Jasmina Varagic

Diastolic dysfunction in hypertension.

Heart failure is one of the most common causes of cardiovascular morbidity and mortality, and hypertension is the most common cause of cardiac failure. Recent studies have shown that isolated diastolic dysfunction very often accompanies hypertensive heart disease. Ventricular diastolic function may be divided into an active relaxation phase and a passive compliance period. These two components have been investigated invasively, and they remain the gold standards for the study of diastolic function. However, in the routine clinical setting, echocardiographic and Doppler techniques are most useful for evaluating ventricular filling. Thus, analysis of E and A waves of mitral flow have provided important and useful information. Unfortunately, these indices depend on too many factors. Newer indices obtained from ventricular time intervals, tissue Doppler imaging, and color M-mode echocardiography have enhanced the means to assess diastolic function. In addition, new methods including MRI and cine CT have also provided better understanding of left ventricular filling in hypertension. Using these techniques, diastolic dysfunction has been found to be common in patients with hypertension, even before left ventricular hypertrophy is demonstrable and before hypertension in young, normotensive male offspring of hypertensive parents has developed. Furthermore, it has been made clear recently that myocardial ischemia and fibrosis are two important factors associated with diastolic dysfunction in hypertension.

The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function

The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1-7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1-7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease.

Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models.

OBJECTIVES The goal of this research was to study the effects of rosuvastatin on systemic and regional hemodynamics in two hypertensive rat models, one genetic, the other induced with inhibition of nitric oxide synthesis. BACKGROUND Rats naturally have low cholesterol levels that are generally unaffected by statin therapy, thus providing a good model for studying cardiovascular effects unrelated to lipid metabolism. METHODS Male 20-week-old spontaneously hypertensive rats (SHR) were divided into five groups and given either vehicle or 1, 5, 10, and 20 mg/kg of rosuvastatin daily, by gavage, for 12 weeks. Wistar-Kyoto rats (WKY) were divided into four groups; the first received vehicle and the second rosuvastatin (20 mg/kg). The third and fourth groups were given N(omega)-nitro-L-arginine (L-NAME) (15 mg/kg/day) in drinking water, and the fourth group received rosuvastatin daily, 20 mg/kg for six weeks. At the end of the respective treatments, systemic and organ hemodynamics (radionuclide-labeled microspheres) and cardiovascular mass were determined in all rats. RESULTS Rosuvastatin reduced arterial pressure in SHR rats, but not in WKY/L-NAME rats. Total peripheral resistance decreased with rosuvastatin in both hypertensive models, whereas cardiac output increased with rosuvastatin in WKY/L-NAME rats. Neither cardiac nor aortic mass was changed. Regional hemodynamics improved with rosuvastatin in both hypertensive models, as evidenced by increased blood flows and decreased vascular resistances. No effect on plasma lipids was observed. CONCLUSIONS These results showed that rosuvastatin reduced arterial pressure in genetic hypertension and improved systemic and regional hemodynamics in both hypertensive models independently of cholesterol levels. Thus rosuvastatin improved systemic and regional hemodynamics by reducing vascular resistance.

Pharmacologic agents on cardiovascular mass, coronary dynamics and collagen in aged spontaneously hypertensive rats.

OBJECTIVE To determine whether antihypertensive treatment could alter hypertension and age-related progressive impairment of coronary hemodynamics and cardiac fibrosis in aged spontaneously hypertensive rats (SHR). DESIGN Old SHR were given their respective therapy for 3 months. To differentiate between hypertension and age-related changes, a comparison was made between left and right ventricular indices since the right ventricle was not exposed to pressure overload. METHODS Male, 65-week-old spontaneously SHR were divided into three groups and were given either vehicle, felodipine (30 mg/kg per day) or enalapril (30 mg/kg per day). After 12 weeks of the respective treatments, systemic and coronary hemodynamics (radionuclide-labelled microspheres), right and left ventricular and aortic mass indices, and right and left ventricular hydroxyproline concentrations (an estimate of collagen) were determined. RESULTS Arterial pressure and total peripheral resistance were reduced to the same extent in SHRs treated with either felodipine or enalapril; however, compared to the control rats, enalapril was more effective in reducing left ventricular and aortic mass indices. Both agents also improved coronary hemodynamics of both ventricles in aged SHR but enalapril was more effective as indicated by a greater increase in coronary flow reserve and a greater decrease in minimal coronary vascular resistance. Furthermore, enalapril but not felodipine reduced left ventricular hydroxyproline concentration; and right ventricular hydroxyproline concentration increased with felodipine but remained unchanged with enalapril. CONCLUSIONS Both enalapril and felodipine ameliorated adverse cardiovascular effects of hypertension in the aged SHRs within 12 weeks, as demonstrated by reduced arterial pressure, diminished left ventricular mass, and improved coronary hemodynamics. Enalapril also decreased aortic mass and left ventricular collagen concentration and appeared to be more effective in improving coronary hemodynamics than felodipine, possibly as a result, in part, of reduced myocardial fibrosis.

Chymase-Dependent Generation of Angiotensin II from Angiotensin-(1-12) in Human Atrial Tissue

Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified 125I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. 125I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, 125I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of 125I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of 125I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that 125I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol×min−1×mg−1, n = 9) from 125I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min−1×mg−1). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12).

Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy.

We examined the effects of 48 h bilateral nephrectomy on plasma and cardiac tissue expression of angiotensin-(1-12) [ANG-(1-12)], ANG I, and ANG II in adult Wistar-Kyoto rats to evaluate functional changes induced by removing renal renin. The goal was to expand the evidence of ANG-(1-12) being an alternate renin-independent, angiotensin-forming substrate. Nephrectomy yielded divergent effects on circulating and cardiac angiotensins. Significant decreases in plasma ANG-(1-12), ANG I, and ANG II levels postnephrectomy accompanied increases in cardiac ANG-(1-12), ANG I, and ANG II concentrations compared with controls. Plasma ANG-(1-12) decreased 34% following nephrectomy, which accompanied 78 and 66% decreases in plasma ANG I and ANG II, respectively (P < 0.05 vs. controls). Contrastingly, cardiac ANG-(1-12) in anephric rats averaged 276 +/- 24 fmol/mg compared with 144 +/- 20 fmol/mg in controls (P < 0.005). Cardiac ANG I and ANG II values were 300 +/- 15 and 62 +/- 7 fmol/mg, respectively, in anephric rats compared with 172 +/- 8 fmol/mg for ANG I and 42 +/- 4 fmol/mg for ANG II in controls (P < 0.001). Quantitative immunofluorescence revealed significant increases in average grayscale density for cardiac tissue angiotensinogen, ANG I, ANG II, and AT(1) receptors of WKY rats postnephrectomy. Faint staining of cardiac renin, unchanged by nephrectomy, was associated with an 80% decrease in cardiac renin mRNA. These changes were accompanied by significant increases in p47(phox), Rac1, and Nox4 isoform expression. In conclusion, ANG-(1-12) may be a functional precursor for angiotensin peptide formation in the absence of circulating renin.

Crosslink breakers: a new approach to cardiovascular therapy.

Purpose of review Advanced glycation end-products accumulate on body proteins with aging, and their formation is greatly enhanced with rising plasma glucose level. Advanced glycation end-products bond together and, consequently, increase protein crosslinking. In the circulatory system, increased collagen crosslinking caused by advanced glycation end-products increases cardiovascular stiffness as well as the risk for cardiovascular morbidity and mortality. A breaker of advanced glycation end-products—related crosslinks, ALT-711, has been recently discovered. This review summarizes the latest evidence that breaking collagen crosslinks may be an efficient new therapeutic approach to the adverse cardiovascular and renal consequences of aging and diabetes. Recent findings The results of recent studies clearly demonstrated that ALT-711, a breaker of advanced glycation end-products—related protein crosslinks, ameliorated the adverse cardiovascular and renal changes associated with aging, diabetes, and hypertension. In diabetic animals, ALT-711 improved left ventricular function, decreased ventricular collagen content and improved its solubility, reduced aortic stiffness, ameliorated diabetic nephrosclerosis, and improved renal function. In older spontaneously hypertensive rats, it reduced left ventricular mass and collagen content, reduced proteinuria, and extended survival. The results of recent studies also indicated that the effects of crosslinks breakers may be mediated in part via reduction in oxidative stress and profibrotic cytokines. Summary The results of experimental studies and one clinical trial have clearly established the usefulness of ALT-711 in the therapy of the cardiovascular and renal disorders associated with aging, diabetes, and hypertension. Thus, breaking advanced glycation end-products-related collagen crosslinks has emerged as a new approach to cardiovascular therapy.

An evolving story of angiotensin-II-forming pathways in rodents and humans.

Lessons learned from the characterization of the biological roles of Ang-(1-7) [angiotensin-(1-7)] in opposing the vasoconstrictor, proliferative and prothrombotic actions of AngII (angiotensin II) created an underpinning for a more comprehensive exploration of the multiple pathways by which the RAS (renin-angiotensin system) of blood and tissues regulates homoeostasis and its altered state in disease processes. The present review summarizes the progress that has been made in the novel exploration of intermediate shorter forms of angiotensinogen through the characterization of the expression and functions of the dodecapeptide Ang-(1-12) [angiotensin-(1-12)] in the cardiac production of AngII. The studies reveal significant differences in humans compared with rodents regarding the enzymatic pathway by which Ang-(1-12) undergoes metabolism. Highlights of the research include the demonstration of chymase-directed formation of AngII from Ang-(1-12) in human left atrial myocytes and left ventricular tissue, the presence of robust expression of Ang-(1-12) and chymase in the atrial appendage of subjects with resistant atrial fibrillation, and the preliminary observation of significantly higher Ang-(1-12) expression in human left atrial appendages.

Advances in the renin angiotensin system focus on angiotensin-converting enzyme 2 and angiotensin-(1-7).

The contribution of the renin angiotensin system to physiology and pathology is undergoing a rapid reconsideration of its mechanisms from emerging new concepts implicating angiotensin-converting enzyme 2 and angiotensin-(1-7) as new elements negatively influencing the vasoconstrictor, trophic, and pro-inflammatory actions of angiotensin II. This component of the system acts to oppose the vasoconstrictor and proliferative effects on angiotensin II through signaling mechanisms mediated by the mas receptor. In addition, a reduced expression of the vasodepressor axis composed by angiotensin-converting enzyme 2 and angiotensin-(1-7) may contribute to the expression of essential hypertension, the remodeling of heart and renal function associated with this disease, and even the physiology of pregnancy and the development of eclampsia.

The role of sodium in hypertension is more complex than simply elevating arterial pressure

Excessive salt intake exacerbates hypertension and further increases left-ventricular mass in clinical essential and experimental hypertension. Additionally, a growing body of evidence strongly suggests that high dietary salt loading exerts detrimental cardiac effects independently of its hemodynamic load. The clinical evidence of cardiac structural and functional alterations associated with salt is, however, scarce. In order to explore the purported beliefs in humans, in this review we draw on our experimental studies in naturally occurring hypertension and discuss the clinical implications of the nonhemodynamic mechanisms underlying these salt-related changes.