G. Riegger

Angiotensin II–Induced Growth Responses in Isolated Adult Rat Hearts Evidence for Load-Independent Induction of Cardiac Protein Synthesis by Angiotensin II

Cardiac myocyte hypertrophy often occurs in response to both hemodynamic and neurohumoral factors. To study whether activation of the renin-angiotensin system by itself may induce a cardiac growth response, the acute effects of angiotensin II on cardiac protein synthesis were studied in isolated rat hearts. New protein synthesis in isolated buffer-perfused adult rat hearts was measured by incorporation of [3H]phenylalanine into cardiac proteins during a 3-hour perfusion protocol. Angiotensin II (1 x 10(-8) mol/L), administered alone or in combination with the alpha 1-blocker prazosin (1 x 10(-7) mol/L), stimulated protein synthesis in both ventricles. The rate of [3H]phenylalanine incorporation into cardiac proteins was 3.9-fold (P < .005) and 2.6-fold (P < .01) higher in angiotensin II-perfused (n = 6) than in vehicle-perfused (n = 6) left and right ventricles, respectively. The induction of new protein synthesis by angiotensin II was blocked by the angiotensin II type 1 (AT1) receptor antagonist losartan (1 x 10(-7) mol/L, n = 5). To study the pathways of angiotensin signal transduction, protein kinase C (PKC)-epsilon as well as cardiac c-fos and c-jun mRNA levels were analyzed. Angiotensin II (1 x 10(-8) mol/L, n = 20) resulted in a transient translocation of PKC-epsilon from the cytosol to the cellular membrane. However, compared with phorbol ester stimulation (phorbol 12-myristate 13-acetate [PMA], 1 x 10(-7) mol/L; n = 20), angiotensin II effects on PKC translocation were significantly less pronounced and required a more prolonged stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blockade of the Renin-Angiotensin System in Cardiac Pressure-Overload Hypertrophy in Rats

Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca(2+)-ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload.

The angiotensinogen T235 variant and the use of antihypertensive drugs in a population-based cohort

Variants of the angiotensinogen gene may increase the risk of developing arterial hypertension, but their effect on the use of antihypertensive medication in the general population remains unclear. Thus, we determined T174M and M235T allele status and angiotensinogen plasma levels in a cross-sectional sample of 634 middle-aged subjects (48.4% men) from the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort study. We found no association between T174M allele status and angiotensinogen levels, blood pressure, or use of antihypertensive drugs. In contrast, multivariate analysis revealed that individuals who carried at least one copy of the T235 allele (n = 418) had higher systolic and diastolic pressures (P = .007) and .008, respectively) and were more likely to use an antihypertensive drug (1.6-fold risk, P = .04) than homozygotes for the M235 allele (n = 216). The likelihood of taking two or more antihypertensive medications was 2.1-fold higher in carriers of the T235 allele (P = .02). Overall, 22.5% of all antihypertensive drugs taken appeared to be attributable to the excess risk associated with this allele. These associations were replicated in two previous surveys carried out on the same individuals over 10 years. Furthermore, the T235 allele was related to higher angiotensinogen plasma levels [15.5 +/- 0.31 versus 16.5 +/- 0.15 (nmol/L)/L in homozygotes for the M235 and T235 alleles, respectively; P < .01], which were also related to systolic pressure (P = .03) and more intensive antihypertensive medication (P = .03). We conclude that the angiotensinogen T235 allele accounts for a substantial proportion of antihypertensive drug use in this middle-aged, population-based group of white subjects.

Evidence for a Vasopressin System in the Rat Heart

Traditionally, a hypothalamo-neurohypophysial system is thought to be the exclusive source of arginine vasopressin (AVP), a potent antidiuretic, vasoconstricting, and growth-stimulating neuropeptide. We have identified de novo synthesis of AVP in the heart as well as release of the hormone into the cardiac effluents. Specifically, molecular cloning of sequence tags amplified from isolated, buffer-perfused, and pressure-overloaded rat hearts allowed the detection of cardiac AVP mRNA. Subsequent experiments revealed a prominent induction of AVP mRNA (peak at 120 minutes, 59-fold, P<0. 01 versus baseline) and peptide (peak at 120 minutes, 11-fold, P<0. 01 versus baseline) in these isolated hearts. Newly induced vasopressin peptide was localized most prominently to endothelial cells and vascular smooth muscle cells of arterioles and perivascular tissue using immunohistochemistry. In addition to pressure overload, nitric oxide (NO) participated in these alterations, because inhibition of NO synthase by Nomega-nitro-L-arginine methyl ester markedly depressed cardiac AVP mRNA and peptide induction. Immediate cardiac effects related to cardiac AVP induction in isolated, perfused, pressure-overloaded hearts appeared to be coronary vasoconstriction and impaired relaxation. These functional changes were observed in parallel with AVP induction and largely prevented by addition of a V1 receptor blocker (10(-8) mol/L [deamino-Pen1, O-Me-Tyr2, Arg8]-vasopressin) to the perfusion buffer. Even more interesting, pressure-overloaded, isolated hearts released the peptide into the coronary effluents, offering the potential for systemic actions of AVP from cardiac origin. We conclude that the heart, stressed by acute pressure overload or NO, expresses vasopressin in concentrations sufficient to cause local and potentially systemic effects.

Gender specific differences in left ventricular adaptation to obesity and hypertension.

Recent reports indicate that the prognostic implications of left ventricular hypertrophy (LVH) are more profound in women than in men. The prognosis of LVH is also related to the underlying geometric pattern. We therefore assessed the relation of separate and concurrent influences of obesity and hypertension on gender- specific patterns of LV adaptation. Five hundred and twenty participants of a community-based study (aged 52 to 67 years) were examined by M-mode echocardiography. Study subjects were divided into four groups: normals, obese, hypertensives, and subjects presenting with both obesity and hypertension. The groups were compared for various measures of left ventricular mass (LVM) and geometry. Relative to normal subjects, the increments in wall thickness, ventricle diameters, and LVM were all significant and of similar magnitude for obese men and women. Likewise, hypertensive men and women showed similar relative increments of LVM and wall thickness but no changes in end-diastolic internal diameters. Accordingly, obesity was predominantly associated with eccentric hypertrophy (men ± 14%, women +17%, P<0.05 vs normals) and hypertension with concentric hypertrophy (men +16%, women +30%, P<0.01 vs normals). Women with concurrent obesity and hypertension presented with a further increase of LVM and wall thickness above values in the merely obese or hypertensive (P<0.001) and they displayed lvh more frequently than only obese or hypertensive women (P<0.05). we conclude that the hearts of postmenopausal women respond more susceptibly to the concurrence of hypertension and obesity. in particular the prognostically less favourable concentric lvh is a common finding. our study may help to explain the higher risk associated with lvh in women.

Marked suppression of renin levels by β-receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from β-blockade

Abstract. Holmer SR, Hengstenberg C, Mayer B, Engel S, Löwel H, Riegger GAJ, Schunkert H (University of Regensburg, Regensburg, and GSF‐Institut für Epidemiologie, Munich‐Neuherberg, Germany). Marked suppression of renin levels by β‐receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from β‐blockade. J Intern Med 2001; 249: 167–172.

Cardiovascular Magnetic Resonance for Direct Assessment of Anatomic Regurgitant Orifice in Mitral Regurgitation

Background—In patients with mitral regurgitation (MR), assessment of the severity of valvular dysfunction is crucial. Recently, regurgitant orifice area has been proposed as the most useful indicator of the severity of MR. The purpose of our study was to determine whether planimetry of the anatomic regurgitant orifice (ARO) in patients with MR is feasible by cardiovascular magnetic resonance (CMR) and correlates with invasive catheterization and echocardiography effective regurgitant orifice [ECHO-ERO] by proximal isovelocity surface area. Methods and Results—Planimetry of ARO was performed with a 1.5-T CMR scanner using a breath-hold balanced gradient echo sequence true fast imaging with steady state precession (TrueFISP). CMR planimetry of ARO was possible in 35 of 38 patients and was closely correlated with angiographic grading (r=0.84, P<0.0001). In patients with MR grade ≥III on catheterization, CMR-ARO (0.60±0.29 cm2 versus 0.30±0.19 cm2, P<0.0001) as well as ECHO-ERO (0.49±0.17 cm2 versus 0.27±0.10 cm2) were significantly elevated in comparison with MR grade <III. Further, CMR-ARO was closely correlated to CMR regurgitant fraction and volume (r=0.90 and r=0.91, P<0.0001, respectively) and catheterization regurgitant fraction and volume (r=0.86 and 0.83, P<0.0001, respectively). The correlation between CMR-ARO and ECHO-ERO was 0.81 (P<0.0001) and CMR slightly overestimated ECHO-ERO by 0.06 cm2 (P<0.05). As assessed by receiver operating characteristic analysis, CMR-ARO at a threshold of 0.40 cm2 detected MR grade ≥III as defined by catheterization, with a sensitivity and specificity of 94% and 94%, respectively. Conclusion—CMR planimetry of the anatomic mitral regurgitant lesion in patients with MR is feasible and permits quantification of MR with good agreement with the accepted invasive and noninvasive methods. Direct measurement by CMR is a promising new method for the precise assessment of ARO area and the severity of MR.

[Epidemiology of left ventricular systolic dysfunction in the general population of Germany: results of an echocardiographic study of a large population-based sample].

The prevalence of left ventricular systolic dysfunction (LVSD) in the general population is poorly defined. Specifically, the number of asymptomatic individuals with LVSD and, thus, the most appropriate strategy to identify and treat such subjects is still unknown. Therefore, the aim of this study was to document LV dysfunction in a middle-aged (25 to 75 years, mean 51.8±13.8) population – based sample in Germany (MONICA Augsburg, n=1678; echocardiography technically adequate n=1418) by M-mode and 2D-echocardiography and to analyze the importance of predisposing contributors.    The overall prevalence of an ejection fraction (EF) less than 48% (mean minus 2 SD=LVSD) was 2.3% (n=33), with a slightly higher rate in men than in women (2.8% vs 1.9%, n.s.). LVSD rate increased with age: from 1.5% in individuals younger than 40 years to 4.0% among those older than 60 years of age (p<0.05). Of 33 participants with reduced left ventricular systolic function, 20 presented with at least one cardiovascular disease. The most frequent diagnoses were arterial hypertension, obesity and coronary heart disease. Only 13 subjects (0.9%) of the study population were asymptomatic without a history of cardiovascular disease. Furthermore, only 6 subjects (0.4%, 4 male) in this population presented with a moderate impairment of LV function (EF of 30 to 40%) and only 1 subject (0.07%, male) had severe LVSD (EF less than 30%). Almost all subjects with an EF less than 40% (6 of 7 individuals) had a known history of cardiovascular disease.    In conclusion, LVSD is a relatively common finding in the general population. However, severe LVSD is rare in subjects without any concomitant cardiovascular disease. Thus, echocardiographic screening cannot be recommended in the unselected, middle-aged population to identify such patients. Die Prävalenz der linksventrikulären Dysfunktion (LVSD) in der Allgemeinbevölkerung Deutschlands ist unbekannt. Insbesondere ist unklar, ob ein großer Anteil der Personen mit LVSD asymptomatisch ist, so dass ein generelles Screening implementiert werden müsste, um eine präventive Behandlung einleiten zu können. Ziel dieser Studie war daher die echokardiografische Untersuchung einer alters- und geschlechtsstratifizierten Bevölkerungsstichprobe Deutschlands (MONICA Augsburg, n=1678; technisch adäquates Untersuchungsergebnis bei n=1418, durchschnittliches Alter 51,8±13,8 Jahre [25–75 Jahre]) zur Ermittlung der LVSD-Prävalenz sowie einer Analyse der prädisponierenden Faktoren.    Der Gesamtteil der Patienten mit einer Ejektionsfraktion (EF) <48% (Mittelwert minus zweifache Standardabweichung) betrug 2,3% (n=33). Männer waren tendentiell häufiger betroffen als Frauen (2,8 vs. 1,9%, n.s.). Die Prävalenz stieg mit zunehmendem Alter an: von 1,5% bei Individuen jünger als 40 Jahre auf 4,0% bei Probanden älter als 60Jahre (p<0,05). Von den 33 Probanden mit LVSD war bei 20 mindestens eine kardiovaskuläre Erkrankung bekannt; darunter waren ein arterieller Hypertonus, Adipositas und KHK am häufigsten vertreten. Demgegenüber waren 13 Probanden (0,9%) asymptomatisch ohne vorbekannte kardiovaskuläre Erkrankung. Nur 6 Probanden (0,4%, 4 Männer) wiesen eine mittelgradig eingeschränkte EF (30–40%) auf, bei lediglich einem Mann (0,07%) zeigte sich eine höhergradig reduzierte EF (<30%). Nahezu alle Probanden (6 von 7 Teilnehmern) mit mindestens moderat eingeschränkter EF (<40%) hatten eine kardiovaskuläre Erkrankung in der Vorgeschichte.    Das Vorkommen einer LVSD ist in der Allgemeinbevölkerung zwar relativ häufig, dennoch findet sich eine asymptomatische schwere linksventrikuläre Dysfunktion bei Individuen ohne vorbekannte kardiovaskuläre Begleiterkrankung selten. Somit ist eine generelle Empfehlung zu echokardiografischen Screening-Untersuchungen nur bei definierten Subpopulationen der Allgemeinbevölkerung (z.B. Patienten mit arterieller Hypertonie oder KHK) sinnvoll.

Epidemiologie der linksventrikulären systolischen Dysfunktion in der Allgemeinbevölkerung Deutschlands

The prevalence of left ventricular systolic dysfunction (LVSD) in the general population is poorly defined. Specifically, the number of asymptomatic individuals with LVSD and, thus, the most appropriate strategy to identify and treat such subjects is still unknown. Therefore, the aim of this study was to document LV dysfunction in a middle-aged (25 to 75 years, mean 51.8±13.8) population – based sample in Germany (MONICA Augsburg, n=1678; echocardiography technically adequate n=1418) by M-mode and 2D-echocardiography and to analyze the importance of predisposing contributors.    The overall prevalence of an ejection fraction (EF) less than 48% (mean minus 2 SD=LVSD) was 2.3% (n=33), with a slightly higher rate in men than in women (2.8% vs 1.9%, n.s.). LVSD rate increased with age: from 1.5% in individuals younger than 40 years to 4.0% among those older than 60 years of age (p<0.05). Of 33 participants with reduced left ventricular systolic function, 20 presented with at least one cardiovascular disease. The most frequent diagnoses were arterial hypertension, obesity and coronary heart disease. Only 13 subjects (0.9%) of the study population were asymptomatic without a history of cardiovascular disease. Furthermore, only 6 subjects (0.4%, 4 male) in this population presented with a moderate impairment of LV function (EF of 30 to 40%) and only 1 subject (0.07%, male) had severe LVSD (EF less than 30%). Almost all subjects with an EF less than 40% (6 of 7 individuals) had a known history of cardiovascular disease.    In conclusion, LVSD is a relatively common finding in the general population. However, severe LVSD is rare in subjects without any concomitant cardiovascular disease. Thus, echocardiographic screening cannot be recommended in the unselected, middle-aged population to identify such patients. Die Prävalenz der linksventrikulären Dysfunktion (LVSD) in der Allgemeinbevölkerung Deutschlands ist unbekannt. Insbesondere ist unklar, ob ein großer Anteil der Personen mit LVSD asymptomatisch ist, so dass ein generelles Screening implementiert werden müsste, um eine präventive Behandlung einleiten zu können. Ziel dieser Studie war daher die echokardiografische Untersuchung einer alters- und geschlechtsstratifizierten Bevölkerungsstichprobe Deutschlands (MONICA Augsburg, n=1678; technisch adäquates Untersuchungsergebnis bei n=1418, durchschnittliches Alter 51,8±13,8 Jahre [25–75 Jahre]) zur Ermittlung der LVSD-Prävalenz sowie einer Analyse der prädisponierenden Faktoren.    Der Gesamtteil der Patienten mit einer Ejektionsfraktion (EF) <48% (Mittelwert minus zweifache Standardabweichung) betrug 2,3% (n=33). Männer waren tendentiell häufiger betroffen als Frauen (2,8 vs. 1,9%, n.s.). Die Prävalenz stieg mit zunehmendem Alter an: von 1,5% bei Individuen jünger als 40 Jahre auf 4,0% bei Probanden älter als 60Jahre (p<0,05). Von den 33 Probanden mit LVSD war bei 20 mindestens eine kardiovaskuläre Erkrankung bekannt; darunter waren ein arterieller Hypertonus, Adipositas und KHK am häufigsten vertreten. Demgegenüber waren 13 Probanden (0,9%) asymptomatisch ohne vorbekannte kardiovaskuläre Erkrankung. Nur 6 Probanden (0,4%, 4 Männer) wiesen eine mittelgradig eingeschränkte EF (30–40%) auf, bei lediglich einem Mann (0,07%) zeigte sich eine höhergradig reduzierte EF (<30%). Nahezu alle Probanden (6 von 7 Teilnehmern) mit mindestens moderat eingeschränkter EF (<40%) hatten eine kardiovaskuläre Erkrankung in der Vorgeschichte.    Das Vorkommen einer LVSD ist in der Allgemeinbevölkerung zwar relativ häufig, dennoch findet sich eine asymptomatische schwere linksventrikuläre Dysfunktion bei Individuen ohne vorbekannte kardiovaskuläre Begleiterkrankung selten. Somit ist eine generelle Empfehlung zu echokardiografischen Screening-Untersuchungen nur bei definierten Subpopulationen der Allgemeinbevölkerung (z.B. Patienten mit arterieller Hypertonie oder KHK) sinnvoll.

ACE-Inhibition bei Myokardinfarktpatienten mit eingeschränkter Ventrikelfunktion : Umsetzung von Therapiestandards in Bevölkerungsstichproben

Several reports indicate the benefit of ACE inhibitors for patients with left ventricular systolic dysfunction after acute myocardial infarction (MI). We sought to determine the implementation of the treatment guidelines in patient samples from the general population. Furthermore we aimed to identify patient characteristics associated with the use of ACE inhibitors.    Screening of two MI-registries allowed the identification of 226 MI patients with left ventricular dysfunction. Patients were considered to be eligible for ACE inhibitor therapy when a EF ≤40% was documented in the patient records of cardiac rehabilitation clinics (REG-MI, n=147) or detected by standardised echocardiography (KORA, n=78). On average 5.5 years following MI, a standardised questionnaire and a detailed medical history was obtained. Specifically, information was collected regarding current medication and potential contraindications for ACE inhibitors.    MI patients with LV dysfunction received ACE inhibitors in 62% (REG-MI) and 45% (KORA). The doses prescribed were substantially smaller than target doses used in the large-scale studies (REG-MI: 40±4%, KORA: 23±3%, % of target doses). Only 13% (REG-MI) and 3% (KORA) received more than 50% of the target dosage. Additionally, actual doses of the most frequently used ACE inhibitors were significantly different (captopril: 23±2%, enalapril: 42±5% of target doses). The likelihood of receiving ACE inhibitors was significantly higher in patients with written recommendation for such medication (odds ratio 6.02, confidence interval 1.93–20.16) and in patients visiting cardiologists (odds ratio 3.69, confidence interval 1.26–11.07) as revealed by multivariate analysis of the REG-MI database.    Despite national and international guidance, a large proportion of MI patients with left ventricular dysfunction is not receiving ACE inhibitors, and when used, the doses prescribed are markely smaller than target doses used in clinical trials that established the utility of these drugs. Medical care by cardiologists and written recommendation of ACE inhibition in patient records were independent predictors of a more appropriate prescription of ACE inhibitors. Bei Myokardinfarktpatienten mit eingeschränkter Ventrikelfunktion ist die prognostische und symptomatische Effizienz von ACE-Inhibitoren hinreichend belegt. Die Umsetzung der entsprechenden Therapierichtlinien in der Allgemeinbevölkerung sowie die Analyse von Faktoren, welche auf die Implementation einer adäquaten Therapie Einfluss haben, waren Gegenstand dieser Studie.    Myokardinfarktpatienten mit einer Ejektionsfraktion (EF) ≤40% wurden anlässlich von Follow-up-Untersuchungen (im Mittel fünf bis sechs Jahre nach Infarkt) des Augsburger Myokardinfarkt-Familienregisters (KORA; n=78) sowie des Regensburger Myokardinfarkt-Familienregisters (REG-MI; n=147) identifiziert. Die EF wurde echokardiografisch bestimmt (KORA) oder den Arztbriefen entnommen (REG-MI). Angaben zur aktuellen Medikation, Ko-Morbidität und ärztlichen Versorgung wurden standardisiert erhoben. Von Herzinfarktpatienten mit linksventrikulärer Dysfunktion nahmen 45% (KORA) bzw. 62% (REG-MI) ACE-Hemmer ein. Allerdings lag die Dosierung nur bei 23±3% bzw. 40±4% der empfohlenen Tagesdosis. Eine ausreichende Therapie (>50% der in Therapiestudien empfohlenen Dosis) fand sich bei 3% (KORA) bzw. 13% (REG-MI). Auffallend war, dass sich Captopril (50% aller Patienten) und Enalapril (26% aller Patienten) in der Einnahme der empfohlenen Tagesdosis deutlich unterschieden (23±2% vs. 42±5%, p<0,01). Als wesentliche Prädiktoren einer Therapie mit ACE-Inhibitioren fanden sich im REG-MI eine entsprechende Empfehlung in den Krankenhausentlassungspapieren sowie die ambulante Behandlung durch Fachärzte (jeweils p<0,01).    Wir folgern, dass etwa die Hälfte der Myokardinfarktpatienten mit eingeschränkter EF ACE-Hemmer einnimmt, deren Dosierung allerdings weit unterhalb der durch Studiendaten abgesicherten Größenordnung liegt. Zudem fallen erhebliche Unterschiede in der Dosierung einzelner Präparate auf. Für die Durchführung einer ACE-Hemmertherapie sind eine entsprechende Empfehlung im Arztbrief und eine durch den Facharzt gesteuerte Behandlung wesentliche unabhängige Prädiktoren.