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Biomedical subjects

R Pick

Publications and source records attributed to R Pick.

At least 19 recordsLinked to original sources
PubMed2001

Relation of thallium uptake to morphologic features of chronic ischemic heart disease: evidence for myocardial remodeling in noninfarcted myocardium.

OBJECTIVES: The aim of this study was to investigate the disparity between the extent of myocardial injury as assessed by thallium and the severity of left ventricular (LV) dysfunction in chronic ischemic heart disease. BACKGROUND: Although it is believed that thallium differentiates between viable and nonviable myocardium, in some patients with chronic ischemic heart disease, viable regions by thallium may fail to improve function after revascularization. METHODS: Thirteen transplant candidates with chronic ischemic heart disease (LV ejection fraction = 14 +/- 6% at rest) were studied prospectively with stress-redistribution-reinjection thallium single-photon emission computed tomography. We examined pretransplantation quantitative thallium uptake and post-transplantation extent and the histological distribution of collagen replacement in infarcted and noninfarcted myocardium and in 13 age-matched control hearts. RESULTS: The volume fraction of collagen varied inversely with wall thickness (r = -0.70, p < 0.001) and was higher in irreversible (30.9 +/- 15.8%) compared with reversible (20.2 +/- 12.6%, p < 0.001) or normal thallium segments (15.0 +/- 8.7%, p < 0.001). The irreversible thallium segments had lower wall thickness and more severe coronary artery narrowing (9.7 +/- 2.8 mm and 95 +/- 8%) compared with reversible (11.7 +/- 2.7 mm and 87 +/- 13%, p < 0.001) and normal thallium segments (12.8 +/- 2.6 mm and 80 +/- 14%, p < 0.001). Mean volume fraction of collagen was significantly lower in noninfarcted than it was in infarcted segments (13 +/- 6% vs. 36 +/- 13%, p < 0.001) but exceeded that in the control hearts (4 +/- 2%, p < 0.001). Noninfarcted segments had predominantly interstitial fibrosis with either microscopic or patchy areas of replacement fibrosis. CONCLUSIONS: In chronic ischemic heart disease with severe LV dysfunction, patterns of normal, reversible and irreversible thallium uptake correlated with the magnitude of collagen replacement, segmental wall thickness and severity of coronary artery narrowing. The finding of scattered areas of replacement fibrosis in noninfarcted myocardium may explain the observed disparity between LV contractile dysfunction and the extent of myocardial injury assessed by thallium.

Adult↗
PubMed2000

Structure-activity relationships in a series of bisquaternary bisphthalimidine derivatives modulating the muscarinic M(2)-receptor allosterically.

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are well-established ligands of the common allosteric binding site of muscarinic M(2) receptors. Previous structure-activity relationships (SAR) revealed two positively charged centers and two lateral phthalimide moieties in a defined arrangement to be essential of a high allosteric potency. The purpose of this study was to replace one carbonyl group of the phthalimides with hydrogens, hydroxy, alkoxy, phenyl, benzyl, and benzylidene groups in order to check the influence of these substituents on the allosteric activity in antagonist-linked receptors. The analysis of the quantitative SAR indicated that a high allosteric potency is related to a certain amount of rigidity as well as polarizibility and the ability to form hydrophobic interactions.

Allosteric Regulation↗
PubMed2000

Ligands for the common allosteric site of acetylcholine M2-receptors: development and application.

Ligands for the allosteric site of acetylcholine M2 receptors are able to retard the dissociation of simultaneously bound ligands for the orthosteric site. This effect promotes receptor occupation by the orthosteric ligand. The allosteric effect opens various therapeutic perspectives, e.g., in organophosphorus poisoning. The aim of our studies was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic M2 receptors, the orthosteric site of which was liganded with the N-methylscolopamine. The phthalimido substituted hexane-bisammonium compound W84 served as a starting point. Previous molecular modelling studies revealed two positive charges and two aromatic imides in a sandwich-like arrangement to be essential for a high allosteric potency. A three-dimensional quantitative structure activity relationship (3D QSAR) analysis predicted compounds with substituents of increasing size on the lateral imide moieties to enhance the affinity for the allosteric binding site. Thus, we synthesized and pharmacologically evaluated compounds bearing "saturated" phthalimide moieties as well as phthalimidines with substituents of systematically increasing size in position 3 or on the aromatic ring at one or both ends of the molecule. Within each series, QSAR could be derived: 1. "Saturation" of the aromatic ring of the phthalimide moiety results in less potent compounds. 2. Increasing the size of the substituents in position 3 of the phthalimide enhances the potency. 3. Putting substituents on the aromatic part of the phthalimide increases the potency more effectively: the introduction of a methyl group in position 5 gave a compound with a potency in the nanomolar concentration range which was subsequently developed as the first radioligand for the allosteric binding site.

Animals↗
PubMed2000

Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a diverse clinical spectrum, in which many of the abnormal structural and pathophysiologic features are consequences of inappropriate left ventricular hypertrophy. METHODS: We analyzed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly. The morphologic appearance and volume fractions of interstitial (matrix) and perivascular (adventitial) collagen were analyzed with polarization microscopy and computerized videodensitometry in picrosirius red-stained sections. Findings were compared with 16 structurally normal hearts, 5 with systemic hypertension and 6 infants who died of HCM. RESULTS: Adults and young children with HCM had an eightfold greater amount of matrix collagen compared with normal controls (14.1 +/- 8.8% vs. 1.8 +/- 1% of the tissue section; p < 0.0001), and a threefold increase compared with patients with systemic hypertension (4.5 +/- 1.3%; p < 0.001) and infants with HCM (4.0 +/- 2.4%; p < 0.001). Compared with normal controls and hypertensives, adults and young children (and infants) with HCM showed increased numbers and thickness of each collagen fiber component of the matrix (perimysial coils, pericellular weaves and struts), which were often arranged in disorganized patterns. In HCM patients, the amount of collagen was not a consequence of other clinical, demographic and morphologic disease variables. CONCLUSIONS: Left ventricular collagen matrix in young, previously asymptomatic patients with HCM who died suddenly is morphologically abnormal and substantially increased in size. The enlarged matrix collagen compartment is present in HCM at an early age, further expands during growth, is partially responsible for increased ventricular septal thickness and likely represents a primary morphologic abnormality in this disease. These findings support the view that the complex HCM disease process is not confined to sarcomere protein abnormalities, but also involves connective tissue elements.

Adolescent↗
PubMed2000

Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor.

Angiotensin-converting enzyme is involved in apoptosis of alveolar epithelial cells (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 277: L1245-L1250, 1999). This study tested the ability of the angiotensin-converting enzyme inhibitor captopril or the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (ZVAD-fmk) to block alveolar epithelial cell apoptosis and lung fibrosis in vivo in response to bleomycin (Bleo). Male Wistar rats received 8 U/kg of Bleo (bleomycin sulfate) or vehicle intratracheally. Subgroups of Bleo-treated rats received captopril, ZVAD-fmk, or vehicle alone. Lung collagen was assessed by picrosirius red or hydroxyproline assay at 1, 7, and 14 days post-Bleo, and apoptosis was detected by in situ end labeling (ISEL). Bleo increased alveolar septal and peribronchial collagen by 100 and 133%, respectively (both P < 0.01), by day 14 but not earlier. In contrast, ISEL was increased in alveolar and airway cells at all time points. Captopril or ZVAD-fmk inhibited collagen accumulation by 91 and 85%, respectively (P < 0. 01). Both agents also inhibited ISEL in alveoli by 99 and 81% and in airways by 67 and 63%, respectively. These data suggest that the efficacy of captopril to inhibit experimental lung fibrogenesis is related to inhibition of apoptosis. They also demonstrate the antifibrotic potential of a caspase inhibitor.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis.

Fibrosis in the heart may result from loss of myocytes, which are replaced by collagens. Apoptosis is now known to contribute to myocyte loss in the failing human heart. The mechanisms underlying the induction of cardiomyocyte apoptosis, and thus the expansion of fibrotic foci in the failing heart, are poorly understood. We hypothesized that viable heart cells adjacent to fibrotic foci might become "predisposed" to apoptosis by expression of the receptor FAS (APO1, CD95). We therefore studied the spatial relationship of FAS expression and fibrosis in patients with heart failure. Left ventricular biopsies were obtained from seven patients undergoing coronary artery bypass grafting. All patients had reduced ejection fraction but varied in New York Heart Association class score at the time of surgery. Heart cell apoptosis, fibrosis, and FAS expression were studied by propidium iodide and in situ end labeling (ISEL) of DNA, Picrosirius red staining, and immunohistochemistry. All patient samples exhibited, albeit to varying degrees, apoptosis detected by ISEL, chromatin condensation, and nuclear fragmentation. In all samples, fibrosis (collagen) was evident both perivascular and in isolated regions of scarring. Regardless of the extent of fibrosis or detectable apoptosis, FAS expression was observed in regions immediately adjacent to the fibrosis, but not in regions distal to fibrosis, nor in fibrotic areas devoid of nuclei. Expression of FAS was found adjacent to both perivascular and diffuse fibrosis, and ISEL-positive nuclei were found within cells reacting positively with anti-FAS antibodies. However, ISEL-positive nuclei were no more abundant in FAS-positive regions (67.6 +/- 5.8% of total nuclei) than in FAS-negative areas (69.5 +/- 9.8%). We conclude that expression of FAS occurs in remaining heart cells adjacent to fibrosis of either perivascular or presumed reparative origin. Although this phenomenon could contribute to the expansion of fibrotic foci, FAS-induced apoptosis in the failing heart may not be more prevalent than apoptosis initiated by other signaling mechanisms.

Aged↗
PubMed1992

Determination of G1-S-G2 phase fraction ratios of tumour subpopulations from DNA histograms.

Authors describe a new mathematical approach based on mixture decomposition and maximum likelihood method for the determination of subpopulations and G1-S-G2 phase fraction ratios in aneuploid, multiploid DNA histograms. A special computer routine was developed for this purpose (DAHSY). The present study relates to DNA histograms obtained by a Leitz Miamed DNA TV image analyser system. Altogether 23 normal, 14 dysplastic and 28 tumours Feulgen stained gastric imprint smears were measured. In addition to determination of subpopulations and G1-S-G2 phase fraction ratios, the authors also performed a morphometric analysis of Feulgen stained nuclei and determined the values of 5c exceeding rate (5cER) and the 2c deviation index (2cDI). More than one subpopulation were found only in tumours. The usual G1-S-G2 phase fraction rates in normal gastric smears were 85.5%, 9.04%, 4.9%, in dysplastic cases 74%, 15.4%, 10.2% and in tumours 53.8%, 22.9%, 18.8%. Significance of the differences were calculated by the T-test. The G1 phase fraction ratio clearly discriminates the malignant lesions from all others. The S+G2 phase fraction ratio, however, distinguishes the normal cases from the dysplastic ones. The 2cDi and 5cEr could support a multivariate diagnostic system. The cell nucleus area was found also to be of diagnostic value.

Algorithms↗
PubMed1991

Coronary vascular remodeling and myocardial fibrosis in the rat with renovascular hypertension. Response to captopril.

Progressive myocardial fibrosis, including the accumulation of collagen within the adventitia of intramyocardial coronary arteries, is seen in the hypertrophied rat myocardium secondary to renovascular hypertension (RHT) and has been held responsible for alterations in myocardial diastolic stiffness. This study was undertaken to test the hypothesis that this presumptive angiotensin-aldosterone mediated fibrosis and its functional consequences could be favorably altered by an antihypertensive oral dose (50 mg/kg/day) of the angiotensin converting enzyme (ACE) inhibitor captopril. Three groups were studied: control; untreated RHT for 8 weeks; treated RHT, with captopril started 48 h before banding and continued for 8 weeks. Interstitial collagen volume fraction and perivascular collagen area (morphometry), the fibrillar nature of collagen (picrosirius polarization), and the end diastolic stress-strain relation of the intact left ventricle were examined in each group. In comparison to untreated animals with RHT, we found that captopril, begun prior to banding, attenuated interstitial and perivascular fibrosis and prevented hypertrophy and the rise in diastolic stiffness 8 weeks later. Thus, an adverse accumulation of collagen in the interstitium and around intramyocardial coronary arteries, and its functional consequences in the rat with RHT, can be prevented by captopril. Other ACE inhibitors may have similar salutary effects, but remain to be evaluated. The pathogenetic origin of myocardial fibrosis in RHT requires further investigation, but appears to be related to the angiotensin-aldosterone system.

Administration, Oral↗
PubMed1991

Cardiac myocyte necrosis induced by angiotensin II.

Although the role of angiotensin II (Ang II) in the pathogenesis and progression of the failing heart is uncertain, previous reports have suggested that myocyte injury may be a component in this process. In this study, we investigated this possibility in more detail. Cardiotoxic effects of nonacutely hypertensive doses of Ang II were examined in 90 rats, including those receiving an angiotensin infusion (200 ng/min i.p.) and those with renovascular hypertension, where endogenous stimulation of Ang II occurred. Myocyte injury and wound healing resulting from these treatments were evaluated by 1) immunofluorescence after in vivo monoclonal antibody labeling of myosin to detect abnormal sarcolemmal permeability, 2) [3H]thymidine incorporation into DNA, to detect fibroblast proliferation, and 3) light microscopic evidence of myocytolysis and subsequent scar formation. We found that exogenous Ang II produced multifocal antimyosin labeling of cardiac myocytes and myocytolysis, which were maximal on days 1-2 of the infusion. Subsequently, DNA synthesis rates were increased, with fibroblast proliferation reaching peak levels on day 2 (Ang II-treated rats, 90.0 +/- 18.6 cpm/micrograms DNA; control rats, 11.4 +/- 2.3 cpm/micrograms DNA; p less than 0.05); microscopic scarring was found on day 14 and represented 0.12 +/- 0.02% of the myocardium. Concurrent treatment with both propranolol (30 mg/kg/day s.c.) and phenoxybenzamine (5 mg/kg/day i.m.) did not attenuate Ang II-induced antimyosin labeling. Increased endogenous Ang II, resulting from renal ischemia after abdominal aortic constriction, produced both antimyosin labeling and increased rates of DNA synthesis like that observed with Ang II infusion. Both myocyte injury and fibroplasia were prevented with captopril (65 mg/day p.o.), but this protective effect was not seen with reserpine pretreatment. Infrarenal aortic banding without renal ischemia, on the other hand, produced hypertension without necrosis. We conclude that pathophysiological levels of endogenous as well as low-dose exogenous Ang II were associated with altered sarcolemmal permeability and myocytolysis with subsequent fibroblast proliferation and scar formation. Myocyte injury was unrelated to the hypertensive or enhanced adrenergic effects of Ang II or to hypertension per se. Captopril was effective in preventing myocyte injury in renovascular hypertension. The mechanism(s) responsible for Ang II-induced necrosis will require further study.

Angiotensin II↗
PubMed1991

Noninvasive estimation of pulmonary arterial blood pressure in burned patients with acute respiratory failure.

Pulmonary arterial hypertension develops in acute respiratory failure and mostly an enhanced PADd-PCWP gradient has an important effect on the outcome of that complication. Considering that this critical state of septic burned patients may last for weeks, the long-term direct monitoring of pulmonary arterial blood pressure with indwelling Swan-Ganz catheter is impossible because of the high risk of endocarditis. Therefore, the aim of this study was to elaborate a noninvasive method to estimate the pulmonary arterial hypertension. Determination of cardiac index and pulmonary arterial blood pressure was carried out with Swan-Ganz catheter, P32 Statham transducer, cardiac output computers (Gould IM 1000, Marquette 7010). Extended systolic time interval measurements (with Medicor 661 polygraph completed by PC program package) were performed simultaneously in 7 burned patients (av. age 38.7 ys, means of TBS 38%) with acute respiratory failure at 38 occasions. The values of cardiac indices with the two methods were practically the same CI t = 3.4 +/- 1.21 1/min/m2 CI s = 3.1 +/- 1.10 1/min/m2; regression equation: CI s = 0.874 CIt + 0.135, r = 0.98, n = 38. Close correlations have been found between PAPm and PO2/FiO2 (r = 0.75), as well as between PAP values and some noninvasively measured hemodynamic data. Using these interrelations: 1) regression equations for PAPs., PAPm, PAPd, PCWP, PVRI were elaborated (r values: 0.855, 0.869, 0.681, 0.644, 0.817 respectively); 2) discriminant analysis with noninvasive parameters correctly classified the cases at critical PAPd-PCWP gradient (greater than 4 mm/Hg) in 84%. These results suggest that a continuous noninvasive hemodynamic and blood gas monitoring completed with a periodic bedside computer analysis of the PC-processed data for calculation of the pulmonary arterial pressure may be enough for the therapy during the long-term critical periods.

Acute Disease↗
PubMed1991

Anacrotic "notch" on the upstroke of external carotid curve may indicate a critically high systolic pulmonary arterial pressure value.

Acute respiratory failure is followed by decreased left ventricular performance probably due to the right ventricle dilatation induced by pulmonary hypertension and intraventricular septal shift to the left. An anacrotic notch on the upstroke slope of the carotid curve was detected in 22 of 36 hemodynamic studies with simultaneous ECG, PCG and external pulse carotid curve recording in 7 burned patients with acute respiratory failure. Comparing the values (x +/- SEM) obtained in group with notch and in group without notch, PAPs, PAPm, PVRI were higher (56 +/- 2.30 mmHg; 32 +/- 0.99 mm Hg; 543 +/- 56.8 dyn x s/cm5/m2 versus 32 +/- 1.08 mm Hg; 20 +/- 0.9 mm Hg; 173 +/- 14.7 dyn x s/cm5/m2) and CI and LVSWI were lower (2.6 +/- 0.17 l/min/m2; 25.8 +/- 2.41 g x m/m2; versus 3.8 +/- 0.26 l/min/m2; 38.3 +/- 2.82 g x m/m2) in group with notch. As it is shown by 11 paired measurements where the notch disappeared immediately after starting vasodilator therapy PAPs, PAPm, PVRI decreased (from 54 +/- 3.1, 35 +/- 0.8 mm Hg, 498 +/- 64.1 dyn x s/cm5/m2 to 35 +/- 0.8, 21 +/- 1.1 mmHg, 189 +/- 18.4 dyn x s/cm5/m2 respectively) and heart performance improved. Since the left ventricle contractility (characterized by EF, PCWP, ICT) was normal in both groups, our findings suggest that critically high PAPs values (over 40 mmHg) cause a septal bulging at the beginning of the systole which in turn narrows the left ventricle outflow tract. Regarding to the clinical importance of the deteriorated biventricular function at the critically high PAPs evidenced by notch phenomenon on carotid curve but measurable only by indwelling pulmonary arterial catheterization always being a source of infection, the noninvasive parameters as independent variables were entered into canonical discriminant analysis. The ratio of the correctly classified cases was 89%.

Acute Disease↗
PubMed1990

Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension.

An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis.

STUDY OBJECTIVE: The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis. DESIGN: In 72 male Wistar rats (250-350 g) the transient stimulus model was based on the administration of isoprenaline (500 micrograms.kg-1) while the sustained stimulus model was produced by abdominal aortic banding with right renal artery constriction. Serial sections of myocardium were examined and compared at 4 and 12 weeks in each model and to corresponding controls. EXPERIMENTAL MATERIAL: The collagen specific stain, Sirius Red F3BA, was used to determine collagen volume fraction and the fibrillar nature of the fibrous tissue response seen by light microscopy. MEASUREMENTS AND MAIN RESULTS: Following isoprenaline a stable reparative fibrosis of the endomyocardium and increase in collagen volume fraction was seen without an interstitial or perivascular fibrosis of the non-involved myocardium. In unilateral renal ischemia, on the other hand, a progressive perivascular fibrosis was evident throughout the myocardium and from which fibrillar collagen extended into the extracellular space between muscle bundles creating an interstitial fibrosis; microscopic scarring of the endomyocardium became evident at 12 weeks. CONCLUSIONS: The reactive perivascular fibrosis of intramyocardial coronary arteries seen in renovascular hypertension is a progressive process that leads to an interstitial fibrosis and eventual microscopic scarring. In contrast, the endomyocardial scarring that follows isoprenaline induced myocyte necrosis is stable and intramural vessels in remote regions are not involved.

Animals↗
PubMed1990

Fibrillar collagen and remodeling of dilated canine left ventricle.

To test the hypothesis that in the failing volume-overloaded ventricle, the extracellular matrix and fibrillar collagen in particular are major determinants of the architectural remodeling of the myocardium, this histopathological study of the dilated, postmortem canine left ventricle secondary to rapid ventricular pacing or aortocaval fistula was undertaken. Using the picrosirius-polarization technique to enhance collagen birefringence, we sought to examine the structural integrity of the collagen matrix and interstitium. In the dilated failing ventricle secondary to rapid pacing, we found 1) interstitial edema and a disruption or disappearance of collagen fibers that were apparent within 6 hours of pacing, persisted for weeks, and subsequently were associated with muscle fiber disorganization within the endomyocardium, 2) interstitial fibrosis that was present in the midwall and epimyocardium with chronic pacing, and 3) an early remodeling of intramyocardial coronary arteries that included medial swelling with smooth muscle degeneration followed by proliferative lesions involving fibroblasts and a subsequent perivascular and medial fibrosis. Many of these findings were still evident 48 hours after pacing had been discontinued. In contrast, the collagen matrix and interstitium seen with ventricular dilatation secondary to the circulatory overload that accompanies an aortocaval fistula were indistinguishable from that in sham-operated controls. Thus, we conclude that unlike the chamber enlargement and preserved ventricular function that accompany an aortocaval fistula, ventricular dilatation and failure caused by rapid pacing are based on an architectural remodeling of the myocardium. This structural dilatation involves the extracellular matrix and interstitium and appears to be related to altered permeability of intramyocardial coronary arteries. The mechanism or mechanisms involved in the pathogenesis of myocardial remodeling with rapid ventricular pacing require further investigation.

Animals↗
PubMed1990

Remodeling of the rat right and left ventricles in experimental hypertension.

Pathological left ventricular hypertrophy in renovascular hypertension is associated with the accumulation of fibrillar collagen within the extracellular space and around intramyocardial coronary arteries. Even though the angiotensin converting enzyme inhibitor captopril was previously found to attenuate this interstitial and perivascular fibrosis, the relative importance of arterial and ventricular systolic pressures versus circulating angiotensin II (AII) and aldosterone (AL) in promoting hypertrophy and collagen accumulation in renovascular hypertension is uncertain. By drawing on the in-parallel arrangement of the right and left ventricles, with respect to their coronary circulation, and the in-series mechanical alignment of the ventricles, with a pressure-overloaded left and a normotensive right ventricle, this study sought to address this uncertainty. Three models of experimental hypertension, each having a different circulating AII and AL profile, were examined and compared with their controls: renovascular hypertension, where both AII and AL are increased; infrarenal aorta banding, where AII and AL are normal; and a chronic infusion of AL, where AII is suppressed or normal and AL is increased. In renovascular hypertension, as well as with AL, we found a significant rise in the interstitial collagen volume fraction and perivascular collagen area of the pressure-overloaded, hypertrophied left ventricle as well as the normotensive, nonhypertrophied right ventricle. This remodeling was not seen in either ventricle with infrarenal aorta banding despite comparable systemic hypertension and left ventricular hypertrophy. Thus, in experimental arterial hypertension in the rat, myocyte and nonmyocyte compartments of the myocardium are under separate controls: myocyte hypertrophy is most closely related to ventricular loading while circulating AII and AL, acting alone or in concert with other humoral factors, regulate the accumulation of collagen within the right and left ventricles.

Aldosterone↗
PubMed1989

Patterns of myocardial fibrosis.

The interstitium of the myocardium is composed of predominantly type I collagen; type III collagen is present to a lesser extent. The fibrillar collagens serve as tethers between muscle cells, muscle fibers, and blood vessels while also providing a scaffolding that supports the muscular and vascular compartments. In pressure overload hypertrophy, a continuous structural remodeling of the fibrillar collagen matrix is seen. What is initially an adaptive process that enhances tensile strength can eventuate in pathologic hypertrophy with muscle fiber entrapment, cell loss, and abnormal diastolic and systolic stiffness of the myocardium. Morphologically distinct patterns of myocardial collagen accumulation, or fibrosis, have been identified based on the alignment of thick and thin collagen fibers to one another and to cardiac muscle. Each pattern, representing either a reactive (without necrosis) or reparative process, can alter stiffness in a unique manner. The manner in which the interstitium regulates the nature and proportion of fibrillar collagen formation is unknown and deserving of further study. Such information may lead to the development of antifibrotic agents that counteract, prevent or modify disproportionate collagen remodeling in pressure overload hypertrophy. These agents may thereby ultimately represent corrective forms of therapy for the management of heart failure.

Animals↗