Subliminal editorial conundra confounding publication of multicenter trials.
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Conflict of Interest↗
Biomedical subjects
Edward D Frohlich
Publications and source records attributed to Edward D Frohlich.
Left ventricular hypertrophy: a "factor of risk": mass is reversible, but is the risk?
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Angiotensin-Converting Enzyme Inhibitors↗
Obesity and suppressed B-type natriuretic peptide levels in heart failure.
OBJECTIVES: This investigation evaluated the relationship between obesity and B-type natriuretic peptide (BNP) in heart failure. BACKGROUND: Obesity is a major risk factor for the development of heart failure, but the precise mechanisms remain uncertain. Physiologically, natriuretic peptides and lipolysis are closely linked. METHODS: A total of 318 patients with heart failure were evaluated between June 2001 and June 2002. Levels of BNP were compared in obese (body mass index [BMI] > or =30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with respect to New York Heart Association functional class and lean body weight-adjusted peak aerobic oxygen consumption. In a subset of 36 patients, plasma levels of tumor necrosis factor-alpha, interleukin-6, and soluble intercellular adhesion molecule-1 were measured. RESULTS: The population's BMI was 29.4 +/- 6.6 kg/m(2); 24% were lean (BMI <25 kg/m(2)), 31% overweight (BMI > or =25 to 29.9 kg/m(2)), and 45% obese (BMI > or =30 kg/m(2)). Obese patients were younger, more often African American, and more likely to have a history of antecedent hypertension, but less likely to have coronary artery disease and with only a trend toward diabetes mellitus. Levels of BNP were significantly lower in obese than in nonobese subjects (205 +/- 22 and 335 +/- 39 pg/ml, respectively; p = 0.0007), despite a similar severity of heart failure and cytokine levels. Multivariate regression analysis identified BMI as an independent negative correlate of BNP level. There were no differences in emergency department visits, heart failure hospitalization, or death between the obese and nonobese patients at 12-month follow-up. CONCLUSIONS: Our investigation indicates that a state of reduced natriuretic peptide level exists in the obese individual with heart failure.
Adult↗
Cardiac structural and functional responses to salt loading in SHR.
Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (V(E)/V(A)), and slower propagation velocity of E wave (V(P)). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased V(E)/V(P), an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.
Aging↗
Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of glomerular dynamics in L-NAME/SHR model.
BACKGROUND: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. METHODS: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 +/- 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 +/- 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). RESULTS: L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 +/- 26.5 vs. 51.9 +/- 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 +/- 9 vs. 29 +/- 9 score/100 glomeruli, p < 0.01; 116 +/- 18 vs. 41 +/- 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 +/- 0.07 vs. 0.39 +/- 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. CONCLUSION: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.
Animals↗
Cardiovascular and renal effects of a collagen cross-link breaker (ALT 711) in adult and aged spontaneously hypertensive rats.
BACKGROUND: Increased formation of advanced glycosylation end-products on body proteins is a consequence of aging and leads to exaggerated collagen cross-linking eventually increasing cardiovascular stiffness. This study reports our initial inquires into the cardiovascular and renal effects of a cross-link breaker (ALT-711) in aged spontaneously hypertensive rats (SHR). METHODS AND RESULTS: The first experiment, in 45-week-old SHR, showed that (among four doses) the dose of 1 mg/kg/d of ALT-711 given for 4 months was most effective in reducing left ventricular and aortic mass indexes. ALT-711 also reduced left ventricular hydroxyproline concentration (5.8 +/- 0.2 v 5.1 +/- 0.3 mg/g in controls, P < .05); however, it did not affect systemic or regional hemodynamics. In older SHR, ALT-711 (1 mg/kg/d) reduced (P < .05) systolic pressure (tail-cuff) (from 203 +/- 3 mm Hg at outset to 187 +/- 3 mm Hg at 8 weeks). Systolic pressure remained unchanged in placebo-treated rats. In addition, left ventricular index (3.09 +/- 0.10 v 3.44 +/- 0.05 mg/g) and aortic mass index (1.54 +/- 0.04 v 1.74 +/- 0.05 mg/mm) were reduced by ALT-711. In the third experiment, 1-year-old SHR were given vehicle or ALT-711 (1 mg/kg/d) or placebo until natural death. After 3 months, ALT-711 markedly reduced urinary protein excretion (74.5 +/- 8.6 v 135.4 +/- 11.8 mg/24 h). Echocardiographic studies, performed at the outset and after 3 and 6 months, revealed two changed indexes. Left ventricular end-diastolic diameter increased more in control than in ALT rats, whereas E-wave deceleration time decreased more in control than in ALT rats. CONCLUSIONS: Therapy with ALT-711 exerted beneficial cardiovascular and renal effects in aged SHR, improving systolic pressure, left ventricular mass, geometry, and hydroxyproline content while reducing urinary protein excretion.
Animals↗
Target organ involvement in hypertension: a realistic promise of prevention and reversal.
The major message from this discussion is that the end points from hypertensive disease (stroke, CHD, and hypertensive emergencies) are now preventable. Cardiac failure and ESRD, however, two exceedingly common end points from long-standing hypertension, remain as major disabilities and causes of death. The former is the most common cause of hospitalization in industrialized societies; hypertension and diabetes mellitus are the most common causes of the latter. The mechanisms of risk of these target organ diseases is not LVH per se, or the elevated arterial pressure alone in the kidney, but the coronary and renal ischemia, organ fibrosis, and, perhaps, apoptosis. Present day therapy now can effectively reverse these costly (economically and by human suffering) complications. Recent experimental studies suggest that, when used early enough, these newer pharmacologic agents may even prevent their occurrences and consequences. The very practical lesson from these experiences is that early detection and treatment of hypertension, effective control of arterial pressure, and the suppression of the underlying disease mechanisms markedly reduce the now increasing prevalence of both cardiac and renal failure.
Aging↗
Insulin and insulin resistance: impact on blood pressure and cardiovascular disease.
Cardiovascular disease is a major cause of mortality in individuals with diabetes. Many factors, including hypertension, contribute to the high prevalence of CVD in this population. Hypertension occurs approximately twice as frequently in patients with diabetes compared with patients without diabetes. Conversely, recent data suggest that hypertensive persons are more likely to develop diabetes than normotensive persons. In addition, up to 75% of CVD in patients with diabetes may be attributed to hypertension, leading to recommendations for more aggressive blood pressure control (ie, < 130/85 mm Hg) in persons with coexistent diabetes and hypertension. Increasing obesity further contributes to both diabetes and hypertension and significantly increases CVD morbidity and mortality. Other important risk factors for CVD in these patients include atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and diabetic cardiomyopathy. The current knowledge regarding these risk factors has been reviewed, placing special emphasis on the metabolic syndrome, hypertension, microalbuminuria, and the role of obesity in these disorders. Although not discussed in detail, it is acknowledged that both hygienic measures (weight loss and aerobic exercise) and treatment strategies that include aspirin, statins, INS sensitizers, and antihypertensive agents that reduce renin-angiotensin-aldosterone system activity have been shown to reduce inflammation, coagulation abnormalities, endothelial function, proteinuria, and in some cases reduce CVD and renal disease progression. Additional therapeutic agents are currently being developed specifically to improve INS sensitivity and other CVD risk factors that are components of the cardiometabolic syndrome.
Angiotensin II↗
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.
Animals↗
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.
Aging↗
Collagen cross-link breakers: a beginning of a new era in the treatment of cardiovascular changes associated with aging, diabetes, and hypertension.
Aging, diabetes, and hypertension are conditions in which arterial and myocardial stiffness is increased. Increased arterial stiffness is manifested by an increased systolic arterial pressure, pulse pressure and pulse wave velocity, whereas increased myocardial stiffness is manifested by impaired left ventricular diastolic filling. Moreover, increased arterial stiffness increases cardiac workload, further aggravating already existing adverse changes in left ventricular structure and function. Indeed, studies in human beings have clearly shown that increased cardiovascular stiffness is a reliable predictor of cardiovascular morbidity and mortality. Increased cardiovascular stiffness is usually attributed to the development of fibrosis (i.e., accumulation of collagen). It has also been recognized that the increased cardiac and vascular stiffness may be due to increased collagen cross-linking due to the formation of advanced glycosylation end-products (AGEs). In agreement with this notion is the finding that an inhibitor of AGEs formation improves vascular stiffness in diabetic rats. More recently, cross-link breakers have been developed, and the beneficial effects of one such agent (ALT-711) have been shown in experimental and clinical settings. This report briefly summarizes age related changes in cardiovascular structure and function and describes results of experimental and clinical studies involving collagen cross-link breakers.
Aging↗
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.
Animals↗
Long-term left ventricular echocardiographic follow-up of SHR and WKY rats: effects of hypertension and age.
Long-term follow-up of left ventricular (LV) function using echocardiography has not been reported and, in this study, was carried out in normotensive (WKY) rats and spontaneously hypertensive rats (SHR). In 10 WKY rats and SHR, LV diastolic and systolic diameter (LVEDD and LVSD), shortening fraction (SF), and weight (LVW) were determined at 8, 15, 20, 35, and 80 wk of age. The ratio of early to late mitral flow and mitral annulus velocity (VE/VA and Em/Am), isovolumic relaxation time (IVRT), deceleration time of the E wave (DTE), Tei index, and mitral flow propagation velocity (Vp) were measured. No difference in LVEDD was found between SHR and WKY rats; however, LVEDD was increased at 80 wk in both strains. SF decreased slightly in old WKY rats. LVW progressively increased from 20 to 80 wk in both strains and was greater in SHR. VE/VA and Em/Am decreased at 80 wk in WKY rats. LV relaxation (IVRT, Tei index, and Vp) was progressively impaired in SHR compared with WKY rats. LV compliance (DTE) was altered in old SHR. Echocardiography permitted a long follow-up of LV function in SHR and WKY rats. Ventricular relaxation was impaired early in the life of SHR and progressed with aging. Furthermore, LV compliance was altered, but systolic function remained unchanged, in old SHR. In contrast, relaxation and SF were only slightly altered in old WKY rats, suggesting that pressure-related changes in LV function were the dominant features in the SHR.
Aging↗
Renoprotective effects of omapatrilat are mediated partially by bradykinin.
AIM: To investigate the effects of omapatrilat on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathological changes as well as the participation of the bradykinin B2 receptor in WKY, SHR, and L-NAME/SHR rats. METHODS: Eight groups of 17-week-old rats were examined using renal micropuncture techniques and histopathological analyses after 3 weeks of treatment: group 1, WKY control; group 2, WKY+omapatrilat (40 mg/kg/day); group 3, SHR control; group 4, SHR+omapatrilat; group 5, SHR+L-NAME (50 mg/l); group 6, SHR+L-NAME+omapatrilat; group 7, SHR+L-NAME for 3 weeks followed by omapatrilat for a subsequent 3 weeks, and group 8, SHR+L-NAME+omapatrilat+bradykinin antagonist icatibant (500 microg/kg/day). RESULTS: In WKY and SHR, omapatrilat significantly reduced the mean arterial pressure, increased effective renal blood flow and single nephron plasma flow associated with reduced glomerular arteriolar resistances. Furthermore, omapatrilat prevented and reversed L-NAME induced urinary protein excretion, glomerular and arteriolar injuries, glomerular morphometric alterations, and glomerular apoptosis (at least, p < 0.05). Icatibant partially inhibited these beneficial effects of omapatrilat. CONCLUSION: Omapatrilat provided potent antihypertensive and renoprotective actions, which were mediated, in part, by bradykinin.
Angiotensin-Converting Enzyme Inhibitors↗
Treating hypertension - what are we to believe?
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Angiotensin-Converting Enzyme Inhibitors↗
Clinical implications of local renin-angiotensin-aldosterone systems.
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Cardiovascular Diseases↗
Management of diabetic and hypertensive cardiovascular disease.
The simultaneous occurrence of essential hypertension and diabetes mellitus is exceedingly common. In recent years the treatment of the cardiovascular and renal complications has not only become more specific but more effective. The evidence-based medicine data have been provided through many large multicenter studies and strongly support the promise not only of effective treatment in retarding the progression of target-organ involvement, but also the potential of reversal. These dramatic therapeutic improvements have been made possible by wedding the involved pathophysiologic disease mechanisms with the actions of pharmacologic agents. Inherent in this concept is the promise of retarding the development of the cardiovascular and renal morbid events and also reducing their associated mortal endpoints.
Adrenergic alpha-Antagonists↗