Treatment of hypertension based on measurement of blood pressure variability: lessons from animal studies

PURPOSE OF REVIEW: Blood pressure variability, a quantitative index for the spontaneous variation in blood pressure, has been proposed as a risk factor for end-organ damage and to determine the efficacy of hypertension treatment. RECENT FINDINGS: Animal studies indicate that blood pressure variability is as important as blood pressure level in determining end-organ damage, and that high blood pressure variability is associated with end-organ damage, including myocardial lesions, aortic hypertrophy, vascular remodeling and renal damage. Although the organ damage induced by high blood pressure variability was similar to that induced by hypertension, comparative studies in sinoaortic-denervated and spontaneously hypertensive rats revealed that aortic hypertrophy is a sensitive index of high blood pressure variability, and left ventricular hypertrophy is a sensitive index of high blood pressure level. The possible mechanisms for high blood pressure variability-induced end-organ damage include: direct endothelial lesions, renin-angiotensin system activation, inflammation initiation and cardiomyocyte apoptosis augmentation. Blood pressure variability reduction contributes importantly to the organ-protective effect of some antihypertensive drugs. SUMMARY: Although animal studies suggest some advantages in blood pressure variability measurements, clinical trials are necessary before the widespread use of blood pressure variability as a predictor of hypertensive organ damage and a new strategy for the treatment of hypertension.     

Hypertensive emergencies and urgencies: Pathophysiology and clinical aspects

A hypertensive urgency should be distinguished from a hypertensive emergency. Although the distinction may not always be obvious, certain guidelines may help the clinician determine which therapeutic approaches are most appropriate for each patient. Hypertensive emergencies include those conditions in which new or progressive severe end-organ damage is present and a delay in appropriate therapy might result in permanent damage, progression of complications, and a poor prognosis. Hypertensive urgencies include those conditions with minimal to no obvious end-organ damage in which blood pressure should be lowered expeditiously. The risk of immediate complications or organ damage is less likely to occur, and thus the immediate prognosis is better, although the ultimate prognosis, if untreated, is poor. There is a marked individual, racial, sexual, and age difference in the ability to tolerate high intraarterial pressure, as evidenced by patients' symptoms and signs of end-organ damage.Patients may have no symptoms of elevated blood pressure until significant intraarterial levels are reached. If symptoms are present, they may include headache, dizziness, blurred vision, shortness of breath (especially with exertion), chest pain, rapid pulse, palpitations, malaise and fatigue, nocturia, or pedal edema.^7,11–14 Signs of hypertensive disease vary and depend not only on the level of blood pressure but also include funduscopic changes with arteriolar narrowing, atrioventricular nicking, hemorrhages, exudates or papilledema, central nervous system changes and neurologic abnormalities, cardiac changes with gallop rhythm, cardiomegaly, tachycardia, ectopic ventricular beats, left ventricular hypertrophy or signs of congestive heart failure, pulmonary edema, and signs of renal insufficiency.^7,11–14Although there is a definite correlation between the level of blood pressure and end-organ damage, there is no definite systolic or diastolic level of blood pressure that induces end-organ damage. Some patients may tolerate very high blood pressures with few symptoms or signs, whereas others may manifest end-organ damage at lower blood pressures. Thus, the definition of hypertensive emergency and urgency depends on the clinical assessment of the blood pressure level and clinical and laboratory assessments of end-organ damage. The absolute blood pressure in itself does not determine the seriousness of the clinical situation, the expediency of treatment, or the need for in-hospital monitoring in a critical care unit.It is important not to lower the blood pressure precipitously or to a subnormal level particularly in patients with end-organ damage. Such treatment may critically reduce blood flow and perfusion to vital organs and induce a cerebrovascular accident, myocardial ischemia, or renal failure. A smooth, gradual reduction in blood pressure is crucial to patient management with oral or parenteral antihypertensive drugs. However, in hypertensive emergencies blood pressure control should be accomplished within 1 hour, whereas with hypertensive urgencies control should be within 24 hours.Those patients who have hypertensive emergencies with malignant hypertension and end-organ damage should be admitted to a hospital intensive care unit for evaluation and treatment. These patients have a diffuse arteritis, as of a result of their hypertension, that may take 4 to 6 weeks to heal. Many patients who present with diastolic blood pressure 120 mm Hg or greater will be found to have a secondary cause of hypertension (such as renovascular hypertension) after careful evaluation. On the other hand, those patients with hypertensive urgencies as defined previously can be treated in the emergency room or outpatient department and can avoid hospital admission. Careful, immediate, and routine follow-up is important in these patients.     

Hypotensive and prophylactic effects of angiotensin II subtype 1 receptor antagonist, irbesartan, in stroke-prone spontaneously hypertensive rats

We determined the acute hypotensive effect of a single administration and the prophylactic effect of chronic treatment with Irbesartan, an angiotensin II receptor antagonist, on the development of end-organ damage in stroke-prone spontaneously hypertensive rats (SHRSP). The acute hypotensive effect was determined by a telemetrical method in SHRSP fed a normal diet. The prophylactic effect was examined by biochemical, histopathological and immunohistochemical methods in SHRSP fed a high-salt and low-protein diet. Irbesartan (3, 10, 30 and 100 mg/kg) reduced blood pressure in a dose-dependent manner without affecting heart rate. Irbesartan (3, 10 and 30 mg/kg) increased the survival rate in SHRSP fed a high-salt and low-protein diet. Furthermore, Irbesartan ameliorated the appearance of stroke symptoms in dose-dependent manner showing association with the prevention of microscopic lesions. Irbesartan ameliorated the increases in urinary protein excretion and N-acetyl-D-glucosamidase activity by preventing nephrosclerosis, as judged by microscopic observations, and ameliorated the increases in the expression of collagen IV and fibronectin in the kidney. These findings demonstrate that Irbesartan is a potent antihypertensive drug offering a protective effect on the development of hypertension-induced end-organ damages in SHRSP. Thus, Irbesartan is useful for the therapy of hypertension with end-organ damage.     

The Importance of Integrated Risk Management When Treating Patients with Hypertension: Benefits of Angiotensin II Receptor Antagonist Therapy

Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with comorbid obesity, diabetes, metabolic disease, or end-organ damage. An integrated CV risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The renin-angiotensin system is integral to blood pressure control and is well established in the pathophysiology of CVD. Angiotensin II receptor blockers (ARBs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in comorbid hypertension, CV pathologies, end-organ damage, and, in diabetes, diabetic nephropathy or metabolic syndrome. ARBs decrease overall risk of CV and end-organ disease, CVD-related mortality, and cerebrovascular events in patients with hypertension.     

The diagnosis and management of hypertensive crises

Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.     

Applying hypertension guidelines to reduce the burden of heart failure

If the recommendations of Joint National Committee 7 are implemented, the incidence of heart failure should continue to decline. These recommendations are designed not only to reduce the incidence of heart failure but also prevent other target end-organ damage and reduce overall cardiovascular morbidity and mortality. The emphasis of these recommendations is to reduce systolic blood pressure, because the risk of mortality caused by heart disease and stroke doubles for every 20-mm Hg increase in systolic blood pressure. Practitioners are encouraged to use a combination of lifestyle changes and pharmacotherapy to achieve systolic blood pressure goals and consider the use of thiazide diuretics as first-line therapy to achieve the ultimate goal of reducing end-organ damage.     

The importance of integrated risk management when treating patients with hypertension: benefits of angiotensin II receptor antagonist therapy

Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with comorbid obesity, diabetes, metabolic disease, or end-organ damage. An integrated CV risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The renin-angiotensin system is integral to blood pressure control and is well established in the pathophysiology of CVD. Angiotensin II receptor blockers (ARBs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in comorbid hypertension, CV pathologies, end-organ damage, and, in diabetes, diabetic nephropathy or metabolic syndrome. ARBs decrease overall risk of CV and end-organ disease, CVD-related mortality, and cerebrovascular events in patients with hypertension.     

Hypertension in the intensive care unit

PURPOSE OF REVIEW: The severity of hypertensive crises is determined by the presence of target organ damage rather than the level of blood pressure. Hypertensive urgencies with no signs of organ dysfunction can therefore be distinguished from hypertensive emergencies in which the presence of severe end-organ damage requires prompt therapy. Hypertensive emergencies include acute aortic dissection, hypertensive encephalopathy, acute myocardial ischaemia, severe pulmonary oedema, eclampsia, and acute renal failure. RECENT DEVELOPMENTS: Malignant hypertension is a severe form of hypertensive emergency demanding special consideration because of the risks of permanent blindness and renal failure. Catecholamine excess and postoperative hypertension may also sometimes require urgent treatment. The management of patients with hypertensive emergencies must be ensured in an intensive care unit, and must include the parenteral administration of antihypertensive drugs and accurate blood pressure monitoring. SUMMARY: Except for acute aortic dissection, the recommended goals of treatment are a reduction of mean arterial pressure by no more than 20% during the first few hours, because an abrupt fall in blood pressure in patients with preexisting hypertension may induce severe ischaemic injury in major organs as a result of the chronic adaptation of autoregulation mechanisms. Hypertension in the context of acute stroke should be treated only rarely and cautiously because of the presence of impaired autoregulation.     

Protective Effects of Valsartan and Benazeprilat in Salt-Loaded Stroke-Prone Spontaneously Hypertensive Rats

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin I1 to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded strokeprone SHR.     

Technical aspects of blood pressure measurement in pediatric patients.

BACKGROUND: Prolonged hypertension in adults has been associated with end-organ damage, in addition to increased morbidity and mortality. Accurate measurement of blood pressure in pediatric and adult patients is imperative for the appropriate diagnosis of hypertension, so that measures may be instituted to prevent these adverse sequelae. Although intermittent office measurement of blood pressure is practiced in most parts of the world, the technique is fraught with problems. Errors during the actual measurement and difficulties in interpretation of the data are well-studied challenges associated with intermittent blood pressure measurements that have been well studied. Ambulatory blood pressure monitoring offers several advantages over intermittent measurement: blood pressure measurements are available over a prolonged period of time (including the sleep period), measurements are not as dependent on observer biases as are intermittent measurements, and in adults the data appear to correlate well to measures of end-organ damage. In children, the ambulatory blood pressure monitor is well tolerated and accurate. This new technology may offer pediatric specialists the opportunity to identify more accurately the child with increased blood pressure, so that preventive measures can be instituted to reduce the well-known morbidity and mortality associated with hypertension. OBJECTIVE: To review the technical aspects of blood pressure measurement in children, with special attention to the emerging field of ambulatory blood pressure monitoring and its potential use in children.     

Hypertensive emergencies

Hypertensive urgencies are common clinical occurrences in hypertensive patients. The definition of hypertensive urgencies (target blood pression) were not consistent, but involved often target end-organ damage in emergencies. Epidemiology and physiopathology are briefly described. Treatment practices of hypertensive crisis were difficult because of the lack of evidence supporting the use of one therapeutic agent over another and its posology.     

Relationship between 24 h ambulatory central blood pressure and left ventricular mass – Rationale and design of a prospective multicenter study

The prognostic superiority of ambulatory over clinic blood pressure has been repeatedly proven. However, due to the mechanical properties of the arterial system, systolic and pulse pressures are higher in the brachial artery than in the ascending aorta. It seems logical that central pressures are more relevant to cardiovascular disease than peripheral (brachial) pressures, and indeed, using clinic blood pressures, it has been shown that central systolic and pulse pressures are more closely associated with hypertensive end-organ damage than their brachial counterparts. Moreover, antihypertensive drugs can have differential effects on central versus brachial blood pressures. All these effects have been described on the basis of clinic blood pressure measurements. Recent advances in technology allow the estimation of central systolic blood pressure from brachial pulse waves recorded with a regular brachial oscillometric blood-pressure cuff, using a transfer-function like algorithm (ARCSolver). This method has been invasively validated and allows the recording of 24 h ambulatory central blood pressure profiles. Our multicenter study now aims for the first time to investigate the relationship between central ambulatory blood pressure monitoring and hypertensive end-organ damage (left ventricular mass) in untreated adults.     

Ambulatory blood pressure monitoring during antihypertensive treatment: the case of non-responder patients

OBJECTIVE: To analyse the discrepancies between casual and ambulatory blood pressure in hypertensive patients during treatment. PATIENTS AND METHODS: Patients were gathered intio two groups according to casual diastolic blood pressure (DBP) and antihypertensive treatment: group A (responders) with casual DBP < 90 mmHg administered one or more antihypertensive drugs and group B (non-responders) with DBP >/= 95 mmHg taking two or more antihypertensive drugs, maintained during three consecutive visits at 2-week intervals. For all of them casual blood pressure measurements, 24 h ambulatory blood pressure monitoring and assessment of end-organ damage were performed. RESULTS: The difference between casual blood pressure and average 24 h ambulatory blood pressure were significantly higher for group B than those observed for group A (26 versus 7 mmHg systolic, 16 versus 5 mmHg diastolic). Thirty per cent of the patients in group B and 16% in group A had casual blood pressure more than 20 mmHg higher than awake ambulatory blood pressure, whereas 8% in group B and 20% in group A had higher values for ambulatory than for casual blood pressure. In group A 8% of patients had awake DBP higher than 95 mmHg and 8% had awake DBP 85-95 mmHg. Patients of group A with awake DBP >/= 85 mmHg were younger than those with awake DBP < 85 mmHg (41.4+/-8.8 and 52.1+/-13.4 years, respectively). In patients of group B, there was less end-organ damage in the patients with awake DBP < 85 mmHg than there was in patients with awake DBP >/= 95 mmHg (World Health Organization grade I/II-III, 6/10 and 3/20, respectively). CONCLUSION: The differences between casual and ambulatory blood pressures were higher in the 'non-responder' patients. In group A the small percentage of patients who had persistently higher ambulatory blood pressure were younger. In group B one-quarter of the patients had 'normal' ambulatory blood pressure and less end-organ damage. Ambulatory blood pressure monitoring will be useful for better assessment of hypertension control in a subset of hypertensive patients.     

Hypertensive crises: challenges and management

Hypertension affects > 65 million people in the United States and is one of the leading causes of death. One to two percent of patients with hypertension have acute elevations of BP that require urgent medical treatment. Depending on the degree of BP elevation and presence of end-organ damage, severe hypertension can be defined as either a hypertensive emergency or a hypertensive urgency. A hypertensive emergency is associated with acute end-organ damage and requires immediate treatment with a titratable short-acting IV antihypertensive agent. Severe hypertension without acute end-organ damage is referred to as a hypertensive urgency and is usually treated with oral antihypertensive agents. This article reviews definitions, current concepts, common misconceptions, and pitfalls in the diagnosis and management of patients with acutely elevated BP as well as special clinical situations in which BP must be controlled.     

Ambulatory blood pressure monitoring and echocardiography—Noninvasive techniques for evaluation of the hypertensive patient

Clinic blood pressure measurements have only limited ability to determine which hypertensive patients are at greatest risk of cardiovascular events. Ambulatory blood pressure monitoring allows for noninvasive measurement of blood pressure throughout the 24-hour period. This may help to clarify discrepancies between blood pressure values obtained in and out of the clinic and confirm the presence of white-coat hypertension, broadly defined as an elevated clinic blood pressure but a normal ambulatory blood pressure. Ambulatory blood pressure values have been shown to have a better relationship to cardiovascular morbidity and mortality and end-organ damage than clinic blood pressure values. Further, patients with white-coat hypertension appear to be at greater risk of cardiovascular morbidity and end-organ damage than a normotensive population, although they are at less overall risk than a hypertensive population. Hypertensive heart disease is characterized by diastolic dysfunction, increased left ventricular mass, and coronary flow abnormalities. Left ventricular hypertrophy increases the risk of coronary heart disease, congestive heart failure, stroke, ventricular arrhythmias, and sudden death. A variety of invasive and noninvasive techniques are described herein that measure left ventricular mass, diastolic function, and coronary blood flow abnormalities. Most antihypertensive treatments promote regression of left ventricular hypertrophy and reversal of diastolic dysfunction, which may decrease symptoms of congestive heart failure and improve survival. Copyright © 1999 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 41, No. 6 (May/June), 1999: pp 397-440     

Renale Sympathikusdenervation bei therapierefrakt?rer arterieller Hypertonie

In patients with therapy refractive arterial hypertension an overactivity of the sympathetic nervous system is the driving force of end-organ damage and poor cardiovascular prognosis. In patients with systolic blood pressure values of ??160?mmHg (??150?mmHg in type 2 diabetes mellitus) a blood pressure reduction of ??10?mmHg in more than 85% of this difficult patient group could be achieved with the new technique of minimally invasive selective renal sympathetic denervation (RD). The current status of controlled multicentric clinical trails proves a sustained treatment effect for more than 3 years of follow-up. Even with longer follow-up times the treatment efficacy seems to increase further due to late RD responders. Smaller clinical trials indicate a beneficial effect of RD on secondary effects and end-organ damage correlated with refractory hypertension. The impact of RD on long-term prognosis of hypertensive patients remains to be investigated by trials with sufficient follow-up duration and statistical power.     

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.     

内皮素-1与原发性高血压

原发性高血压时血浆内皮素-1水平升高,可导致外周阻力增加,并且通过激活ETA和ETB受体可加重高血压病心、肾、动脉系统的损害,形成恶性循环。ETA/ETB受体阻滞剂或选择性的ETA受体阻滞剂均能使全身血压下降,保护高血压病的靶器官。     

Role of leptin in blood pressure regulation and arterial hypertension

Leptin is a 16-kDa protein secreted by white adipose tissue that is primarily involved in the regulation of food intake and energy expenditure. Plasma leptin concentration is proportional to the amount of adipose tissue and is markedly increased in obese individuals. Recent studies suggest that leptin is involved in cardiovascular complications of obesity, including arterial hypertension. Acutely administered leptin has no effect on blood pressure, probably because it concomitantly stimulates the sympathetic nervous system and counteracting depressor mechanisms such as natriuresis and nitric oxide (NO)-dependent vasorelaxation. By contrast, chronic hyperleptinemia increases blood pressure because these acute depressor effects are impaired and/or additional sympathetic nervous system-independent pressor effects appear, such as oxidative stress, NO deficiency, enhanced renal Na reabsorption and overproduction of endothelin. Although the cause-effect relationship between leptin and high blood pressure in humans has not been demonstrated directly, many clinical studies have shown elevated plasma leptin in patients with essential hypertension and a significant positive correlation between leptin and blood pressure independent of body adiposity both in normotensive and in hypertensive individuals. In addition, leptin may contribute to end-organ damage in hypertensive individuals such as left ventricular hypertrophy, retinopathy and nephropathy, independent of regulating blood pressure. Here, current knowledge about the role of leptin in the regulation of blood pressure and in the pathogenesis of arterial hypertension is presented.     

Surrogates of surrogates: the story of hypertension and 24 h blood pressure monitoring

Ambulatory blood pressure (ABP) monitoring is emerging as a useful tool in the diagnosis and management of hypertension. It is particularly useful in certain settings, such as the identification of patients with 'white coat hypertension', the evaluation of patients with unexplained symptoms or end-organ damage, the study of circadian variations in BP and the management of patients with refractory hypertension (as assessed by office BP measurements), and as a guide to antihypertensive treatment. Recent data suggest that ABP monitoring may be superior to office BP measurements in the assessment of risk of hypertensive end-organ damage and clinical events. However, further evidence that the use of ABP monitoring can improve patients' clinical outcomes is needed and would make the use of this promising technique more compelling and more widely accepted.