Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunc- (Circulation 1990;81:491-497) In animals, acetylcholine produces endotheliumdependent dilation of normal arteries and vasoconstriction in pathologic states such as hypersee p 697 cholesterolemia, hypertension, or atherosclerosis.1-9 Clinical studies have shown that intracoronary acetylcholine infusion constricts atherosclerotic coronary arteries.9-11 Smooth segments may also constrict in patients with coronary artery disease evident in

The remarkable facts, that the paroxysm, or indeed the disease itself, is excited more especially upon walking up hill, and after a meal; that thus excited, it is accompanied with a sensation, which threatens instant death if the motion is persisted in; and, that on stopping, the distress immediately abates, or altogether subsides; have. .. formed a constituent part of the character of Angina Pectoris. 1 " R emarks on Angina Pectoris" by John Warren, M.D., appeared in 1812 as the first article in the first issue of The New England Journal of Medicine and Surgery. 1 Warren's description of angina pectoris (derived from the Latin angina, "infection of the throat"; from the Greek άγχο′νη, "strangling"; and from the Latin pectus, "chest") is equally apt for physicians and medical students today. At the time, the pathogenesis was unknown, and treatment consisted of bloodletting, a tincture of opium, bed rest, or a combination thereof. In 1799, Caleb H. Parry speculated that Syncope Anginosa was related to coronary-artery ossification (i.e., calcification), occurring predominantly in men at about 50 years of age and rarely in women or children. 2 Medical knowledge in the 18th and 19th centuries was grounded in clinical observation and anatomical dissection. Cardiovascular science emerged in the physiological era of the late 19th and early 20th centuries, first in Europe and subsequently in North America. To celebrate the 200th anniversary of the New England Journal of Medicine, our essay focuses on the themes of coronary artery disease and myocardial infarction to highlight the interplay between science and medicine, emphasizing how the remarkable advances in our understanding of the pathogenesis of heart disease have produced life-saving and life-extending therapies. The Emergence of C orona r y A r ter y Dise a se After Heberden's clinical description of angina 3 in 1772, it took almost a century for pathologists to focus their attention on the coronary arteries and describe thrombotic occlusions in addition to "ossification." However, for decades thereafter, these observations were not related to the symptoms of myocardial ischemia, which had become well known to physicians. Near the end of the 19th century, cardiovascular physiologists noted that occlusion of a coronary artery in the dog caused "quivering" of the ventricles and was rapidly fatal. 4,5 These three great branches of medical knowledge-clinical medicine, pathology, and physiology-advanced in separate yet parallel universes. In 1879, the pathologist Ludvig Hektoen concluded that myocardial infarction is caused by coronary thrombosis "secondary to sclerotic changes in the coronaries." 6 In 1910, two Russian clinicians who were trained in pathology described five patients with the clinical picture of acute myocardial infarction, which was confirmed at postmortem examination. 7 Two years later,

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.

Objective-Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results-We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (PϽ0.0001) in coronary arteries. Conclusion-We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients.HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. Key Words: aging Ⅲ atherosclerosis Ⅲ pathology Ⅲ peripheral arterial disease Ⅲ progeria H utchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, fatal, progressive premature aging syndrome. Symptoms usually begin with failure to thrive or sclerodermatous skin changes, heralding generalized loss of subcutaneous fat, alopecia, osteopenia and acroosteolysis, and joint contracture. Death occurs at a mean age of 13 years because of myocardial infarction or stroke. 1 The majority of HGPS cases are caused by a single de novo nucleotide substitution at position 1824 (C3 T) in the LMNA gene. 2,3 The normal LMNA protein product, lamin A, is a key component of the inner nuclear lamina, which functions in nuclear structure, chromatin organization, and gene transcription. 4 The silent mutation in HGPS leads to alternative splicing at the 3Ј end of the LMNA mRNA and a 150-nucleotide deletion from the prelamin A transcript resulting in a mutant lamin A protein called progerin, which lacks 50 amino acids near its C-terminal end. 5 In non-HGPS individuals, there is convincing evidence that the HGPS splice site is functional and can lead to progerin accumulation over time, although to a lesser degree than in children with HGPS. 6 In HGPS, the cryptic donor splice site shares 6 of 7 bases with the consensus splice sequence, while non-HGPS individuals share 5 of 7 bases with the consensus splice sequence. Thus, non-HGPS individuals utilize the splice site less often. Progerin is not apparent in early passage non-HGPS cultured fibroblasts and skin biopsies, but it accumulates with increasing cell passage and donor age. 7,8 Thus, progerin is likely a previous...

Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. ‘Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.

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Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.