A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1.

Longitudinal evaluation of a seven generation kindred with an inherited conduction system defect and dilated cardiomyopathy demonstrated autosomal dominant transmission of a progressive disorder that both perturbs atrioventricular conduction and depresses cardiac contractility. To elucidate the molecular genetic basis for this disorder, a genome-wide linkage analysis was performed. Polymorphic loci near the centromere of chromosome 1 demonstrated linkage to the disease locus (maximum multipoint lod score = 13.2 in the interval between D1S305 and D1S176). Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy.

A comparison of the mechanical and structural properties of fibrin fibers with other protein fibers.

In the past few years a great deal of progress has been made in studying the mechanical and structural properties of biological protein fibers. Here, we compare and review the stiffness (Young's modulus, E) and breaking strain (also called rupture strain or extensibility, epsilon(max)) of numerous biological protein fibers in light of the recently reported mechanical properties of fibrin fibers. Emphasis is also placed on the structural features and molecular mechanisms that endow biological protein fibers with their respective mechanical properties. Generally, stiff biological protein fibers have a Young's modulus on the order of a few Gigapascal and are not very extensible (epsilon(max) < 20%). They also display a very regular arrangement of their monomeric units. Soft biological protein fibers have a Young's modulus on the order of a few Megapascal and are very extensible (epsilon(max) > 100%). These soft, extensible fibers employ a variety of molecular mechanisms, such as extending amorphous regions or unfolding protein domains, to accommodate large strains. We conclude our review by proposing a novel model of how fibrin fibers might achieve their extremely large extensibility, despite the regular arrangement of the monomeric fibrin units within a fiber. We propose that fibrin fibers accommodate large strains by two major mechanisms: (1) an alpha-helix to beta-strand conversion of the coiled coils; (2) a partial unfolding of the globular C-terminal domain of the gamma-chain.

Clinical characteristics of sudden death victims in heritable (chromosome 1p1-1q1) conduction and myocardial disease.

OBJECTIVES: The purpose of this study was to identify the clinical characteristics of family members at risk of sudden death. BACKGROUND: The significance of sudden death in heritable cardiac disorders with delayed expression is incompletely understood. Additional insights come from a four-decade experience of seven generations of a family of German origin with autosomal dominant (chromosome 1p1-1q1) cardiac conduction and myocardial disease. METHODS AND RESULTS: A total of 38 family members (20 males; 18 females) were identified with sudden death. Twenty-eight family members (mean age 48+/-8 years) from earlier generations had no pacemaker at the time of sudden death. In this group, 15 subjects were asymptomatic prior to sudden death. Ten family members with sudden death, from later generations, had chronically implanted pacemakers for high grade atrioventricular block. This group was older (mean age 57+/-2 years), with decreased functional status (New York Heart Association class II to IV), enlarged left atria, dilated left ventricles with reduced systolic function and documented ventricular fibrillation in three members. Twenty-eight family members with sudden death were descendants of sib lineages 2 or 6; 21 family members with sudden death were offspring of a parent who also suffered sudden death. CONCLUSION: Sudden death is an important late outcome in heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease. Pacemaker therapy is important for the treatment of symptomatic bradycardia, but it does not prevent sudden death. Family members who are beyond the third decade of life with reduced functional capacity, left ventricular dysfunction, pacemakers and who are the offspring of a parent with sudden death appear to be at greatest risk

Left atrial performance indices in chronic mitral valve disease.

Multidimensional left atrial (LA) performance indices have not been extensively studied in chronic mitral valve disease. LA maximal volume, stroke volume (LA volume at atrial systole minus LA minimal volume), LA ejection fraction (stroke volume/volume at atrial systole) and A-wave velocity, were measured in 14 patients with mitral stenosis (mean mitral valve area 1.5 cm2); 14 patients with chronic mitral regurgitation all in sinus rhythm; and were compared to 20 age and sex matched normal control subjects using biplane transthoracic echo and pulsed Doppler. Although LA volumes--maximal and at onset of atrial systole--were greater in mitral regurgitation and mitral stenosis (p < 0.01) compared to normal subjects, LA ejection fraction was not statistically different among the three groups. LA stroke volume was greater in mitral regurgitation and mitral stenosis compared to normal subjects, p < 0.01. LA kinetic energy (LAKE) = 1/2 mv2 (m = LA stroke volume x 1.06, blood's specific gravity, v = A wave velocity) was increased in mitral stenosis and mitral regurgitation compared to normal subjects (p < 0.001). An inverse correlation (r = 0.66, p < 0.01) was present between LAKE and mitral valve area in mitral stenosis. It is concluded that LA function, a complex interplay of multiple factors, requires multidimensional methods of analysis beyond standard measurements of size and volume, which provide additional insight into normal LA function, and better definition of LA function changes involved in the natural history of chronic mitral valve disease.

The mechanical properties of single fibrin fibers.

SUMMARY BACKGROUND: Blood clots perform the mechanical task of stemming the flow of blood. OBJECTIVES: To advance understanding and realistic modeling of blood clot behavior we determined the mechanical properties of the major structural component of blood clots, fibrin fibers. METHODS: We used a combined atomic force microscopy (AFM)/fluorescence microscopy technique to determine key mechanical properties of single crosslinked and uncrosslinked fibrin fibers. RESULTS AND CONCLUSIONS: Overall, full crosslinking renders fibers less extensible, stiffer, and less elastic than their uncrosslinked counterparts. All fibers showed stress relaxation behavior (time-dependent weakening) with a fast and a slow relaxation time, 2 and 52 s. In detail, crosslinked and uncrosslinked fibrin fibers can be stretched to 2.5 and 3.3 times their original length before rupturing. Crosslinking increased the stiffness of fibers by a factor of 2, as the total elastic modulus, E(0), increased from 3.9 to 8.0 MPa and the relaxed, elastic modulus, E(infinity), increased from 1.9 to 4.0 MPa upon crosslinking. Moreover, fibers stiffened with increasing strain (strain hardening), as E(0) increased by a factor of 1.9 (crosslinked) and 3.0 (uncrosslinked) at strains epsilon > 110%. At low strains, the portion of dissipated energy per stretch cycle was small (< 10%) for uncrosslinked fibers, but significant (approximately 40%) for crosslinked fibers. At strains > 100%, all fiber types dissipated about 70% of the input energy. We propose a molecular model to explain our data. Our single fiber data can now also be used to construct a realistic, mechanical model of a fibrin network.

Strength and failure of fibrin fiber branchpoints.

See also Weisel JW. Biomechanics in hemostasis and thrombosis. This issue, pp 1027-9; Liu W, Carlisle CR, Sparks EA, Guthold M. The mechanical properties of single fibrin fibers. This issue, pp 1030-6.

Fibrin fibers have extraordinary extensibility and elasticity.

Blood clots perform an essential mechanical task, yet the mechanical behavior of fibrin fibers, which form the structural framework of a clot, is largely unknown. By using combined atomic force-fluorescence microscopy, we determined the elastic limit and extensibility of individual fibers. Fibrin fibers can be strained 180% (2.8-fold extension) without sustaining permanent lengthening, and they can be strained up to 525% (average 330%) before rupturing. This is the largest extensibility observed for protein fibers. The data imply that fibrin monomers must be able to undergo sizeable, reversible structural changes and that deformations in clots can be accommodated by individual fiber stretching.

Long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance: double blind, prospective, randomised study.

OBJECTIVE: To study the long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance. PATIENTS: 181 African American subjects with insulin resistance and normal glucose tolerance test were randomised to receive glipizide 5 mg/day (n = 25), metformin 500 mg/day (n = 59), or placebo (n = 97) for 24 months. Insulin sensitivity, glucose tolerance, lipid profile, left ventricular mass (echocardiography), aortic distensibility (echocardiography, blood pressure), aortic pulse wave velocity (PWV, carotid to femoral artery, Doppler) were measured at baseline and at 12 and 24 months after randomisation. RESULTS: A significant increase in PWV was observed in both glipizide (mean (SEM) change at 24 months 2.8 (2.7) m/s, p = 0.012) and metformin (2.2 (0.7) m/s, p = 0.01) groups during the follow up period. In contrast, PWV remained unchanged in the placebo group. The increase in PWV in the treatment groups was significant compared with placebo (analysis of variance p < 0.05). Other cardiovascular or metabolic variables did not change significantly compared with placebo during follow up. CONCLUSIONS: The observed increase in PWV is consistent with a decrease in the elastic properties of the aorta. The use of oral antidiabetic agents for the prevention of cardiovascular complications in non-diabetic African Americans with insulin resistance needs to be critically evaluated.

Cardiovascular effects of aging. Interrelationships of aortic, left ventricular, and left atrial function.

BACKGROUND: Previous studies have shown that elastic properties of the aorta decrease, while left atrial dimensions, the contribution of left atrial systole to left ventricular filling, and left ventricular mass increase with age. In most studies, however, aortic function, and ventricular and atrial parameters were performed in different populations, and thus, the earliest manifestation of aging in the cardiovascular system is not known. The present study was undertaken to define the earliest cardiovascular abnormality(ies) occurring in the cardiovascular system with age. PATIENTS AND METHOD: In 181 normotensive subjects (147 females and 34 males) age 22-64 years, left ventricular mass, volumes, function and work (echocardiography and blood pressure), left atrial volumes and stroke volume (biplane area-length method by echo), pulse wave velocity (PWV) (carotid to femoral artery, Doppler), and left atrial kinetic energy were measured simultaneously: left atrial kinetic energy = 1/2 mv2, where m = left atrial stroke volume x 1.06 (blood specific gravity), v = transmitral A wave velocity. Regression analyses were performed to correlate all measured cardiovascular parameters with age. RESULTS: Pulse wave velocity (r = 0.51), left atrial kinetic energy (r = 0.42), and A wave velocity (r = 0.38) were correlated to age, while left ventricular mass, function and work were not. Multiple regression analysis among ten clinical and echocardiographic parameters demonstrated that only age contributed independently to pulse wave velocity; only age and pulse wave velocity were contributed independently to left atrial kinetic energy; and only age contributed independently to A wave velocity. CONCLUSIONS: The data demonstrate that age-related alterations in aortic function and left atrial work (left atrial kinetic energy) can be defined prior to changes in left ventricular structure and systolic function. Simultaneous studies of left atrial, left ventricular, and aortic function are required to better understand the effect of aging on the cardiovascular system.