Myocardial fibrosis is an integral component of most cardiac pathologic conditions and contributes to the development of both systolic and diastolic dysfunction. Because of the availability of genetically manipulated animals, mouse models are essential for understanding the mechanisms involved in the pathogenesis of cardiac fibrosis. Accordingly, we characterized the inflammatory and fibrotic response in a mouse model of cardiac pressure overload due to transverse aortic constriction (TAC). Following TAC, mouse hearts exhibited induction of chemokines and proinflammatory cytokines, associated with macrophage, but not neutrophil, infiltration. Induction of inflammatory cytokines was followed by a late upregulation of Transforming Growth Factor (TGF)-β isoforms, activation of the Smad2/3 and Smad1/5 pathways, induction of matricellular proteins, and deposition of collagen. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted, accompanied by ventricular dilation and systolic dysfunction. Late induction of inhibitory mediators, such as TGF-β may play an essential role in the transition from inflammation to fibrosis by suppressing inflammatory gene synthesis while inducing matrix deposition. Our findings identify molecular mediators and pathways with a potential role in cardiac fibrosis laying the foundations for studies exploring the pathogenesis of fibrotic cardiac remodeling using genetically targeted mice.

Serum specimens from patients admitted to a respiratory disease hospital were examined by the histoplasmin latex agglutination, the complement fixation, and the agar gel immunodiffusion tests. Of 300 sera examined, 21 (7.0%) gave an apparent false positive reaction at a dilution of 1:16 or greater. Fourteen (66%) of the 21 patients studied has culturally proven tuberculosis. One patient each had a diagnosis of hypertensive cardiovascular disease with congestive heart failure, infection with atypical mycobacteria (Runyon group III), chronic pneumonitis secondary to gunshot wound, and pulmonary abscess of unknown etiology; two had bronchogenic carcinoma; and one serum specimen came from an apparently healthy employee. The results of the histoplasmin latex agglutination test should be interpreted with caution, particularly if only one serological determination has been made and the titer is low.

Cardiac pressure overload results in hypertrophy and fibrotic remodeling of the ventricle. We hypothesized that development of fibrosis in the pressure‐overloaded heart may be preceded by activation an inflammatory cascade; subsequent induction of inhibitory pathways (such as TGF‐β) may suppress inflammation while inducing fibrosis. C57/BL6 mice underwent transverse aortic constriction (TAC) protocols. Chemokine (MCP‐1, MIP‐1alpha, RANTES and Lymphotactin) and pro‐inflammatory cytokine (TNF‐alpha and IL‐1beta) expression was induced in the pressure overloaded heart after 3–7 days of TAC. Upregulation of inflammatory mediators was associated with perivascular and interstitial macrophage infiltration. Induction of pro‐inflammatory mediators was followed by a late upregulation of TGF‐β isoforms associated with expression of the matricellular proteins tenascin‐C, OPN and TSP‐1. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted. The development of fibrosis was associated with cardiac hypertrophy, ventricular dilation and systolic dysfunction. In the pressure overloaded heart, late induction of inhibitory mediators, such as TGF‐β, may suppress inflammation while inducing fibrosis. Experiments using genetically targeted animals will dissect the mechanisms responsible for fibrotic remodeling of the ventricle (R01 HL‐76246).