Increasing major cardiovascular events and risk of death The reduction of endpoints in NIDDM with the angiotensin II antagonist losartan study showed that chronic kidney disease combined with LVH is an predictor of increased CK level in plasma/end-stage renal disease (Hazard Ratio (HR) = 1.42; P = 0.03) and cardiovascular event (HR = 1.68; P = 0.001).[53] The Framingham study shows that persons who acquire ECG-LVH have an eightfold increased risk of CVD death and a six-fold increased risk of CHD death.[54] The following studies coherently verify that ECG-LVH is associated with the incidence of cardiovascular diseases, death from cardiovascular disease, and death from all causes.[55-60] Furthermore, there is a continuous relation between LVH severity and CVD risks.[61] Significance of reversing left ventricular hypertrophy Preclinical and clinical researches have verified that blood pressure control can effectively reverse LVH.[62,63] Regression of LVH can decrease the risk of cardiovascular events, regardless of endpoint reduction of blood pressure.[64,65] Therefore, more attention should be paid to patients with hypertension-induced LVH, and early prevention and/or regression of LVH should be one of the therapeutic targets for clinical hypertension treatment. Reducing risk of cardiovascular events Some studies revealed that prevention/regression of ECG-LVH could significantly reduce morbidity and mortality from cardiovascular events. A meta-analysis including five studies and comprising 2449 patients found that compared with patients of LVH persistence/LVH development, the total risk of cardiovascular events was reduced by 46% in patients of LVH regression/persistent normal.[66] Mathew et al.[8] found that prevention and regression of ECG-LVH are associated with reduced clinical endpoints including the risk of death, myocardial infarction, stroke, and congestive heart failure.[7] A total of 941 prospectively identified patients aged 55-80 years with essential hypertension and electrocardiographic LV hypertrophy had LV mass measured by echocardiography at enrolment in the The Losartan Intervention For Endpoint reduction (LIFE) trial and thereafter are followed up annually for a mean (standard deviation of 4.8 (1.0) years for CV events. The LIFE study used a composite endpoint of CV death, myocardial infarction, or stroke. The multivariable Cox regression model showed a strong association between lower LV mass index and reduced rate of the composite cardiovascular end point. Risk of cardiovascular event declined 22% (P = 0.009) for 1 reduction of LVMI standard deviation (25.3 g/m2). Reduction of LVMI was proved to be a more suitable predictor for reduced risk of cardiovascular events than the decrease of blood pressure. Lower LVMI is associated with lower rates of all clinical endpoints, including CV death (HR = 0.62; P = 0.0001), stroke (HR = 0.76; P = 0.02), myocardial infarction (HR = 0.85; P = 0.33) and all-cause mortality (HR = 0.72; P = 0.002).[64,65] Other benefits In addition to reducing the risk of cardiovascular events, Okin et al.[67] found new benefits of antihypertensive therapy. Electrocardiographic hypertrophy was evaluated over time in 7998 hypertensive patients without diabetes at baseline in the Losartan Intervention for endpoint reduction in hypertension (LIFE) study. During a mean follow-up of 4.6 ± 1.2 years, resolution or continued absence of LVH during antihypertensive therapy is associated with a lower likelihood of new-onset diabetes. Diagnosis and Differential Diagnosis of Hypertension-Associated Left Ventricular Hypertrophy The diagnostic criteria for hypertensive-associated LVH include three aspects as follows: (1) the definitive diagnosis of hypertension; (2) the definitive diagnosis of LVH; and (3) elimination of other causes of LVH. The clinical diagnosis methods for left ventricular hypertrophy The diagnostic approaches include ECG, ECHO, and cardiac magnetic resonance (CMR). These methods have different sensitivity, specificity, costs and feasibility, as shown in Figure 1. When it comes to clinical use, the individualized diagnostic method should be considered.Figure 1:: Diagnostic pathway for hypertension-associated left ventricular ECG is and is by a of guidelines as the most method for LVH The of ECG to LVH is lower than other and diagnostic for and LVH is and The of ECG is much higher than sensitivity, for hypertensive patients, the is as high as the and of ECG criteria for LVH are differences in ECG criteria for LVH and the independent predictor of decreased ECG are a of ECG-LVH criteria in the guidelines and in the and method has and The most prevalent criteria are guidelines for hypertension, Japanese guidelines for or Chinese guidelines for prevention and treatment of guidelines for guidelines for Left ventricular as can be used as a for primary was reported that ECG-LVH was associated with an increased risk of cardiovascular events, and stroke study revealed that in addition to electrocardiographic such as and independent risk factors for is more than ECG in the diagnosis of LVH, and the LVMI by body or is for detection of LVH; the method is more used than the The method for LVMI is the The criteria for the diagnosis of LVH by for Hypertension Taiwan Hypertension and Japanese for Hypertension are as follows: LVMI LVMI LVM = + + + Left ventricle diastolic Left ventricular wall LVMI = LVM = = + body + = + body to = and the of left ventricular in LVH, the guidelines also LVH into three as shown in [Table of of left ventricular criteria in adult hypertension are and/or and and/or This is a more for diagnosis of concentric and LVH with concentric hypotrophy is the most criteria for of cardiovascular for and as criteria for LVH is In clinical or be used to LVH LVMI is not or is used as diagnostic criteria of LVH. 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