Impact of T lymphocytes on cardiac remodeling in hypertension: more questions than answers.

In their intriguing article appearing in this issue of Hypertension, Yu et al1 provide evidence for a role of T lymphocytes in modulating cardiac matrix remodeling resulting from hypertension. The investigators compared the impact of comparable N -nitro-L-arginine methyl ester (LNAME)–induced hypertension on cardiac function and matrix composition among 3 strains of mice with widely different T-lymphocyte profiles. They found increased ventricular stiffness, accompanied by enhanced collagen deposition and crosslinking in the strain of mice that were Th2 dominant (BALB/c). In contrast, in mice that were T(and B-) lymphocyte deficient (C57BL/6 SCID), hypertension resulted in a diminution of collagen content and cross-linking that was generally associated with heart dilation. No changes in ventricular stiffness or collagen were observed in mice that were Th1 dominant (C57BL/6 WT). Because these different responses of the heart to hypertension were observed under pre-existing dissimilar and extreme immune backgrounds, an obvious question is what impact, if any, T lymphocytes have on hypertension-associated cardiac remodeling in more common scenarios. Will it turn out that the well-established neurohormonal input into cardiac remodeling is actually an immunoneurohormal system or only that the neurohormonal component of remodeling is susceptible to modulation by extreme immune conditions? Other than this broad question, several specific questions come to mind from the work of Yu et al.1 First, how relevant is the use of L-NAME to induce hypertension and cardiac remodeling? Chronic pressure overload of the heart in animal models typically induces changes in the heart that include both increased extracellular matrix deposition and so-called compensatory left ventricular hypertrophy because of enlargement of individual cardiac myocytes.2 In contrast, whereas inhibition of NO synthesis with L-NAME causes prominent hypertension, left ventricular hypertrophy does not occur (as in the study of Yu et al1) or is minimal. The reason for this has never been adequately explained but may have to do with reduced venous return. An inhibitory effect of L-NAME on amino acid membrane transporters and protein synthesis likely plays a role too.3 Nonetheless, chronic treatment of rats with L-NAME was found to induce a concentric geometric pattern of cardiac remodeling, characterized by a reduction in left ventricular chamber size relative to wall thickness.3 Echocardiography has shown that this pattern is in fact slightly more common than concentric hypertrophy among individuals with arterial hypertension.4 Conventional thinking is that the concentric geometric pattern is an early stage, preceding concentric cardiac hypertrophy, in the ongoing remodeling of the heart in response to hypertension that ultimately leads to heart dilation and failure. A related question is what impact L-NAME had on T-lymphocyte function and subpopulation profile or, more broadly, the immune systems of the different strains of mice? Cytokines are a major means by which cells of the immune system communicate with one another, and NO synthesis is induced by many cytokines, especially interferon (IFN). Evidence shows that regulated NO signaling is important in the behavior and actions of T cells, in determining the Th1/Th2 balance, and in the interaction between the innate and adaptive immune systems.5 In this context, analysis of the cytokine profile and Th1/Th2 ratio (in the BALB/c and C57BL/6 WT mice) over the course of L-NAME treatment, not just before, would be informative. Might that consideration explain the apparent contradiction between the findings of the present study and a previous one by this laboratory? In that study,6 evidence was reported that selective induction of Th1 lymphocytes in C57BL/J mice caused increased ventricular stiffness through decreased matrix metalloproteinase (MMP) activity and increased collagen synthesis and crosslinking. In contrast, enhanced MMP activity and decreased collagen synthesis and cross-linking, leading to ventricular dilation and decreased stiffness, was observed with Th2 enhancement. How might T lymphocytes respond to increased wall stress in the heart? A likely answer is provided by the sequela of L-NAME–induced hypertension, which involves much more than increased vascular tone because of NOS inhibition.7 Chronic L-NAME administration has been shown to result in enhanced activity of both the renin–angiotensin and sympathetic nervous systems, as well as enhanced production of prostaglandins and superoxide anions. In addition, L-NAME was shown to upregulate expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aorta and to induce inflammatory cell infiltration in the heart.8 Thus, the overall consequence of L-NAME administration is a condition of cardiovascular inflammation. The proinflamThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Molecular Cardiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, College of Medicine; Scott & White; and Central Texas Veterans Health Care System, Temple, Tex. Correspondence to George W. Booz, Cardiovascular Research Institute, Texas A&M College of Medicine, 1901 S 1st St, Bldg 205, Temple, TX 76504. E-mail [email protected] (Hypertension. 2006;48:1-2.) © 2006 American Heart Association, Inc.