Pathophysiology Of Left Ventricular Hypertrophy Research Articles

24-LB: Diabetic Microvascular Disease Is Associated with Left Ventricular Hypertrophy in Patients with Type 2 Diabetes Mellitus

Background: Left ventricular hypertrophy (LVH) is an important feature in patients with diabetes mellitus and increased the risk of cardiac events. The pathophysiology of LVH in diabetes mellitus remains unclear and is not fully explained by hyperglycemia and hypertension. Microvascular diseases, the most common and specific complications of diabetes mellitus, which may be involved in LVH. Therefore, we aimed to explore the association between diabetic microvascular diseases and LVH in patients with type 2 diabetes mellitus (T2DM). Material and methods: In the cross-sectional study, we enrolled 2912 patients with T2DM, including 360 patients with LVH. Demographic data, medical history, anthropometric indices, laboratory examination, diabetic microvascular diseases and cardiac ultrasound index were collected. Correlation analysis and regression analysis were performed to analyze the relationship between diabetic microvascular diseases and LVH in whole population and in gender subgroup. Result: Patients with LVH were older and had larger BMI, waist circumference and hip circumference. And a higher proportion of males had LVH compared with females. Patients with LVH had a larger proportion of hypertension, coronary heart disease, diabetic retinopathy (DR), and diabetic kidney disease (DKD). After adjusting potential confounding factors, patients with one or two microvascular diseases especially DR and DKD, had more possibility of LVH (OR = 1.287 and OR = 2.118 respectively). In gender subgroup analysis, microvascular diseases obviously increased the risk of LVH, especially in males. Moreover, the risk of LVH gradually increased with the number of diabetic microvascular diseases. Conclusions: Diabetic microvascular diseases, especially DR and DKD, were positively and independently associated with LVH in T2DM. In addition, the risk of LVH obviously increased with the number of microvascular diseases in male. Disclosure J. Ke: None. X. Feng: None. L. Zhu: None. Y. Xu: None. S. Liu: None. L. Yang: None. D. Zhao: None.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Is a Biomarker Associated with Left Ventricular Hypertrophy in the Elderly, Specifically in Women.

Left ventricular hypertrophy (LVH) may result in the development of heart failure, which is widespread among people of advanced age. The pathophysiology of LVH is complex and its biochemical pathways are not fully understood in this group. Elevated soluble urokinase-type plasminogen activator receptor (suPAR), a biomarker of immune activation, including fibrosis, reflects subclinical organ damage in systematic diseases. The present study assesses the clinical role of suPAR measurement in determination of LVH-associated cardiac disorders in the elderly. The studied population consisted of 238 individuals aged 76-91 years; of these, 139 (58%) were diagnosed with LVH. Serum biomarkers measurement (suPAR, troponin T, NT-proBNP and CRP) and echocardiography were performed in all subjects. The suPAR level was significantly higher in the LVH group (4.01 vs. 3.82 ng/mL, p = 0.033) and correlated with the parameters of cardiac diastolic function. Stepwise logistic regression found suPAR level (OR = 1.55, p = 0.016), BMI (OR = 1.17, p = 0.0003) and hypertension (OR = 2.42, p = 0.046) to be independently associated with LVH in women. In men, the strongest predictors of LVH were hypertension (OR = 7.52, p = 0.014) and BMI (OR = 1.42, p = 0.032). The observations indicate suPAR as a promising marker reflecting LVH, especially in women at advanced age, independent of age-associated cardiac remodeling.

Left Ventricular Hypertrophy in Diabetic Cardiomyopathy: A Target for Intervention.

Heart failure is an important manifestation of diabetic heart disease. Before the development of symptomatic heart failure, as much as 50% of patients with type 2 diabetes mellitus (T2DM) develop asymptomatic left ventricular dysfunction including left ventricular hypertrophy (LVH). Left ventricular hypertrophy (LVH) is highly prevalent in patients with T2DM and is a strong predictor of adverse cardiovascular outcomes including heart failure. Importantly regression of LVH with antihypertensive treatment especially renin angiotensin system blockers reduces cardiovascular morbidity and mortality. However, this approach is only partially effective since LVH persists in 20% of patients with hypertension who attain target blood pressure, implicating the role of other potential mechanisms in the development of LVH. Moreover, the pathophysiology of LVH in T2DM remains unclear and is not fully explained by the hyperglycemia-associated cellular alterations. There is a growing body of evidence that supports the role of inflammation, oxidative stress, AMP-activated kinase (AMPK) and insulin resistance in mediating the development of LVH. The recognition of asymptomatic LVH may offer an opportune target for intervention with cardio-protective therapy in these at-risk patients. In this article, we provide a review of some of the key clinical studies that evaluated the effects of allopurinol, SGLT2 inhibitor and metformin in regressing LVH in patients with and without T2DM.

Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology.

Left ventricular hypertrophy (LVH) can be adaptive, as arising from exercise, or pathological, most commonly when driven by hypertension. The pathophysiology of LVH is consistently associated with an increase in cytochrome P450 (CYP)1B1 and mitogen-activated protein kinases (MAPKs) and a decrease in sirtuins and mitochondria functioning. Treatment is usually targeted to hypertension management, although it is widely accepted that treatment outcomes could be improved with cardiomyocyte hypertrophy targeted interventions. The current article reviews the wide, but disparate, bodies of data pertaining to LVH pathoetiology and pathophysiology, proposing a significant role for variations in the N-acetylserotonin (NAS)/melatonin ratio within mitochondria in driving the biological underpinnings of LVH. Heightened levels of mitochondria CYP1B1 drive the ‘backward’ conversion of melatonin to NAS, resulting in a loss of the co-operative interactions of melatonin and sirtuin-3 within mitochondria. NAS activates the brain-derived neurotrophic factor receptor, TrkB, leading to raised trophic signalling via cyclic adenosine 3′,5′-monophosphate (cAMP)-response element binding protein (CREB) and the MAPKs, which are significantly increased in LVH. The gut microbiome may be intimately linked to how stress and depression associate with LVH and hypertension, with gut microbiome derived butyrate, and other histone deacetylase inhibitors, significant modulators of the melatonergic pathways and LVH more generally. This provides a model of LVH that has significant treatment and research implications.

Plasma xanthine oxidase activity is related to increased sodium and left ventricular hypertrophy in resistant hypertension

BackgroundThe extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN). MethodsThe study group included persons with RHTN (n = 91), defined as a blood pressure > 140/90 mmHg on ≥ 3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (n = 19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses. ResultsXO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio. ConclusionsThese results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone.

Therapeutic Attenuation of Cardiac Remodeling After Acute Myocardial Infarction: A Conversation With Marc A. Pfeffer, MD, PhD.

Marc Pfeffer, MD, PhD, is the Dzau Professor of Medicine at Harvard Medical School; and Senior Physician, Cardiovascular Division at Brigham and Women’s Hospital. He was born in Brooklyn, NY, and obtained his MD and PhD at the University of Oklahoma. He married his late wife and research collaborator, Janice Pfeffer, PhD, in 1970. He has won numerous awards, including the American Heart Association James B. Herrick Award for Outstanding Achievements in Clinical Cardiology (2013) and the American Heart Association Distinguished Scientist Award (2015), the American College of Cardiology Distinguished Scientist Award (Translational Domain; 2017), and an Honorary Doctoral Degree from Sahlgrenska Academy, University of Gothenburg, Sweden (2014). ### Dr Rutherford asks: In the early 1970s, you, and your late wife Janice, studied adrenergic mechanisms and cardiac hypertrophy and ventricular function, as well, in spontaneously hypertensive rats. What led to your initial animal studies on acute myocardial infarction and your interest in the renin-angiotensin-aldosterone system? Dr Pfeffer replies: As graduate students in the Department of Physiology and Biophysics at the University of Oklahoma, my late wife, Janice, and I had the privilege to work under the tutelage of Edward D. Frohlich, MD, who is a pioneer in the hemodynamics of hypertension with a major emphasis on the response of the heart to the augmented workload imposed by hypertension. He was keenly interested in the functional consequences of developing left ventricular hypertrophy and obtained breeding stock of the newly developed Japanese strain of the SHR. We developed methods to assess hemodynamics and left ventricular function to compare normotensive with hypertensive rats during aging. We found a marked age-associated deterioration in contractile performance in the hypertensive rats that could be prevented by a variety of antihypertensive agents. Our studies of the longitudinal changes in ventricular structure and function in an animal model of genetic hypertension caught the attention of Eugene Braunwald, MD, who was organizing a Program Project Grant on the Pathophysiology of Left Ventricular Hypertrophy at the then Peter Bent Brigham Hospital. We moved to the Brigham in 1976 as his postdoctoral fellows (me as a medical intern) …

Left Ventricular Hypertrophy in ADPKD: Changing Demographics

Left ventricular hypertrophy (LVH) has been recognized as an early and important complication in patients with autosomal dominant polycystic kidney disease (ADPKD). LVH is associated with arrhythmias, congestive heart failure, and increased cardiac mortality. The increase in left ventricular mass is attributed to the compensatory myocardial remodeling associated with systemic hypertension, which is also highly prevalent in those with ADPKD. Several observational studies over the past decades using echocardiography have estimated the prevalence of LVH in adults to range from 20-40%. More recently, the HALT-PKD study detected an LVH prevalence of less than 4% using magnetic resonance imaging. Some of the differences may relate to the imaging modality, variations in parameters used to define LVH, or demographic differences in the study populations. Nonetheless, there likely exists a shift in the pathophysiology of LVH in patients with ADPKD. Factors that explain this evolving trend include earlier detection and treatment of hypertension, more rigorous blood pressure control, and an increased use of renin-angiotensin-aldosterone system (RAAS) antagonists. The use of RAAS inhibitors has been shown to induce regression of LVH, and this may continue to play an important role in the cardiovascular risk management in patients with ADPKD. The results of ongoing studies will help elucidate these relationships.

Biomarkers of Left Ventricular Hypertrophy and Remodeling in Blacks

Left ventricular (LV) hypertrophy, a marker for adverse cardiovascular events, is more common in blacks than in non-Hispanic whites. Mechanisms leading to LV hypertrophy and mediating its clinical sequelae in blacks are not fully understood. We investigated the associations of 39 candidate biomarkers in distinct biological pathways with LV mass and geometry in blacks. Participants included 1193 blacks (63±9 years of age; 72% women; 78% hypertensive) belonging to hypertensive sibships. LV mass was measured by transthoracic echocardiography and indexed to height.(2.7) LV geometry was categorized as normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Generalized estimating equations were used to assess associations of the 39 biomarkers with LV mass index after adjustment for age, sex, and conventional risk factors. After adjustment for potential confounders, log-transformed levels of the following biomarkers were independently associated with LV mass index: N-terminal pro-brain natriuretic peptide (β±SE=0.07±0.01 pg/mL; P<0.0001), mid-regional pro-atrial natriuretic peptide (β±SE=0.08±0.02 pmol/L; P<0.0001), mid-regional pro-adrenomedullin (β±SE=0.09±0.03 nmol/L; P=0.0006), C-terminal pro-endothelin (β± SE=0.05±0.02 pmol/L; P=0.0009), and osteoprotegerin (β±SE=0.07±0.02 pg/mL; P=0.0005) (β is for 1 log increase in biomarker level). The associations of these biomarkers with LV mass index were mainly due to their association with eccentric hypertrophy. Higher circulating levels of natriuretic peptides, adrenomedullin, endothelin, and osteoprotegerin were associated with increased LV mass index, providing insights into the pathophysiology of LV hypertrophy in blacks.

Common Variation at the 11-β Hydroxysteroid Dehydrogenase Type 1 Gene Is Associated With Left Ventricular Mass

Polymorphisms in 11-β hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) have been reported to be associated with obesity-related cardiovascular risk factors, such as type II diabetes and hypertension. Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular death associated with these factors but has significant additional heritability, the cause of which is undetermined. The 11β-HSD1 is believed to maintain tonic inhibition of the mineralocorticoid receptor in cardiomyocytes, and mineralocorticoid receptor activation is involved in the pathophysiology of LVH. We assessed the association between polymorphisms in the HSD11B1 gene and left ventricular mass (LVM) in 248 families ascertained through a proband with hypertension. LVM was measured by electrocardiography and echocardiography in 868 and 829 participants, respectively. Single-nucleotide polymorphisms (SNPs) tagging common variation in the HSD11B1 gene were genotyped by mass spectrometry. The rs846910 SNP, which lies in the flanking region 5' to exon 1B of HSD11B1, was associated with LVM both by electrocardiography (≈5% lower LVM per copy of the rare allele, P=0.02) and by echocardiography (≈10% lower LVM per copy of the rare allele, P=0.003). Genotype explained 1% to 2% of the population variability in LVM, or approximately 5% of the heritable fraction. There were no significant associations between any HSD11B1 SNP and blood pressure or body mass index that could have confounded the association with LVM. Genotype at HSD11B1 has a small, but significant effect on LVM, apparently independently of any effect on obesity-related traits. These findings suggest a novel action of 11β-HSD1 in the human cardiomyocyte, which may be of therapeutic importance.

Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy

Currently, a high carbohydrate/low fat diet is recommended for patients with hypertension; however, the potentially important role that the composition of dietary fat and carbohydrate plays in hypertension and the development of pathological left ventricular hypertrophy (LVH) has not been well characterized. Recent studies demonstrate that LVH can also be triggered by activation of insulin signaling pathways, altered adipokine levels, or the activity of peroxisome proliferator-activated receptors (PPARs), suggesting that metabolic alterations play a role in the pathophysiology of LVH. Hypertensive patients with high plasma insulin or metabolic syndrome have a greater occurrence of LVH, which could be due to insulin activation of the serine-threonine kinase Akt and its downstream targets in the heart, resulting in cellular hypertrophy. PPARs also activate cardiac gene expression and growth and are stimulated by fatty acids and consumption of a high fat diet. Dietary intake of fats and carbohydrate and the resultant effects of plasma insulin, adipokine, and lipid concentrations may affect cardiomyocyte size and function, particularly in the setting of chronic hypertension. This review discusses potential mechanisms by which dietary carbohydrates and fats ca affect cardiac growth, metabolism, and function, mainly in the context of pressure overload-induced LVH.

Involvement of the Nicotinamide Adenosine Dinucleotide Phosphate Oxidase Isoform Nox2 in Cardiac Contractile Dysfunction Occurring in Response to Pressure Overload

This study sought to examine the role of Nox2 in the contractile dysfunction associated with pressure-overload left ventricular hypertrophy (LVH). Reactive oxygen species (ROS) production is implicated in the pathophysiology of LVH. The nicotinamide adenosine dinucleotide phosphate oxidase isoform, Nox2, is pivotally involved in angiotensin II-induced hypertrophy but is not essential for development of pressure-overload LVH. Its possible impact on contractile function is unknown. The effects of aortic banding or sham surgery on cardiac contractile function and interstitial fibrosis were compared in adult Nox2-/- and matched wild-type (WT) mice. Banding induced similar increases in left ventricular (LV) mass in both groups. Banded Nox2-/- mice had better LV function than WT by echocardiography (e.g., fractional shortening 33.6 +/- 2.5% vs. 21.4 +/- 2.2%, p < 0.05). Comprehensive LV pressure-volume analyses also showed significant contractile dysfunction in banded WT compared with sham, whereas banded Nox2-/- mice had preserved function (e.g., maximum rate of rise of LV pressure: banded WT, 4,879 +/- 213; vs. banded Nox2-/-, 5,913 +/- 259 mm Hg/s; p < 0.05). Similar preservation of function was observed in isolated cardiomyocytes. The 24-h to 36-h treatment of banded WT mice with N-acetylcysteine resulted in recovery of contractile function. Cardiac interstitial fibrosis was significantly increased in banded WT but not Nox2-/- mice, together with greater increases in procollagen I and III mRNA expression. The Nox2 oxidase contributes to the development of cardiac contractile dysfunction and interstitial fibrosis during pressure overload, although it is not essential for development of morphologic hypertrophy per se. These data suggest divergent downstream effects of Nox2 on different components of the overall response to pressure overload.

Genes for left ventricular hypertrophy.

Left ventricular (LV) hypertrophy is very common, particularly among hypertensives. The presence of LV hypertrophy profoundly affects morbidity and mortality from cardiovascular diseases and stroke, and is now recognized as the most important predictor of chronic heart failure. Hypertension, obesity, and diabetes are important determinants of LV hypertrophy, but they fail to identify many individuals with the condition, suggesting that other factors, likely genetic in origin, play a role. Although much research has been undertaken to understand the causes of hypertrophy and the medical treatments that can lead to its regression, much remains unknown about its genetic basis. LV hypertrophy is considered a complex genetic disease, likely representing an interaction of several genes with the environment. The heritability of LV mass, measured as a quantitative trait, falls between 0.3 and 0.7 in different populations, suggesting it has a familial component. Genes encoding proteins involved in LV structure, as well as genes encoding cell signal transduction, hormones, growth factors, calcium homeostasis, substrate metabolism, and blood pressure are likely candidates for the development of common forms of LV hypertrophy. An overview of the pathophysiology of LV hypertrophy and dysfunction is provided, in addition to evidence of the genetic basis for LV hypertrophy in humans and animal models.

Are all antihypertensive drug classes equal in reducing left ventricular hypertrophy?

Left ventricular hypertrophy (LVH) is a major cardiovascular risk factor for morbidity and mortality. It is caused by arterial hypertension, although various hemodynamic and nonhemodynamic factors contribute to its development. Especially, the renin-angiotensin-aldosterone system is involved in the pathophysiology of LVH. The Treatment of Mild Hypertension study demonstrated that in mild essential hypertension, nonpharmacologic treatment is an effective tool for treating LVH. There are at least three major meta-analyses with several thousand patients examining the ability of antihypertensive drugs on the reversal of LVH. The results of these meta-analyses are very consistent. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers achieve significantly better results than b-blockers. The most recently published Losartan Intervention For Endpoint reduction in hypertension study confirmed the superiority of angiotensin receptor blockers against b-blockers in a large-scale prospective trial. It also proves for the first time that regression of LVH is associated with better cardiovascular outcome.

Genetic contributions to left ventricular hypertrophy.

Left ventricular (LV) hypertrophy is a common condition that profoundly affects morbidity and mortality from cardiovascular diseases, including myocardial infarction, congestive heart failure, and stroke. Noninvasive imaging methods have greatly expanded our ability to evaluate cardiac structural and functional characteristics, and enhanced our understanding of the natural history of LV hypertrophy. The etiology of LV hypertrophy is likely due to the effects of multiple genes interacting with other genes and the environment. Although hypertension is recognized as a strong determinant of LV hypertrophy, blood pressure explains only a limited amount of the interindividual variation in LV mass. Moreover, LV hypertrophy occurs in the absence of hypertension, and in some cases precedes its development. Genes encoding proteins involved in the structure of the LV, as well as genes encoding cell signal transduction, hormones, growth factors, calcium homeostasis, and blood pressure, are likely candidates for the development of common forms of LV hypertrophy. An overview of the epidemiology and pathophysiology of LV hypertrophy and dysfunction is provided, in addition to evidence of the genetic basis for LV hypertrophy.

Renin-angiotensin system gene polymorphisms and left ventricular hypertrophy. The case against an association.

There is accumulating evidence for association between genetic polymorphisms of components of the renin angiotensin system (RAS), especially angiotensin-converting enzyme (ACE), and cardiovascular disease. However, there is lack of agreement that the ACE polymorphism is associated with left ventricular hypertrophy (LVH) in hypertension. A possible paradigm for the development of LVH involves the ACE gene polymorphism influencing cardiac mass by an action on plasma and/or tissue levels of angiotensin II. Such a model has experimental support and provides the basis for examining the lack of agreement between studies. The finding of lack of association between RAS gene polymorphism and LVH may be due to methodological problems, differences in genetic background between populations, interactions between genetic variants of RAS components or to the model being inappropriate. Low predictability of ACE genotype markers for LVH together with conflicting reports on the influence of RAS genetic variants on angiotensin II production suggests that the simple RAS paradigm may not apply for hypertension. Further information on the nature of the link between the ACE polymorphism and ACE regulation as well as the relation between the RAS and pathophysiology of LVH is needed. At present there is insufficient evidence to accept ACE gene polymorphism as a susceptibility marker for LVH.

TCV−116, a newly developed angiotensin II receptor antagonist, induces regression of cardiac hypertrophy through suppression of the tissue renin-angiotensin system in spontaneously hypertensive rats

Previously, we reported that an orally active angiotensin II (Ang II) receptor antagonist Losartan induces regression of left ventricular hypertrophy with reduction in the tissue Ang II contents in spontaneously hypertensive rats (SHR). To further address the role of the cardiac renin-angiotensin system in the pathophysiology of hypertensive left ventricular hypertrophy, we examined the effects of TCV−116, a newly developed, highly specific nonpeptide Ang II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin I (Ang I) and Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with TCV-116 (1 mg/kg per day) lowered blood pressure markedly. TCV−116 reduced significantly the left ventricular weight by about 11% compared with control animals. The left ventricular Ang I and Ang II contents were lowered by TCV−116 (12.9±1.4 vs. 30.4±2.5 pg/tissue, control, p<0.01, for Ang II 15.1±0.6 vs. 18.7±0.4 pg/tissue, control, p#0.01, for Ang II), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and TCV−116-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content ( r=0.681, p<0.01). These results not only further support the view that cardiac Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension, but imply also that TCV−116 induces regression of hypertensive left ventricular hypertrophy through suppression of the tissue renin-angiotensin system.

Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 ± 0.9 pg/tissue; 21.9 ± 0.9 pg/tissue, c control, p < 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p < 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.

Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats.

To examine the role of the tissue renin-angiotensin system in left ventricular hypertrophy, converting enzyme inhibitors were administered orally to 12-week-old male spontaneously hypertensive rats (SHR) for 4 weeks, and cardiac tissue angiotensin II was measured. Treatment with enalapril (10 mg/kg per day) and trandolapril (1 mg/kg per day) lowered systolic blood pressure, left ventricular weight and left ventricular angiotensin II content. Plasma angiotensin II concentration was increased by the treatment with enalapril whereas trandolapril did not cause any change. There was significantly positive correlation between left ventricular weight and angiotensin II content. Because angiotensin II promotes cell proliferation, these results suggest that cardiac tissue angiotensin II, rather than circulating angiotensin II, may account for the pathophysiology of left ventricular hypertrophy in SHR.

Biochemistry and Pharmacology of the Renin-Angiotensin System

Knowledge of the structure, function and distribution of the components of the renin-angiotensin-aldosterone system (RAS) and the integrated physiological role of this hormonal system is rapidly increasing, although many questions remain unanswered. The primary structure and localisation of RAS such as renin, prorenin, angiotensinogen, angiotensin-converting enzyme (ACE) and the angiotensins have now been described. Moreover, the genes for the production of renin and ACE have been cloned and their nucleotide sequences determined. In addition to its well-established role as a circulating endocrine system, the renin-angiotensin system has more recently been ascribed a local autocrine or paracrine function. Physiologically active levels of components such as renin and angiotensin, or their messenger RNAs, have been identified in several extrarenal tissues, notably the central nervous system. The components of such tissue renin-angiotensin systems may be derived from de novo tissue synthesis and/or from the circulation by endocytosis. Angiotensin has pharmacological actions on a wide range of body tissues, including the kidney, heart, brain, gastrointestinal tract and reproductive organs. In many of these locations, angiotensin receptors have been isolated and characterised. The most firmly established roles of angiotensin are the control of blood pressure and local blood flow, and in salt and water homeostasis; the physiological significance of many of angiotensin's tissue effects is unknown. In some areas of clinical interest, such as the pathophysiology of left ventricular hypertrophy, ACE inhibitors are very useful for elucidating the possible influences of the renin-angiotensin system.

Left ventricular hypertrophy in hypertension. Prevalence and relationship to pathophysiologic variables.

In less than a decade since development of echocardiographic measurement of left ventricular muscle mass, studies using this technique have provided considerable information about the prevalence and pathophysiology of left ventricular hypertrophy in human hypertension. Increased left ventricular mass has been found in a significant minority of patients with systemic hypertension, with the exact prevalence dependent both on how a population is selected and on the sex, race, and possibly age composition of its members. All published studies have reported that left ventricular hypertrophy is more closely related to blood pressure recorded in the patient's natural setting during normal activity or exercise-whether measured by portable recorder or home manometer-than to blood pressure measured by the physician. In addition, studies indicate that the classic hypertensive abnormalities of concentric left ventricular hypertrophy and increased peripheral resistance are interrelated, while left ventricular hypertrophy is absent in a subgroup of patients with mild essential hypertension who exhibit high cardiac output and evidence of supernormal myocardial contractility. Conversely, the left ventricular functional response to exercise is inversely related to the degree of hypertrophy. High levels of blood viscosity, which would tend to blunt the reduction in peripheral resistance expected during sleep or exercise, have also been associated with left ventricular hypertrophy in patients with essential hypertension. Echocardiographic studies have provided evidence both for and against the hypothesis that activity of the sympathetic or reninangiotensin systems plays a direct role in causing hypertensive cardiac hypertrophy. These findings demonstrate the useful role that echocardiographic assessment of left ventricular structure and function may play in hypertension research.