Hypertension and diastolic heart failure

In patients with hypertension, pressure overload leads to left ventricular hypertrophy (LVH), myocardial fibrosis, and impaired diastolic filling without systolic dysfunction. Presently, diastolic heart failure accounts for about 50% of the heart failure population. Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. As a group, patients with diastolic heart failure are older and predominantly female. Diuretics are effective for treating congestive symptoms. β Blockers and heart rate-lowering calcium blockers show benefit in smaller studies but have not been evaluated in definitive clinical trials. Renin-angiotensin-aldosterone system blockers reduce blood pressure, LVH, and myocardial fibrosis; however, long-term studies with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers demonstrate little effect on symptoms or survival, and inconsistent effects on heart failure hospitalization. At present, evidence-based treatment includes antihypertensive therapy to reduce progression from hypertension to heart failure. In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms.     

Myocardial fibrosis and diastolic dysfunction in patients with hypertension: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)

OBJECTIVES: Hypertensive left ventricular hypertrophy (LVH) is associated with cardiomyocyte hypertrophy and an excess in myocardial collagen. Myocardial fibrosis may cause diastolic dysfunction and heart failure. Circulating levels of the carboxy-terminal propeptide of procollagen type I (PICP), an index of collagen type I synthesis, correlate with the extent of myocardial fibrosis. This study examines myocardial fibrosis in relation to blood pressure, left ventricular mass (LVM), and diastolic function. METHODS: We examined PICP levels in 115 patients with hypertensive LVH, 38 with hypertension but no hypertrophy, and 38 normotensive subjects. Patients with LVH were subsequently randomly assigned to the angiotensin II type 1 receptor blocker irbesartan or the beta1 receptor blocker atenolol for 48 weeks. Diastolic function was evaluated by tissue velocity echocardiography (n=134). We measured basal septal wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). RESULTS: Compared with the normotensive group, PICP was elevated and left ventricular diastolic function was impaired in the hypertensive groups, with little difference between patients with and without LVH. PICP related to blood pressure, IVRTm, Em, and E/Em, but not to LVM. Irbesartan and atenolol reduced PICP similarly. Only in the irbesartan group did changes in PICP relate to changes in IVRTm, and LVM. CONCLUSION: Myocardial fibrosis and diastolic dysfunction are present in hypertension before LVH develops. The findings with irbesartan suggest a role for angiotensin II in the control of myocardial fibrosis and diastolic function in patients with hypertension with LVH.     

Hypertensive heart disease.

Left ventricular hypertrophy (LVH) and diastolic dysfunction (CHF-D) are the early manifestations of cardiovascular target organ damage in patients with arterial hypertension and signify hypertensive heart disease. Identification of hypertensive heart disease is critical, as these individuals are more prone to congestive heart failure, arrhythmias, myocardial infarction and sudden cardiac death. Regression of left ventricular (LV) mass with antihypertensive therapy decreases the risk of future cardiovascular events. The goal of antihypertensive therapy is to both lower blood pressure (BP) and interrupt BP-independent pathophysiologic processes that promote LVH and CHF-D. The purpose of this review is to summarize current and emerging approaches to the pathophysiology and treatment of hypertensive heart disease.     

Hypertensive heart disease and microangiopathy

Cardiac alterations in patients with arterial hypertension comprise the manifestation of stenosis in epicardial arteries, disease of coronary resistive vessels, prothrombotic changes and endothelial dysfunction, pronounced perivascular and interstitial fibrosis, left ventricular hypertrophy, dilatation of the left atrium, increased sympathetic drive and degeneration of aortic valve. These alterations leads to the major clinical manifestations of hypertensive heart disease, that are symptoms of reduced coronary conductance, left ventricular hypertrophy, diastolic and systolic dysfunction with or without left ventricular enlargement and arrhythmia. Different non-invasive and invase procedures are available for screening and follow up of patients with hypertensive heart disease. The primary therapeutic target is, apart from lowering blood pressure, to reverse cardiac manifestations of arterial hypertension using specific therapeutic algorithms.     

Primary diastolic heart failure

Diastolic heart failure is defined clinically when signs and symptoms of heart failure are present in the presence of preserved left ventricular systolic function (ejection fraction >45%). The incidence and prevalence of primary diastolic heart failure increases with age and it may be as high as 50% in the elderly. Age, female gender, hypertension, coronary artery disease, diabetes, and increased body mass index are risk factors for diastolic heart failure. Hemodynamic consequences such as increased pulmonary venous pressure, post-capillary pulmonary hypertension, and secondary right heart failure as well as decreased cardiac output are similar to those of systolic left ventricular failure, although the nature of primary left ventricular dysfunction is different. Diagnosis of primary diastolic heart failure depends on the presence of preserved left ventricular ejection fraction. Assessment of diastolic dysfunction is preferable but not mandatory. It is to be noted that increased levels of B-type natriuretic peptide does not distinguish between diastolic and systolic heart failure. Echocardiographic studies are recommended to exclude hypertrophic cardiomyopathy, infiltrative heart disease, primary valvular heart disease, and constrictive pericarditis. Myocardial stress imaging is frequently required to exclude ischemic heart disease. The prognosis of diastolic heart failure is variable; it is related to age, severity of heart failure, and associated comorbid diseases such as coronary artery disease. The prognosis of severe diastolic heart failure is similar to that of systolic heart failure. However, cautious use of diuretics and/or nitrates may cause hypotension and low output state. Heart rate control is essential to improving ventricular filling. Pharmacologic agents such as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers are used in selected patients to decrease left ventricular hypertrophy. To decrease myocardial fibrosis, aldosterone antagonists have a potential therapeutic role. However, prospective controlled studies will be required to establish their efficacy in primary diastolic heart failure.     

Hypertensive cardiopathy. From arterial hypertension to congestive heart failure]

Arterial hypertension (HBP) is a very important cardiovascular risk factor. According to the data from the Framingham Study, 90% of the patients with chronic heart failure (CHF) have a clinical history of HBP, and the risk of developing CHF is 2 to 3 times greater in hypertensive persons. Studies of general population by multivariate analysis have shown that HBP is responsible for 39% of CHF cases in males and 59% in females. On the other hand, there is a significant relation between HBP and coronary artery disease (CAD), another very important cause of CHF. HBP very frequently originates left ventricular hypertrophy (LVH) and this is one of the most important links between HBP, myocardium ischaemia, CAD, and sudden death from arrhythmias, to which it can lead. Recent studies on left ventricle systolic function in hypertensive patients indicate that about 1/6 of HBP patients with LVH present systolic dysfunction. Even more frequently, diastolic function is prematurely deteriorated in HBP. In spite of the existence of a significant relation between the grade of LVH and the severity of this disfunction, it may be present even before LVH is detectable. The transition from LVH would be related to quantitative and qualitative changes in the three compartments of the myocardium: hypertrophy of cardiomyocytes with reinduction of fetal genetic program, reactive and cicatricial fibrosis of the interstice, and functional and structural changes of coronary arteries. These modifications will progressively increase, leading to LV dilation which seems to signal transition to heart failure. In recent papers the transition from LVH to CHF has been related to a marked increase in microtubular intracytoplasmic structure, the reduction of Ca++ ATPase concentration of the sarcoplasmic reticulum, and the increased myocardial expression of growth factor TGF beta 1, which influences interstitial fibrosis. In the same way, stimulation of apoptosis by myocardial expression of tumor necrosis factor alpha and the subquent increase in inducible NO-synthase and oxidative stress has been related to the progression for CHF. Prevention of CHF will not only consist in the treatment of HBP but, very probably, also in the prevention of regression of LVH, and normalization of myocardial components, as well as the correction of all the factors involved in CHF establishment. In accordance with form of treatment, we must give special emphasis to drugs interfering with the renin-angiotensin system and, possibly in the near future, to gene therapy.     

Arterial hypertension and systolic left ventricular dysfunction: therapeutic approach

Arterial hypertension is a cardinal precursor of congestive heart failure, and diastolic dysfunction is the most frequent mechanism for it. Systolic left ventricular dysfunction, although less frequent, has a worse prognosis. Most cases of systolic dysfunction in patients with hypertension is due to acute myocardial infarction, although other mechanisms can be involved. In some studies, non-ischemic hypertensive systolic dysfunction is the etiology of chronic heart failure in up to 10% of patients with dilated cardiomyopathy. Diastolic dysfunction and left ventricular hypertrophy are also associated with a higher risk of heart failure and systolic dysfunction. Given the poor prognosis of patients with congestive heart failure and dilated cardiomyopathy, it is fundamental to try to prevent the development of left ventricular dysfunction by means of a correct control of blood pressure, regression of left ventricular hypertrophy and prevention of coronary artery disease. When systolic dysfunction is established, angiotensin converting enzyme inhibitors are the treatment of choice; diuretics and digoxin can be added in patients with overt congestive heart failure. Recent studies suggest that other drugs, such as carvedilol and losartan, can be beneficial, but current evidence is still scarce.     

Comprehensive assessment of hypertensive heart disease: cardiac magnetic resonance in focus

Arterial hypertension represents the most frequent cardiovascular risk factor that is associated with cardiac remodeling. Hypertensive heart disease was defined by the presence of left ventricular hypertrophy (LVH) and diastolic dysfunction, and it has been diagnosed by echocardiography in everyday clinical practice. Interstitial myocardial fibrosis is the underlying cause of hypertension-induced cardiac remodeling, and it could not be visualized with different echocardiographic methods. Cardiac magnetic resonance (CMR) and its methods such as late gadolinium enhancement, and T1 mapping provides qualitative and quantitative assessment of interstitial myocardial fibrosis in hypertensive patients. Furthermore, CMR can provide differentiation of LVH between hypertensive patients and cardiomyopathies (hypertrophic or Fabry disease). Timely diagnosis of cardiac impairment and early treatment is essential because regression of LVH could be achieved with adequate treatment. Diffuse cardiac fibrosis in hypertensive patients might be an underlying mechanism that explains the increased cardiovascular morbidity and mortality in this population. Future longitudinal investigations are necessary to determine causal relationship between diffuse fibrosis and cardiovascular outcome in these patients. The aim of this review is to summarize the current knowledge regarding CMR techniques and their potential usage in patients with hypertensive heart disease.

     

Hypertensive cardiomyopathy:A clinical approach and literature review

Hypertensive cardiomyopathy(HTN-CM) is a structural cardiac disorder generally accompanied by concentric left ventricular hypertrophy(LVH) associated with diastolic or systolic dysfunction in patients with persistent systemic hypertension.It occurs in the absence of other cardiac diseases capable of causing myocardial hypertrophy or cardiac dysfunction.Persistent systemic hypertension leads to structural and functional myocardial abnormalities resulting in myocardial ischemia,fibrosis,and hypertrophy.HTN-CM is predominantly a disease of impaired relaxation rather than impaired contractility,so patients are usually asymptomatic during resting conditions.However,their stiff left ventricles become incapable of handling increased blood volume and cannot produce appropriate cardiac output with the slight change of circulating volume that may occur during exercise.Importantly,the accompanying LVH is itself a risk factor for mortality and morbidity.Therefore,early detection of LVH development in patients with hypertension(referred to as HTN-CM) is critical for optimal treatment.In addition to pathological findings,echocardiography and cardiac magnetic resonance imaging are ideal tools for the diagnosis of HTN-CM.Timely diagnosis of this condition and utilization of appropriate treatment are required to improve morbidity and mortality in hypertensive patients.This review article presents an overview of the multidimensional impact of myocardial disorder in patients with hypertension.Relevant literature is highlighted and the effects of hypertension on cardiac hypertrophy and heart failure development are discussed,including possible therapeutic options.     

Obesity and the heart

Obesity has been identified as an independent risk factor for coronary heart disease and congestive heart failure. Although congestive heart failure can be secondary to coronary heart disease, in morbid obesity these conditions can be independent. Cardiac structure and function can be altered even in the absence of systemic hypertension and underlying organic heart disease. In obese patients total blood volume increases and creates a high cardiac output state that may cause ventricular dilatation and ultimately eccentric hypertrophy of the left (and possibly the right) ventricle. Eccentric left ventricular hypertrophy produces diastolic dysfunction. Systolic dysfunction may ensue due to excessive wall stress if wall thickening fails to keep pace with dilatation. This disorder is referred to as obesity cardiomyopathy. The frequent coexistence of systemic hypertension in obese individuals facilitates development of left ventricular dilatation and hypertrophy. Congestive heart failure may occur and may be attributable to left ventricular diastolic dysfunction or to combined diastolic and systolic dysfunction. The risk of coronary heart disease seems to be more strictly correlated to central obesity than to increased body mass index. Insulin resistance seems to be the key factor that links obesity and ischaemic heart disease. In such a condition the so called Syndrome X appears. It is characterized by: obesity, systemic hypertension, diabetes mellitus, hypertriglyceridaemia and reduced HDL cholesterol levels. Considering that left ventricular hypertrophy is often present, many risk factors coexist in obese patients. Weight loss is very useful in obese patients. It may reduce mortality and morbidity for coronary heart disease and delay or avoid the appearance of congestive heart failure. It is proved that after weight loss, blood pressure, glucose, cholesterol, triglycerides and left ventricular mass decrease.     

Arterial hypertension and chronic heart failure

Arterial hypertension, alone or in combination with ischemic heart disease, precedes the development of heart failure. The Framingham study demonstrated that hypertension was the major risk factor in the development of heart failure. Arterial hypertension is not a sole factor contributing to the development of heart failure. The syndrome of heart failure is a consequence of multiple systemic responses and the development of heart failure is a complex and progressive process associated with cardiovascular disease resulting from risk factors: hypertension, obesity, smoking and dyslipidaemia. Arterial hypertension is the main precursor of left ventricular hypertrophy. Initially, this process causes diastolic dysfunction in the early stages of primary hypertension. Systolic dysfunction is rarely observed in those subjects. Left ventricular hypertrophy is also an important risk factor for myocardial infarction and ventricular arrhythmias. Asymptomatic systolic and diastolic left ventricular dysfunction may both progress to overt HFThe primary prevention of heart failure patients should be based upon strategies providing tight and sustained blood pressure control. This therapy should include an agent that inhibits the renin–angiotensin–aldosterone system. Treatment of arterial hypertension in patients with HF must take into account the prevalent type of cardiac dysfunction—diastolic or systolic.     

Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.

OBJECTIVE: To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. STUDY SELECTION: Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. DATA SYNTHESIS: Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. RESULTS: In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. CONCLUSIONS: Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.     

Hochdruckherz und hypertensive Mikroangiopathie

Cardiac alterations in patients with arterial hypertension comprise the manifestation of stenosis in epicardial arteries, disease of coronary resistive vessels, prothrombotic changes and endothelial dysfunction, pronounced perivascular and interstitiell fibrosis, left ventricular hypertrophy, dilatation of the left atrium, increased sympathetic drive and degeneration of aortic valve. These alterations leads to the major clinical manifestations of hypertensive heart disease, that are symptoms of reduced coronary conductance, left ventricular hypertrophy, diastolic and systolic dysfunction with or without left ventricular enlargement and arrythmia. Different non-inavsive and invase procedures are available for screening and follow up of patients with hypertensive heart disease. The primary therapeutic target is, apart from lowering blood pressure, to reverse cardiac manifestations of arterial hypertension using specific therapeutic algorithms.     

Clinicopathological study on left ventricular hypertrophy in elderly hypertensive patients

The correlations between blood pressure, left ventricular hypertrophy and left atrial enlargement were examined in 2,010 autopsied cases. The cases were classified into 3 groups: 972 (48.2%) normotension cases, 313 cases (15.5%) of systolic hypertension and 725 cases (36.1%) of diastolic hypertension. The incidence of left ventricular hypertrophy (LVH) was significantly higher in systolic and diastolic hypertensive cases than in normotensives (p less than 0.05), but no significant difference in LVH incidence was found between the 2 hypertensive groups. The incidence of an enlarged left atrium was also significantly higher in both hypertensive groups than in the normotensive group (p less than 0.05). The incidence of congestive heart failure and a large CTR were also higher in both hypertensive groups. However, there were no intergroup differences in atrial fibrillation incidence, despite significant differences in atrial size. Finally, the incidence of moderate to severe coronary artery stenosis was significantly higher in both hypertensive groups, but no difference was found between the 2 types of hypertension. We concluded that both systolic and diastolic hypertension contributed to the genesis of left ventricular hypertrophy, left atrial dilatation, coronary sclerosis and congestive heart failure.     

Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction

OBJECTIVE: Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident. METHODS: Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks. RESULTS: Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings' upregulation. CONCLUSIONS: This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.     

Antihypertensive drugs and the heart

Left ventricular hypertrophy (LVH) and diastolic dysfunction (CHF-D) are early signs of cardiac end-organ damage (hypertensive heart disease) in patients with arterial hypertension. The presence of LVH or CHF-D confers increased risk of cardiovascular morbidity and mortality in patients with hypertension. Regression of left ventricular mass with antihypertensive therapy is associated with reduction in cardiovascular events. Antihypertensive therapy should be geared to both lower blood pressure and specifically reverse the pathophysiologic processes that may be independent of actual blood pressure. This review summarizes current and emerging approaches to the treatment of individuals with hypertensive heart disease.     

Diabetic cardiomyopathy: concept,heart function,and pathogenesis

The diabetic cardiomyopathy is a disease caused by diabetes and is characterised by the presence of diastolic and/or systolic left ventricular dysfunction. Diabetes may produce metabolic alterations, interstitial fibrosis, myocellular hypertrophy, microvascular disease and autonomic dysfunction. It is thought that all of them may cause cardiomyopathy. Other abnormalities that are usually associated with diabetes such as hypertension, coronary artery disease and nephropathy should be excluded before diagnosing diabetic cardiomyopathy. There is no evidence that diabetic cardiomyopathy alone can produce heart failure. However, subclinical ventricular dysfunction has been described in young asymptomatic diabetic patients without other diseases that could affect the cardiac muscle. In these cases we should consider that diabetes is the only cause of the myocardial disease. More studies are needed to know the natural history of diabetic cardiomyopathy.     

Das Herz bei arterieller Hypertonie

The term hypertensive heart disease covers the entities of left ventricular hypertrophy, microangiopathy and endothelial dysfunction resulting in diastolic and systolic dysfunction, arrhythmias and increased cardiovascular risk. From the pathophysiological point of view, this is caused by the hypertrophy of cardiac myocytes, interstitial fibrosis and media hypertrophy of the arterioles. Microangiopathy can be diagnosed as the earliest sign of hypertensive heart disease, with diastolic dysfunction also being found as an early change. In further persisting arterial hypertension left ventricular hypertrophy develops (often asymmetric) and later a systolic dysfunction. Clinically, the patients suffer from angina pectoris, dyspnea and rhythm disorders. Left ventricular hypertrophy is associated with an increased risk of malignant ventricular arrhythmias. Thus, the main therapeutic principle should be antihypertensive therapy with the goal of regression of hypertrophy leading to decreased mortality risk.     

Angiotensin converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.     

Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis.

There is increasing evidence that myocardial fibrosis plays a role in the pathogenesis of diastolic dysfunction in hypertensive heart disease. However, it has been difficult to explore the mechanisms of isolated diastolic dysfunction in hypertensive hearts because of the lack of adequate animal models. Recently, we demonstrated that Wistar rats with a suprarenal aortic constriction (AC) can be used as a model of cardiac hypertrophy associated with preserved systolic, but impaired diastolic function without overt congestive heart failure. In this model, acute pressure elevation induces reactive myocardial fibrosis (perivascular fibrosis followed by intermuscular interstitial fibrosis) and myocyte/left ventricular (LV) hypertrophy. Perivascular macrophage infiltration, which is mediated by monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1, exerts a key role in myocardial fibrosis, but not in myocyte/LV hypertrophy. Transforming growth factor (TGF)-beta is crucial for reactive fibrosis in AC rats. MCP-1 function blocking not only inhibits macrophage infiltration and TGF-beta induction but also prevents reactive fibrosis and diastolic dysfunction, without affecting blood pressure, myocyte/LV hypertrophy, or systolic function. Accordingly, a substantial role of inflammation is indicated in myocardial fibrosis and diastolic dysfunction in hypertensive hearts. Currently, the precise mechanisms whereby acute pressure elevation triggers inflammation remain unknown, but it is likely that activation of the tissue angiotensin system is involved in the induction of the inflammatory process.