Christian G. Brilla

Lisinopril-Mediated Regression of Myocardial Fibrosis in Patients With Hypertensive Heart Disease

BackgroundIn arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial. Methods and ResultsA total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9±0.6% to 6.3±0.6% (P <0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9±0.3 to 8.3±0.4 &mgr;g/mg of LV dry weight (P <0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72±0.04 to 0.91±0.06 (P <0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123±9 to 81±5 ms (P <0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22.1±0.6 to 20.7±0.7 &mgr;m (P <0.01 versus lisinopril). ConclusionsIn patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function.

Renin–angiotensin–aldosterone system and myocardial fibrosis

See article by Bishop et al. [26] (pages 57–67) in this issue. nnDuring the past decade, evidence has been provided that the circulating and local renin–angiotensin–aldosterone systems (RAAS) promote the development of myocardial fibrosis in hypertensive heart disease and chronic heart failure [1,2] including in vitro experiments using adult rat cardiac fibroblasts where both angiotensin II (AngII) [3–5] and aldosterone [3] stimulate collagen synthesis in a dose-dependent manner while AngII additionally suppresses the activity of matrix metalloproteinase 1, the key enzyme of interstitial collagen degradation [3], that synergistically leads to progressive collagen accumulation within the myocardial interstitium. This could be proved in in vivo studies in renovascular hypertension [1], with chronic administration of aldosterone [1,6,7], or in the spontaneously hypertensive rat (SHR) model of genetic hypertension [8–12] where a local cardiac AngII generating system is operative [13]. Therefore, the physiological role of RAAS on the development of myocardial fibrosis could be established. In particular, in various models of experimental hypertension with comparable degrees of elevated systolic arterial pressure and left ventricular hypertrophy (LVH), myocardial fibrosis was found only in the presence of stimulated circulating RAAS, i.e., in renovascular hypertension, or when aldosterone was chronically infused via subcutaneously implanted osmotic minipumps to raise plasma aldosterone levels as seen in congestive heart failure. There, interstitial and perivascular fibrosis was found in either ventricle, the pressure-overloaded, hypertrophied left ventricle and the non-overloaded, not hypertrophied right ventricle [1]. In contrast, myocardial fibrosis was absent in either ventricle of hypertensive rats with infrarenal aortic band where RAAS was not activated although LVH was present [1].nnFurthermore, low output heart failure models, like rapid pacing in dogs, were associated with activation of RAAS and progressive increase in preload. There, myocardial fibrosis was seen in either ventricle [14]. On the … nn* Tel.: +49-6421-286-4980; fax: +49-6421-286-8954 brilla{at}t-online.de

Aldosterone and myocardial fibrosis in heart failure.

Cardiac fibroblasts are known to have high affinity corticoid receptors for aldosterone and account for the accumulation of collagen within the interstitium of the rat myocardium in acquired and genetic hypertension. This interstitial fibrosis is an important determinant of pathologic hypertrophy in chronic heart failure.To examine the relationship between aldosterone and myocardial fibrosis, collagen volume fraction of the left and right ventricles were analyzed by videodensitometry of sirius red stained tissue in the following rat models: 2 kidney/1 clip model of renovascular hypertension; continuous aldosterone administration via osmotic minipumps (0.75 μg/hour s. c.), or in each model of primary and secondary hyperaldosteronism with concomitant treatment with either low (20 mg/kg/day) or high doses (200 mg/kg/day) of s. c. spironolactone for 8 weeks as well as in age matched controls. Systolic arterial pressure and left ventricular weight normalized to body weight were each increased with either model of experimental hypertension and were normalized with high-dose spironolactone treatment. Myocardial fibrosis induced by chronic aldosterone administration was comparable to renovascular hypertension and occurred in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophied right ventricle. The competitive aldosterone receptor antagonist, spironolactone, was able to prevent fibrosis in both ventricles in either model of arterial hypertension irrespective of the development of left ventricular hypertrophy and hypertension. To examine whether aldosterone stimulates collagen synthesis in adult rat cardiac fibroblasts collagen synthesis, normalized per total protein synthesis, was measured by 3H-proline incorporation in cultured fibroblasts after 24 hours incubation with aldosterone at 10−11 to 10−6 M concentrations, or with 10−9 M aldosterone + 10−9 M spironolactone. Under serum-free conditions, aldosterone was able to stimulate collagen synthesis in a dose-dependent manner and at concentrations (10−9 M) which were comparable to stimulated states in vivo (e. g., renovascular hypertension, or chronic heart failure). At equimolar concentrations, spironolactone abolished the aldosterone-mediated increase in collagen synthesis.Thus, in-vivo and in-vitro evidence could be provided that the mineralocorticoid, aldosterone, plays a pivotal role in promoting myocardial fibrosis and that could be antanonized by its competitive receptor blocker, spironolactone. These cardioprotective effects of spironolactone may explain the prognostic value of anti-aldosterone therapy in patients with severe chronic heart failure evaluated in the RALES mortality trial.ZusammenfassungTrotz Therapie mit Angiotensinkonversionsenzym-(ACE-)Hemmern ist die Ü,berlebensdauer von Patienten mit fortgeschrittener Herzinsuffizienz erheblich eingeschränkt. Eine weitergehende Behandlung ist erforderlich, wenn man die Prognose der Patienten verbessern will. Ein Therapieansatz ist die Wiederherstellung einer normalen Myokardstruktur und damit einhergehend die Beseitigung strukturbedingter Funktionsstörungen bei linksventrikulärer Hypertrophie von Patienten mit chronischer Herzinsuffizienz infolge einer hypertensiven Herzkrankheit, einer dilatativen Kardiomyopathie oder nach Myokardinfarkt. Dabei kommt dem Umbau der Kollagenmatrix des Myokards bei linksventrikulä,rer Hypertrophie eine wesentliche Bedeutung zu, denn die Kollagenmatrix bestimmt die Gewebeelastizität und damit die diastolische Ventrikelfunktion und beeinträchtigt bei fortgeschrittenem Umbau mit progressiver diffuser Myokardfibrose und konsekutiver myozytärer Atrophie auch die systolische Funktion.Kardiale Fibroblasten, welche die Strukturproteine der Kollagenmatrix, Kollagen Typ I und Typ III, synthetisieren und das Schlüsselenzym der interstitiellen Kollagendegradation, die Matrixmetalloproteinase (MMP) 1, produzieren, unterliegen der Regulation durch das Renin-Angiotensin-Aldosteron-System (RAAS), das bei Herzinsuffizienz aktiviert ist. Aufgrund experimenteller Befunde bei renovaskulärer Hypertonie, primärem Hyperaldosteronismus und nicht reninabhängiger Hypertonus nach infrarenalem Aortenbanding stellte sich die physiologische Bedeutung des RAAS für die Entwicklung einer Myokardfibrose als unabhängig von hämodynamischen Bedingungen und unabhängig von der Wachstumsregulation kardialer Myozyten heraus. Denn eine Myokardfibrise trat bei primärem oder sekundärem Hyperaldosteronismus sowohl im druckbelasteten, hypertrophierten linken Ventrikel als auch im normotensiven, nicht hypertrophierten rechten Ventrikel auf. Im Gegensatz dazu trat keine Myokardfibrose auf, wenn das RAAS nach infrarenalem Aortenbanding nicht stimuliert war, trotz vergleichbarer arterieller Hypertonie und linksventrikulärer Hypertrophie. An kultivierten kardialen Fibroblasten konnte die direkte Wirkung der Effektorhormone des RAAS auf die Fibroblastenfunktion nachgewiesen werden. Angiotensin II und Aldosteron stimulieren unter serumfreien Bedingungen die Kollagensynthese in kardialen Fibroblasten. Dabei sind Aldosteronkonzentrationen wirksam (10−9 M), wie sie in vivo im Plasma bei kongestiver Herzinsuffizienz gefunden werden. Während Aldosteron die Kollagendegradation nicht beeinflusst, senkt Angiotensin II in synergistischer Weise die MMP-1-Aktivität, was die Kollagenakkumulation im Interstitium des Myokards noch verstärkt. Selektive Angitensin-II- und Aldosteronrezeptorantagonisten sind in der Lage, die Wirkungen der Effektorhormone des RAAS auf die kardiale Fibroblastenfunktion aufzuheben. In vivo geschieht dies effektiv mit dem Aldosteronantagonisten Spironolacton, der bei Sprague-Dawley-Ratten mit primärem oder sekundärem Hyperaldosteronismus die Entwicklung einer Myokardfibrose verhindern konnte, wobei schon niedrige, nicht blutdruckwirksame Dosen von Spironolacton ausreichten (20 mg/kg/Tag), um die Myokardfibrose unabhängig von der Entwicklung einer linksventrikulären Hypertrophie zu verhindern.Klinisch kommt es unter chronischer ACE-Hemmung häufig zu einem Aldosteron-“Escape”, das heißt zu einem Wiederanstieg der Plasmaaldosteronkonzentration trotz unverändert supprimierter Angiotensin-II-Bildung. Ursächlich dafür sind vermutlich erhöhte Serumkaliumspiegel, wobei schon Erhöhungen um 0,2 mval/l stimulierend auf die Aldosteronsekretion der Zona-glomerulosa-Zellen der Nebennierenrinde wirken. Daneben kommt es lokal über die gehemmte Kiniase-H-Wirkung zu einer erhöhten Prostaglandin-E2-Produktion, welches ebenfalls die Aldosteronbiosynthese steigert. Das mineralocorticoide Hormon Aldosteron führt über eine zunehmende Wasserl- und Na+-Retention zu einer progredienten Volumenüberladung des insuffizienten Herzens, das schon primär nicht in der Lage ist, das angebotene Blutvolumen mit einem adäquaten Schlagvolumen zu bewältigen. Die Folge sind progrediente Ödeme. Zudem kommt es über die fibrotische Aldosteronwirkung auf das Myokard zu einem progredienten pathologischen Myokardumbau mit zusätzlicher Beeinträchtigung der Myokardfunktion.In der “Randomized Aldactone Evaluation Study (RALES)” wurde deshalb an 1663 Patienten mit schwerer chronischer Herzinsuffizienz geprüft, ob die zusätzliche Gabe von Spironolacton (12,5 bis 50 mg/die), zusätzlich zur Basistherapie mit ACE-Hemmer und Schleifendiuretikum, die Mortalität dieser Patienten beeinflusst. Die RALES-Mortalitä,tsstudie zeigte eindrucksvoll, dass die Überlebensrate schwer herzinsuffizienter Patienten unter einer zusätzlichen Spironolactontherapie signifikant verbessert wird. Unter Spironolacton konnte das Mortalitätsrisiko um 30% gesenkt werden, sodass RALES aus ethischen Gründen vorzeitig abgebrochen werden musste, weil es nicht mehr vertretbar war, schwer herzinsuffizienten Patienten eine solche Therapie vorzuenthalten.

Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease.

In hypertensive heart disease, reactive myocardial fibrosis represents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium. The fact, that the myocardium of both ventricles is involved, irrespective of ventricular loading conditions, suggests that circulating factors, and not the hemodynamic load are primary responsible for this adverse response of the myocardial fibrous tissue. In various experimental in vivo models, it has been shown that myocardial fibrosis is always associated with activation of circulating or local renin-angiotensin-aldosterone systems (RAAS). Cardiac collagen metabolism is regulated by cardiac fibroblasts which express mRNAs for types I and III collagens, the major fibrillar collagens in the heart, and for interstitial collagenase or matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation. In order to elucidate the role of the RAAS effector hormones, angiotensin II (AngII) and aldosterone (ALDO), in the regulation of collagen synthesis or inhibition of MMP 1 production, adult human cardiac fibroblasts were cultured. Collagen synthesis was determined by 3H-proline incorporation, and MMP 1 activity by degradation of 14C-collagen measured under serum-free conditions in confluent fibroblasts after 24 hour-incubation with either AngII or ALDO over a wide range of concentrations (10(-11)-10(-6)M). In addition, the effects of the mineralocorticoid, deoxycorticosterone (DOC), and prostaglandin E2 (PGE2) on cardiac fibroblast function were determined. Compared with untreated control fibroblasts, collagen synthesis, normalized per total protein synthesis, showed a significant and dose-dependent increase after incubation with either mineralocorticoid hormone, ALDO or DOC, or after incubation with AngII. In contrast, collagen synthesis of cardiac fibroblasts was significantly decreased by PGE2 treatment. AngII type 1 or mineralocorticoid receptor antagonists, respectively, were able to completely inhibit the AngII- or mineralocorticoid-mediated increase of collagen synthesis. Furthermore, AngII significantly decreased MMP 1 activity while ALDO or DOC had no effect on cardiac fibroblast-mediated collagen degradation. In contrast, PGE2 significantly increased MMP 1 activity. Thus cardiac fibroblast function is modulated by either effector hormone of the RAAS, AngII and ALDO, via specific receptors that lead to progressive myocardial fibrosis in disease states where circulating or local RAAS is activated, i.e., in hypertensive heart disease. In contrast, PGE2, which would be elevated in myocardial tissue after angiotensin-converting enzyme inhibition, counteracts the fibrotic effects of the RAAS on myocardial tissue.

Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover.

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation

SummaryThe interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.

Regression of myocardial fibrosis in hypertensive heart disease: diverse effects of various antihypertensive drugs.

OBJECTIVEnIn left ventricular hypertrophy (LVH) due to systemic hypertension, myocardial fibrosis is an important determinant of pathologic hypertrophy. Therefore, it is most relevant to utilize an antihypertensive regimen that permits a regression in myocardial fibrosis along with blood pressure normalization and regression of LVH.nnnMETHODSnTo address this issue we examined 60 Sprague-Dawley rats. We treated 16-week-old rats having established LVH and myocardial fibrosis due to 8-week renovascular hypertension (RHT) with either 6 mg/kg/day zofenopril (ZOF), 30 mg/kg/day nifedipine (NIF) or 40 mg/kg/day labetalol (LAB) for 12 weeks. Systolic arterial pressure (SAP, mmHg), left ventricular/body weight ratio (LV/BW, mg/g), and left and right ventricular collagen volume fractions (LVCVF, RVCVF, %) were obtained and compared with age/sex matched untreated rats with RHT and sham-operated controls.nnnRESULTSnIn RHT, SAP was significantly elevated compared with controls (188+/-11 vs. 125+/-5 mmHg; P<0.001) while in each treated group SAP was normalized. LV/BW was significantly increased in RHT (2.61+/-0.12 mg/g; P<0.00001) while in each treated group LVH was completely regressed (P<0.002 vs. untreated RHT) with LV/BW values comparable to controls (1.82+/-0.03 mg/g) irrespective of the utilized antihypertensive agent. In untreated RHT, myocardial fibrosis was present in the left (LVCVF: 12.3+/-1.9%; P<0.0005 vs. 4.5+/-0.2% of controls) and right ventricles (RVCVF: 20.6+/-2.5%; P<0.00005 vs. 8.8+/-0.4% of controls). In rats treated with ZOF or NIF, LVCVF was significantly reduced to 5.6+/-0.4 and 5.4+/-0.6%, respectively (P<0.005 vs. untreated RHT), and RVCVF was decreased as well (ZOF: 11.0+/-0.9%; NIF: 10.4+/-2.4%; P<0.007 vs. untreated RHT) where no significant difference to controls remained. In contrast, treatment with LAB did not affect myocardial fibrosis where LVCVF was 9.3+/-1.3% and RVCVF was 19.8+/-2.8%, i.e., remained significantly elevated compared with controls (P<0.007).nnnCONCLUSIONSnIn rats with renovascular hypertension and hypertensive heart disease that included LVH and fibrosis, equipotent doses of ZOF, NIF, and LAB normalized arterial pressure associated with regression of LVH while only ZOF and NIF were found to regress myocardial fibrosis.

Effect of the renin-angiotensinaldosterone system on the cardiac interstium in heart failure

The interaction of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of great interest in chronic heart failure. The pressure or volume overloaded heart shows a hypertrophic growth of the myocardium, i.e., an enlargement of cardiac myocytes. In addition, cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. This remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure.The growth of cardiac fibroblasts is not primarily regulated by the hemodynamic load.In vivo andin vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone has been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for interstitial collagen degradation in the myocardium.These findings may serve as rationale for a remedial therapy with angiotensin converting enzyme inhibition or blockage of the RAAS in congestive heart failure in patients with hypertensive heart disease, post myocardial infarction or with dilated cardiomyopathy.

Effects of ACE Inhibition versus Non-ACE Inhibitor Antihypertensive Treatment on Myocardial Fibrosis in Patients with Arterial Hypertension

Background and Purpose:In experimental arterial hypertension, left ventricularnhypertrophy (LVH) becomes pathologic with impaired myocardialnfunction if myocardial fibrosis occurs. Myocardial fibrosis isnassociated with activated circulating or localnrenin-angiotensin-aldosterone systems. The primary objective ofnthis retrospective study was to determine whether patients withnarterial hypertension treated with angiotensin-converting enzymeninhibitors (ACEI) have less myocardial fibrosis than patients onnnon-ACEI treatment.Material and Methods:We examined left ventricular (LV) endomyocardial biopsiesnof 97 consecutive patients with hypertensive heart disease duento primary hypertension treated with either any ACEI for atnleast 6 months (n = 34; HTN + ACEI) or non-ACEI antihypertensivendrugs (n = 63; HTN). Normal hearts designated for heartntransplantation served as controls (n = 23; CTR). Myocytendiameter (MyoD) and collagen volume fraction (CVF) were measurednby morphometry, and pro-matrix metalloproteinases (proMMPs) 2nand 9 by zymography. In a subset of 35 patients, LV myocardialnstiffness was determined by left heart catheterization withncalculation of stiffness constant k.Results:In HTN + ACEI or HTN, MyoD (21.8 ± 0.3 µm and 22.4 ± 0.3nµm, respectively) and CVF (5.3 ± 0.6% and 7.6 ± 0.7%,nrespectively) were increased (p < 0.01) compared with CTRn(16.0 ± 0.4 µm and 0.5 ± 0.2%, respectively). In HTN + ACEI, CVFnwas significantly lower (p < 0.02) and proMMP 2 was highern(0.063 ± 0.013 OD/mg) compared with HTN (0.037 ± 0.006 OD/mg; pn< 0.05) while no significant difference of MyoD was evident.nWe found no correlation between CVF and MyoD (r = 0.13; p =n0.47), a positive correlation between k and CVF (r = 0.71; pn< 0.00001), and no correlation between k and MyoD (r = 0.22;np = 0.24).Conclusion:In patients with hypertensive heart disease, myocytenhypertrophy and myocardial fibrosis are present. Myocardialnfibrosis and not myocyte hypertrophy determines myocardialnstiffness. ACEI appear to diminish myocardial fibrosisnassociated with enhanced collagen degradation irrespective ofnLVH regression.Hintergrund und Ziel:Bei experimenteller arterieller Hypertonie geht dienEntwicklung einer Myokardfibrose mit aktivierten zirkulierendennoder lokalen Renin-Angiotensin-Aldosteron-Systemen einher. Diesnführt zu einer pathologischen linksventrikulären Hypertrophien(LVH) mit eingeschränkter Myokardfunktion. Sowohlntierexperimentell als auch in einer kleinen prospektivennklinischen Untersuchung an Patienten mit primärem Bluthochdrucknkonnte gezeigt werden, dass eine Behandlung mit einemnAngiotensinkonversionsenzym-(ACE-)Hemmer zu einer Regression dernMyokardfibrose führt, einhergehend mit einer Verbesserung dernMyokardfunktion. In der vorliegenden retrospektiven Untersuchungnsoll geprüft werden, ob die Rückbildung einer letztlich zurnHerzinsuffizienz führenden Myokardfibrose durch einenACE-Hemmer-Therapie auch bei einem größeren Patientenkollektivnnachweisbar ist.Material und Methodik:In die Untersuchung wurden alle Patienten mit primärernarterieller Hypertonie einbezogen, die am Zentrum für InnerenMedizin, Universität Marburg, wegen des klinischen Verdachts aufndas Vorliegen einer koronaren Herzkrankheit invasivnkardiologisch untersucht wurden und bei denen nachnkoronarangiographischem Ausschluss bei vorliegender LVHnlinksventrikuläre Endomyokardbiopsien zur weiteren Abklärungnentnommen wurden. In diesem Patientengut befanden sich 34nPatienten, die vor der Untersuchung über mindestens 6 Monate mitneinem ACE-Hemmer antihypertensiv behandelt wurden (Gruppe: HTN +nACEI), und 63 Patienten, die auf eine Hochdruckbehandlung ohnenACE-Hemmer eingestellt waren (Gruppe: HTN; Tabelle 1).nLinksventrikuläres Gewebematerial von 23 gesunden Herzen, dienzwecks Herztransplantation explantiert worden waren, diente alsnKontrolle. Insgesamt wurden linksventrikulärenEndomyokardbiopsien von 120 Individuen untersucht.Der Myozytendurchmesser (MyoD) und dienKollagenvolumenfraktion (CVF) des linksventrikulären Myokardsnwurden morphometrisch mittels quantitativer Videodensitometriengemessen. Die Pro-Matrix-Metalloproteinasen (proMMP) 2 und 9nwurden durch Zymographie und quantitative Laserdensitometrienbestimmt. Bei einem Teilkollektiv von 35 Patienten wurde mittelsnDurchführung einer zweiten Lävokardiographie undnlinksventrikulären Druckmessung während der diagnostischennLinksherzkatheteruntersuchung die linksventrikuläre myokardialenSteifheit durch Kalkulation der Steifheitskonstanten knermittelt.Ergebnisse:Bei den Patientengruppen HTN + ACEI bzw. HTN waren MyoDn(21,8 ± 0,3 µm bzw. 22,4 ± 0,3 µm; Abbildung 1) und CVF (5,3 ±n0,6% bzw. 7,6 ± 0,7%; Abbildung 2) signifikant erhöht (p <n0,01) im Vergleich zur Kontrollgruppe (MyoD = 16,0 ± 0,4 µm, CVFn= 0,5 ± 0,2%). In der mit ACE-Hemmern behandeltennPatientengruppe (HTN + ACEI) fanden sich CVF signifikantnniedriger (p < 0,02) and proMMP 2 (Abbildungen 3a und 3b)nsignifikant höher (0,063 ± 0,013 OD/mg) im Vergleich zurnPatientengruppe ohne ACE-Hemmer-Behandlung (HTN; 0,037 ± 0,006nOD/mg; p < 0,05), wogegen in diesen Patientengruppen MyoDnnicht signifikant unterschiedlich war. Es fanden sich keinenKorrelation zwischen CVF und MyoD (r = 0,13; p = 0,47), einenpositive Korrelation zwischen k and CVF (r = 0,71; p <n0,00001) und wiederum keine Korrelation zwischen k and MyoD (r =n0,22; p = 0,24; Abbildungen 4a bis 4c.).Schlussfolgerung:Bei Patienten mit hypertensiver Herzkrankheit ist die LVHnmorphologisch durch eine Myozytenhypertrophie und Myokardfibrosencharakterisiert. Dabei determiniert die Myokardfibrose und nichtndie Myozytenhypertrophie die myokardiale Steifheit. Einenantihypertensive Behandlung mit ACE-Hemmern scheint dienMyokardfibrose, einhergehend mit einer stimuliertennKollagendegradation, zu vermindern. Dies geschiehtnoffensichtlich unabhängig von einer LVH-Regression.

The Concept of Cardioreparation: Part 1. Pathophysiology of Remodelling

Purpose Left ventricular hypertrophy is common in patients with hypertension or congestive heart failure and in survivors of myocardial infarction. It is associated with increased risks of adverse cardiovascular events, including angina, myocardial infarction and congestive heart failure. We aimed to explain these observations in terms of changes in the structure of the heart, collectively described as remodelling. Data extraction Laboratory investigations of animal models of cardiovascular diseases were reviewed. The most prominent features of remodelling are myocyte hypertrophy, excessive accumulation of collagen in the heart (myocardial fibrosis) and pathological changes in the coronary blood vessels. Remodelling disrupts the structure of the heart and impairs its pumping function and blood supply. The reversal of remodelling, termed cardioreparation, could restore cardiac structure and function towards normal and improve the prognosis of patients with cardiovascular diseases. Conclusions Cardioreparation implies the regression of myocyte hypertrophy and myocardial fibrosis. Myocyte hypertrophy is primarily a response to chronic pressure or volume overload of the ventricles, whereas myocardial fibrosis depends on activation of circulating and tissue renin-angiotensin-aldosterone systems. Angiotensin converting enzyme inhibitors reduce blood pressure and inhibit these systems. They might therefore induce cardioreparation.