Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction.

While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague-Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible-nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-α, transforming growth factor (TGF)-ß(1) and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study.

Galectin-3 and Beclin1/Atg6 genes in human cancers: using cDNA tissue panel, qRT-PCR, and logistic regression model to identify cancer cell biomarkers.

BACKGROUND: Cancer biomarkers are sought to support cancer diagnosis, predict cancer patient response to treatment and survival. Identifying reliable biomarkers for predicting cancer treatment response needs understanding of all aspects of cancer cell death and survival. Galectin-3 and Beclin1 are involved in two coordinated pathways of programmed cell death, apoptosis and autophagy and are linked to necroptosis/necrosis. The aim of the study was to quantify galectin-3 and Beclin1 mRNA in human cancer tissue cDNA panels and determine their utility as biomarkers of cancer cell survival. METHODS AND RESULTS: A panel of 96 cDNAs from eight (8) different normal and cancer tissue types were used for quantitative real-time polymerase chain reaction (qRT-PCR) using ABI7900HT. Miner2.0, a web-based 4- and 3-parameter logistic regression software was used to derive individual well polymerase chain reaction efficiencies (E) and cycle threshold (Ct) values. Miner software derived formula was used to calculate mRNA levels and then fold changes. The ratios of cancer to normal tissue levels of galectin-3 and Beclin1 were calculated (using the mean for each tissue type). Relative mRNA expressions for galectin-3 were higher than for Beclin1 in all tissue (normal and cancer) types. In cancer tissues, breast, kidney, thyroid and prostate had the highest galectin-3 mRNA levels compared to normal tissues. High levels of Beclin1 mRNA levels were in liver and prostate cancers when compared to normal tissues. Breast, kidney and thyroid cancers had high galectin-3 levels and low Beclin1 levels. CONCLUSION: Galectin-3 expression patterns in normal and cancer tissues support its reported roles in human cancer. Beclin1 expression pattern supports its roles in cancer cell survival and in treatment response. qRT-PCR analysis method used may enable high throughput studies to generate molecular biomarker sets for diagnosis and predicting cancer treatment response.

Quantitative analysis of p53 expression in human normal and cancer tissue microarray with global normalization method.

Tissue microarray based immunohistochemical staining and proteomics are important tools to create and validate clinically relevant cancer biomarkers. Immunohistochemical stains using formalin-fixed tissue microarray sections for protein expression are scored manually and semi-quantitatively. Digital image analysis methods remove some of the drawbacks of manual scoring but may need other methods such as normalization to provide across the board utility. In the present study, quantitative proteomics-based global normalization method was used to evaluate its utility in the analysis of p53 protein expression in mixed human normal and cancer tissue microarray. Global normalization used the mean or median of ß-actin to calculate ratios of individual core stain intensities, then log transformed the ratios, calculate a mean or median and subtracted the value from the log of ratios. In the absence of global normalization of p53 protein expression, 44% (42 of 95) of tissue cores were positive using the median of intensity values and 40% (38 of 95) using the mean of intensities as cut-off points. With global normalization, p53 positive cores changed to 20% (19 of 95) when using median of intensities and 15.8%(15 of 95) when the mean of intensities were used. In conclusion, the global normalization method helped to define positive p53 staining in the tissue microarray set used. The method used helped to define clear cut-off points and confirmed all negatively stained tissue cores. Such normalization methods should help to better define clinically useful biomarkers.

Postmyocardial infarct remodeling and heart failure: potential contributions from pro- and antiaging factors.

Myocardial infarction and adverse postinfarct remodeling in older persons lead to poor outcome and need greater understanding of the contributions of age-related factors on abnormal cardiac function and management. In this perspective, how normal aging processes could contribute to the events of post-myocardial infarction and remodeling is reviewed. Post-myocardial infarction and remodeling involve cardiomechanical factors and neurohormonal response. Many factors prevent or accelerate aging including immunosenescence, recruitment and regeneration of stem cells, telomere shortening, oxidative damage, antiaging hormones klotho and melatonin, nutrition, and Sirtiun protein family, and these factors could affect post-MI remodeling and heart failure. Interest in stem cell repair of myocardial infarcts to mitigate post-MI remodeling needs more information on aging of stem cells, and potential effects on stem cell use in infarct repair. Integrating genomics and proteomics methods may help find clinically novel therapy in the management of post-MI remodeling and heart failure in aged individuals.

Human cancer classification: a systems biology- based model integrating morphology, cancer stem cells, proteomics, and genomics.

Human cancer classification is currently based on the idea of cell of origin, light and electron microscopic attributes of the cancer. What is not yet integrated into cancer classification are the functional attributes of these cancer cells. Recent innovative techniques in biology have provided a wealth of information on the genomic, transcriptomic and proteomic changes in cancer cells. The emergence of the concept of cancer stem cells needs to be included in a classification model to capture the known attributes of cancer stem cells and their potential contribution to treatment response, and metastases. The integrated model of cancer classification presented here incorporates all morphology, cancer stem cell contributions, genetic, and functional attributes of cancer. Integrated cancer classification models could eliminate the unclassifiable cancers as used in current classifications. Future cancer treatment may be advanced by using an integrated model of cancer classification.

Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker.

BACKGROUND: Elderly patients with reperfused ST-segment-elevation myocardial infarction are at increased risk for left ventricular remodeling. Extracellular matrix damage has been implicated in early remodeling. We hypothesized that aging results in enhanced early reperfusion injury and left ventricular remodeling after reperfused ST-segment-elevation myocardial infarction and that early therapy initiated at the time of reperfusion with an angiotensin II type 1 receptor blocker such as candesartan attenuates age-related increases in reperfusion injury and remodeling. METHODS AND RESULTS: We randomized 3 groups of dogs (age, 1 to 2, 2.1 to 5, and 5.1 to 10 years) with reperfused ST-segment-elevation myocardial infarction (90 minutes of ischemia, 2 hours of reperfusion) to therapy with placebo or candesartan (1 mg/kg CV-11974) over 30 minutes from the onset of reperfusion. Reperfusion in placebo groups was associated with aging-related changes in the ischemic zones in markers of damage (increased ischemic injury, infarct size [as percent risk], cardiomyocyte apoptosis, blood flow impairment, no reflow), structural remodeling (increased left ventricular dilation and dysfunction), extracellular matrix remodeling (increased expression of secretory leucocyte protease inhibitor, secreted protein acidic and rich in cysteine, osteopontin, a disintegrin and metalloproteinase-10 and -17, and matrix metalloproteinase-9 and -2), and inflammation (increased inducible nitric oxide synthase, proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, and transforming growth factor-beta(1); decreased antiinflammatory cytokine interleukin-10). Compared with placebo, candesartan attenuated these age-dependent changes. CONCLUSIONS: Aging results in age-dependent early increases in markers of damage and adverse structural and matrix remodeling after ST-segment-elevation myocardial infarction reperfused after 90 minutes of ischemia, and early therapy initiated at the time of reperfusion with the angiotensin II type 1 receptor blocker candesartan attenuates these changes. This strategy needs clinical confirmation.

Cutaneous solitary neural hamartoma: report of an unusual case.

Cutaneous hamartomas are tumor-like proliferations of tissue indigenous to the organ but arranged abnormally. There are examples in the literature of cutaneous hamartomas composed of a variety of different components. To our knowledge, there is no previous report of such cutaneous solitary neural hamartoma. Our case occurred in a 51-year-old man with pain and paresthesia in the right shoulder associated with a nodule that was surgically removed. There was no history of trauma, other skin nodules, neurofibromatosis, or tuberous sclerosis. Histologically, there was an unencapsulated nodule, composed of mature nerve bundles noted abnormally high within the papillary dermis, extending to the reticular dermis with periadnexal distribution. Immunohistochemically, the nerve bundles were positive for S-100, including the smaller nerve twigs, and the perineurium was highlighted by epithelial membrane antigen, reminiscent of normal peripheral nerves. Although, neural components including mature nerve bundles have been described in various cutaneous hamartomas, this represents a peculiar case of a cutaneous mature peripheral nerve hamartoma. Whether this is related to other entities of cutaneous hamartomas (ie, neurofollicular hamartoma, folliculosebaceous cystic hamartoma) is not yet apparent, although it is probably a unique entity.

Immunohistochemistry in diagnostic surgical pathology: contributions of protein life-cycle, use of evidence-based methods and data normalization on interpretation of immunohistochemical stains.

Immunohistochemical (IHC) staining of formalin-fixed and paraffin-embedded tissues (FFPE) is widely used in diagnostic surgical pathology. All anatomical and surgical pathologists use IHC to confirm cancer cell type and possible origin of metastatic cancer of unknown primary site. What kinds of improvements in IHC are needed to boost and strengthen the use of IHC in future diagnostic pathology practice? The aim of this perspective is to suggest that continuing reliance on immunohistochemistry in cancer diagnosis, search and validation of biomarkers for predictive and prognostic studies and utility in cancer treatment selection means that minimum IHC data sets including "normalization methods" for IHC scoring, use of relative protein expression levels, use of protein functional pathways and modifications and protein cell type specificity may be needed when markers are proposed for use in diagnostic pathology. Furthermore evidence based methods (EBM), minimum criteria for diagnostic accuracy (STARD), will help in selecting antibodies for use in diagnostic pathology. In the near future, quantitative methods of proteomics, quantitative real-time polymerase chain reaction (qRT-PCR) and the use of high-throughput genomics for diagnosis and predictive decisions may become preferred tools in medicine.

Role of healing-specific-matricellular proteins and matrix metalloproteinases in age-related enhanced early remodeling after reperfused STEMI in dogs.

We assessed whether aging augments left ventricular (LV) damage, remodeling, and dysfunction and alters expression of healing-specific-matricellular proteins (HSMPs), matrix metalloproteinases (MMPs) and other pertinent proteins after acute reperfused-ST-segment-elevation myocardial infarction (RSTEMI) in the dog model. The findings suggest a novel role for HSMPs, MMPs, and the other proteins in the age-related increase in LV damage, remodeling, and dysfunction. Potentially detrimental effects of the altered proteins appear to outweigh beneficial effects and contribute to adverse outcome. Deleterious changes include the increase in matrix-degrading MMPs, inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, HSMPs such as secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN), the blunted increase in endothelial-NOS (eNOS), and the decrease in IL-10 and neuronal NOS (nNOS). Potentially beneficial changes include increases in the HSMP secretory-leucocyte-protease-inhibitor (SLPI) and cytokine transforming growth factor (TGF)-beta(1). Targeting these proteins may mitigate enhanced LV remodeling and dysfunction with aging.

Comparison of vasopeptidase inhibitor omapatrilat and angiotensin receptor blocker candesartan on extracellular matrix, myeloperoxidase, cytokines, and ventricular remodeling during healing after reperfused myocardial infarction.

We determined effects of the vasopeptidase inhibitor (VPI) omapatrilat and angiotensin II type 1 receptor (AT(1)R) blocker (ARB) candesartan in rats during healing between day-2 and day-21 after reperfused myocardial infarction (RMI) on left ventricular (LV) remodeling and function, and regional matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-3, inducible-nitric-oxide-synthase (iNOS), oxidant-generating myeloperoxidase (MPO), and cytokines tumor-necrosis-factor (TNF)-alpha, interleukin (IL)-6 and IL-10, and transforming-growth-factor (TGF)-beta(1), and collagens. Compared to RMI-placebo, both agents reversed adverse LV remodeling and systolic and diastolic dysfunction, improved collagen remodeling, and normalized MMP-9 (activity, protein, and mRNA), TIMP-3 (protein and mRNA), and iNOS, MPO, TNF-alpha, IL-6, and TGF-beta(1) proteins, and improved MMP-9/TIMP-3 balance and IL-10 levels in previously ischemic zones. The results suggest that modulation of matrix proteases, oxidants, cytokines, and NOSs with omapatrilat and candesartan contribute to reversal of adverse collagen and LV remodeling and attenuation of LV dysfunction during healing after RMI.

A floor of mouth teratoid cyst with tract in a newborn--case report and English literature review unraveling erroneous quotes and citations.

Dysontogenetic cysts are thought to fall into one of three classes: epidermoids, dermoids or teratoids. Floor of mouth teratoid cysts are the least common presentation reported. Over the last 70 years, fewer than 20 histologically proven cases have been described in the English literature. We report an infant presenting with this lesion in association with a midline tract. The cyst was identified at birth and interfered with feeding. It was surgically excised with no recurrence at 10 month point of follow-up. A literature search revealed that confusing terminology and indirect quotation disseminated false beliefs regarding the epidemiology. Contrary to most reports, floor of mouth teratoid cysts are most commonly encountered in childhood with only a handful of cases in older age groups.

Oxidative stress and matrix metalloproteinase-9 activity in the liver after hypoxia and reoxygenation with 21% or 100% oxygen in newborn piglets.

We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1-3 days old, weight 1.5-2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10-15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.

Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures.

We investigated whether therapeutic drugs given during healing following acute myocardial infarction (AMI) modify infarct collagens and left ventricular (LV) distensibility. We treated dogs with drugs from major classes (i.e., indomethacin, ibuprofen, captopril, enalapril, verapamil, amlodipine, propranolol, isosorbide dinitrate [ISDN] and digoxin) between day 2 and 6 weeks and measured hemodynamics, LV remodeling and function during healing over 6 weeks after transmural anterior AMI, and regional collagens, LV distensibility under increasing pressure, rupture threshold (RT), and topography at 6 weeks. Relative to sham, AMI controls showed infarct zone (IZ) expansion and thinning, 9.3-fold increase in IZ collagen, LV dilation and dysfunction, and no change in distensibility and RT. Relative to controls, indomethacin as well as enalapril, captopril and amlodipine decreased IZ collagen. Infarct expansion was attenuated by ibuprofen, captopril, amlodipine and ISDN but augmented by indomethacin. Infarct thinning was prevented by captopril, amlodipine and ISDN but enhanced by indomethacin. Importantly, indomethacin and enalapril enhanced LV distensibility and lowered RT. Distensibility correlated positively with IZ type III collagen and negatively with type I/III collagen ratio and pyridinoline cross-links whereas RT correlated positively with IZ type I collagen. Systolic volume and ejection fraction deteriorated with indomethacin but were improved or preserved with other therapies. The results demonstrate that different therapeutic drugs may produce different effects on IZ collagens during healing post-AMI: drugs that attenuate or adversely alter IZ collagens also enhance LV distensibility, augment adverse remodeling and lower RT, suggesting that testing for these effects post-AMI is warranted.

Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction.

To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

Tissue-specific changes in glutathione content of hypoxic newborn pigs reoxygenated with 21% or 100% oxygen.

We compared the responses towards oxidative stress in the liver, lung, brain, heart, kidney and small intestine of hypoxic newborn animals resuscitated with 21% or 100% oxygen. After stabilization, piglets (1-3 days, 1.6-2.0 kg, n=8/group) were randomized to receive 2 h of alveolar hypoxia (FiO(2)=0.10-0.14) followed by reoxygenation with 21% or 100% oxygen for 1 h and then another hour with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. At the end of the experiment, tissues from liver, lung, brain, heart, kidney and small intestine were collected and tested for GSH, GSSG and lipid peroxidation levels and histological examination. In normoxic controls, liver had the highest GSH level, followed by brain, heart, lung, small intestine and kidney which had the highest level of oxidative stress markers (GSSG level and GSSG:GSH ratio). Hypoxic-reoxygenated piglets had the highest GSSG levels and GSSG:GSH ratio in the kidney. Hypoxic piglets resuscitated with 100% oxygen had higher GSSG:GSH ratios in the lung and liver, but not in the kidney, brain, heart and small intestine, than controls, which were not different from the 21% group. No significant differences in peroxidation and histological tissue damage were found between groups in the liver and lung. We concluded that although hypoxic piglets resuscitated with 100% oxygen have higher oxidative stress in the liver and lung than with 21% oxygen, there are no significant differences in peroxidation and histological tissue damage acutely.

Spindle checkpoint protein hMad2 and histone H3 phosphoserine 10 mitosis marker in pediatric solid tumors.

Pediatric solid tumors of different histologic types are often treated with drugs (such as vincristine) that directly or indirectly target the mitotic spindle and the spindle checkpoint, leading to mitotic arrest, mitotic catastrophe and apoptosis. hMad2 (mitosis arrest deficient 2) expression in neuroblastoma has suggested utility in predicting prognosis. The present study was undertaken to determine hMad2 expression patterns in pediatric solid tumors, and its relationship to overall treatment response and short-term survival (2-years). The expression of hMad2 and histone H3-serine 10 phosphoprotein (mitosis marker) were examined using immunohistochemical staining methods in 26 pediatric solid tumors (six neuroblastomas, eight Wilm's, five sarcomas, four lymphomas and three hepatoblastomas). hMad2 expression paralleled overall histone H3 phosphoserine 10 expression in most tumor types. Low hMad2 score tumors (0-3.5) exhibited lower complete response (66.67%) and a higher recurrence/progressive disease (33.33%) than high score tumors (4-6) (78.57% and 21.43. %), consistent with predicted hMad2 function and reports in adult tumors. Histone H3 serine 10 phosphoprotein is useful in mitosis enumeration and hMad2 expression may provide additional help in neuroblastoma profiling and could be useful when spindle checkpoint specific target drugs are used.

Apoptosis and oncosis in acute coronary syndromes: assessment and implications.

The rational design of therapeutic interventions for protection of ischemic myocardium from ultimate death requires an understanding of the mechanistic basis of cardiomyocyte (CM) cell death, its timing and the tools for its quantification. Until recently, CM cell death following ischemia and/or reperfusion was considered to involve necrosis or 'accidental cell death' from very early on. Collective evidence over the past decade indicates that early CM cell death after myocardial ischemia and post-ischemic reperfusion involves apoptosis with cell shrinkage and drop-out, and/or oncosis with cell swelling followed by necrosis. This paradigm shift suggests that different approaches for cardioprotection are required. Oncologists, pathologists, anatomists and basic scientists who have studied apoptosis over the last three decades separated physiological apoptosis from inappropriate apoptosis in pathological states. Until recently, cardiologists resisted the concepts of CM apoptosis and regeneration. Cumulative evidence indicating that apoptosis in the heart may occur in different cell types, spread from one cell type to another, and occur in bursts, may have profound implications for therapies aimed at protection of ischemic myocardium by targeting CM apoptosis in acute coronary syndromes. This review focuses on a critique of the methods used for the assessment of CM apoptosis and the implications of CM apoptosis in acute coronary syndromes.

Vascular remodeling during healing after myocardial infarction in the dog model: effects of reperfusion, amlodipine and enalapril.

OBJECTIVES: We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ). BACKGROUND: The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined. METHODS: We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks. RESULTS: Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ. CONCLUSIONS: The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.