Coronary artery calcium scoring: an evidence-based guide for primary care physicians.

Primary care physicians often must decide whether statin therapy would be appropriate (in addition to lifestyle modification) for managing asymptomatic individuals with borderline or intermediate risk for developing atherosclerotic cardiovascular disease (ASCVD), as assessed on the basis of traditional risk factors. In appropriate subjects, a simple, noninvasive measurement of coronary artery calcium can help clarify risk. Coronary atherosclerosis is a chronic inflammatory disease, with atherosclerotic plaque formation involving intimal inflammation and repeated cycles of erosion and fibrosis, healing and calcification. Atherosclerotic plaque formation represents the prognostic link between risk factors and future clinical events. The presence of coronary artery calcification is almost exclusively an indication of coronary artery disease, except in certain metabolic conditions. Coronary artery calcification can be detected and quantified in a matter of seconds by noncontrast electrocardiogram-gated low-dose X-ray computed tomography (coronary artery calcium scoring [CACS]). Since the publication of the seminal work by Dr. Arthur Agatston in 1990, a wealth of CACS-based prognostic data has been reported. In addition, recent guidelines from various professional societies conclude that CACS may be considered as a tool for reclassifying risk for atherosclerotic cardiovascular disease in patients otherwise assessed to have intermediate risk, so as to more accurately inform decisions about possible statin therapy in addition to lifestyle modification as primary preventive therapy. In this review, we provide an overview of CACS, from acquisition to interpretation, and summarize the scientific evidence for and the appropriate use of CACS as put forth in current clinical guidelines.

Molecular Genetic Characterization of Thyroid Dyshormonogenesis in a French Bulldog.

BACKGROUND: A case of congenital hypothyroidism with goiter (CHG) in a juvenile French bulldog was identified and hypothesized to be caused by dyshormonogenesis of genetic etiology. OBJECTIVES: To describe case management, unusual phenotypic aspects, and a CHG-causing mutation in a French bulldog. ANIMALS: Thyroid tissue and blood from a CHG-affected French bulldog and 4 normal control dogs and buccal brush samples of 125 French bulldogs were studied. METHODS: Standard clinical assessment and laboratory tests were applied. Thyroid peroxidase (TPO) iodide oxidation activity was measured in vitro, and TPO protein was assessed on Western blots. Thyroid peroxidase exons and flanking splice sites were amplified from genomic DNA and sequenced. Thyroid peroxidase cDNA was amplified from thyroid RNA and sequenced. RESULTS: At 9 months of age, the affected dog had signs of cretinism, but near-normal skeletal maturation. The enlarged thyroid glands exhibited noninflammatory fibrosis and aberrant follicular organization. Thyroid peroxidase activity and immunocrossreactive protein were undetectable. There was a T>C mutation of the intron 12 splice donor consensus that caused abnormally spliced mRNA, consistent with absent TPO function. The mutant allele was not observed in 125 clinically normal French bulldogs. CONCLUSIONS: Presumptive CHG in a French bulldog with unusual clinical presentation is described. Genetic etiology was confirmed by identifying the underlying TPO mutation.

Tortuosity of coronary bifurcation as a potential local risk factor for atherosclerosis: CFD steady state study based on in vivo dynamic CT measurements.

The purpose of the present study was to determine whether in vivo bifurcation geometric factors would permit prediction of the risk of atherosclerosis. It is worldwide accepted that low or oscillatory wall shear stress (WSS) is a robust hemodynamic factor in the development of atherosclerotic plaque and has a strong correlation with the local site of plaque deposition. However, it still remains unclear how coronary bifurcation geometries are correlated with such hemodynamic forces. Computational fluid dynamics simulations were performed on left main (LM) coronary bifurcation geometries derived from CT of eight patients without significant atherosclerosis. WSS amplitudes were accurately quantified at two high risk zones of atherosclerosis, namely at proximal left anterior descending artery (LAD) and at proximal left circumflex artery (LCx), and also at three high WSS concentration sites near the bifurcation. Statistical analysis was used to highlight relationships between WSS amplitudes calculated at these five zones of interest and various geometric factors. The tortuosity index of the LM-LAD segment appears to be an emergent geometric factor in determining the low WSS amplitude at proximal LAD. Strong correlations were found between the high WSS amplitudes calculated at the endothelial regions close to the flow divider. This study not only demonstrated that CT imaging studies of local risk factor for atherosclerosis could be clinically performed, but also showed that tortuosity of LM-LAD coronary branch could be used as a surrogate marker for the onset of atherosclerosis.

Magnetic resonance elastography in the liver at 3 Tesla using a second harmonic approach.

Magnetic resonance elastography (MRE) using mechanical stimulation has demonstrated diagnostic value and clinical promise in breast, liver, and kidney at 1.5 Tesla (T). However, MRE at 1.5T suffers from long imaging times and would benefit from greater signal-to-noise for more robust postprocessing. We present an MRE sequence modified for liver imaging at 3.0T. To avoid artifacts in the phase images, the sequence maintains a short TE by using a second harmonic approach, including stronger motion encoding gradients, shorter radio frequency pulses and an echo-planar readout. Scan time was decreased by a factor of approximately 2 relative to 1.5T by using an EPI readout and a higher density sampling of the phase waveform was used to calculate shear stiffness and viscosity. Localized (small region of interest) and global (whole-liver region of interest) measurements in normal healthy subjects compared very favorably with previously published results at 1.5T. There was no significant difference between global and localized measures.

CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene.

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.

Effect of durotomy on functional outcome of dogs with type I thoracolumbar disc extrusion and absent deep pain perception.

Spinal cord durotomy is performed as a diagnostic aid in determining spinal cord structural integrity, and this may be useful as an indicator of prognosis in cases with loss of deep pain perception (DPP). It has been suggested that a durotomy may relieve intramedullary compression but there is some debate about the therapeutic value. The purpose of this study was to compare ambulatory outcome of dogs that had loss of DPP treated with hemilaminectomy with durotomy versus hemilaminectomy without durotomy. Medical records of 81 dogs diagnosed with type I thoracolumbar IVD were reviewed. Dogs were included in the study if DPP was absent upon initial neurological examination and surgical decompression via hemilaminectomy was performed. Of the 81 cases, 48 were included in this study. The number of dogs that recovered ambulatory function were compared between durotomy and non-durotomy groups with a chi-squared test (p < 0.05). No differences were found. The findings of this study suggest that durotomy is useful as a diagnostic modality and that performing a durotomy does not significantly affect post-operative recovery of voluntary motor function.

Quantitative prediction of improvement in cardiac function after revascularization with MR imaging and modeling: initial results.

PURPOSE: To evaluate a model that can be used quantitatively to predict changes in postrevascularization left ventricular function based on classification of myocardial tissue as hibernating, scarred, or normal with cine magnetic resonance (MR) imaging. MATERIALS AND METHODS: Eleven patients with chronic left ventricular dysfunction were studied before and after revascularization with cine MR imaging. Regional myocardial contractility and wall thickness were used in the model to predict postrevascularization ejection fraction (EF). The actual EF from the postrevascularization MR images was compared with the EF from the prerevascularization images predicted with the model by using regression analysis and Bland-Altman analysis. RESULTS: Correlation between the actual EF after revascularization and the EF predicted by using the model yielded an R value of 0.98, with a standard error of 1.3 EF percentage points. Predicting changes in function in a myocardial segment was less successful because only 55% of segments classified as hibernating actually improved resting function after revascularization. In nonimproved segments, 78% were either adjacent to infarcted segments or had nontransmural wall thinning. CONCLUSION: A simple mathematical model combined with functional information provided by MR imaging was used to predict improvements in global EF resulting from revascularization.

Evaluation of left ventricular endocardial volumes and ejection fractions computed from gated perfusion SPECT with magnetic resonance imaging: comparison of two methods.

BACKGROUND: Two methods of computing left ventricular volumes and ejection fraction (EF) from 8-frame gated perfusion single photon emission computed tomography (SPECT) were compared with each other and with magnetic resonance (MR) imaging. METHODS AND RESULTS: Thirty-five subjects underwent 8-frame gated dual-isotope SPECT imaging and 12- to 16-frame gated MR imaging. Endocardial boundaries on short-axis MR images were hand traced by experts blinded to any SPECT results. Volumes and EF were computed with the use of Simpson's rule. SPECT images were analyzed for the same functional variables with the use of 2 automatic programs, Quantitative Gated SPECT (QGS) and the Emory Cardiac Toolbox (ECTb). The mean difference between MR and SPECT EF was 0.008 for ECTb and 0.08 for QGS. QGS showed a slight trend toward higher correlation for EF (r = 0.72, SE of the estimate = 0.08) than ECTb (r = 0.70, SE of the estimate = 0.09). For both SPECT methods, left ventricular volumes were similarly correlated with MR, although SPECT volumes were higher than MR values by approximately 30%. CONCLUSIONS: QGS and ECTb values of cardiac function computed from 8-frame gated perfusion SPECT correlate very well with each other and correlate well with MR. Averaged over all subjects, ECTb measurements of EF are not significantly different from MR values but QGS significantly underestimates the MR values.

Six unaffected livebirths following preimplantation diagnosis for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a severe neurodegenerative autosomal recessive disorder, second only in frequency to cystic fibrosis. In its most severe form, SMA type I (Werdnig-Hoffman), death invariably ensues before age 2 years from respiratory failure or infection. Around 98% of clinical cases of SMA are caused by the homozygous absence of a region of exons 7 and 8 of the telomeric copy of the SMN gene (SMN1) on chromosome 5. We have developed a novel means of preimplantation diagnosis of SMA using a nested polymerase chain reaction (PCR) amplification of exon 7 of SMN, followed by a HinfI restriction digest of the PCR product enabling the important SMN1 gene to be distinguished from the centromeric SMN2 gene which has no clinical phenotype. This method was designed to reduce the likelihood of misdiagnosis. Five couples were treated using this method. Four proceeded to embryo transfer which resulted in six liveborns (one singleton, one twin and one triplet), all free of SMA. Embryo transfer was not performed in one cycle because of PCR contamination.

Evaluation of the precision of magnetic resonance phase velocity mapping for blood flow measurements.

Evaluating the in vivo accuracy of magnetic resonance phase velocity mapping (PVM) is not straightforward because of the absence of a validated clinical flow quantification technique. The aim of this study was to evaluate PVM by investigating its precision, both in vitro and in vivo, in a 1.5 Tesla scanner. In the former case, steady and pulsatile flow experiments were conducted using an aortic model under a variety of flow conditions (steady: 0.1-5.5 L/min; pulsatile: 10-75 mL/cycle). In the latter case, PVM measurements were taken in the ascending aorta of ten subjects, seven of which had aortic regurgitation. Each velocity measurement was taken twice, with the slice perpendicular to the long axis of the aorta. Comparison between the measured and true flow rates and volumes confirmed the high accuracy of PVM in measuring flow in vitro (p > 0.85). The in vitro precision of PVM was found to be very high(steady: y = 1.00x + 0.02, r = 0.999; pulsatile: y = 0.98x + 0.72, r = 0.997; x: measurement #1, y: measurement #2) and this was confirmed by Bland-Altman analysis. Of great clinical significance was the high level of the in vivo precision (y = 1.01x - 0.04, r = 0.993), confirmed statistically (p = 1.00). In conclusion, PVM provides repeatable blood flow measurements. The high in vitro accuracy and precision, combined with the high in vivo precision, are key factors for the establishment of PVM as the "gold-standard" to quantify blood flow.

Magnetic resonance phase-shift velocity mapping in pediatric patients with pulmonary venous obstruction.

OBJECTIVES: This study evaluated the accuracy, advantages and clinical efficacy of magnetic resonance (MR) phase-shift velocity mapping, in delineating the site and the hemodynamic severity of pulmonary venous (PV) obstruction in patients with congenital heart disease (CHD). BACKGROUND: Magnetic resonance phase-shift velocity mapping of normal pulmonary veins and of obstructed PV pathways have been previously reported in a mainly adult population. METHODS: The study population (33 pts) underwent MR phase-shift velocity mapping of their PV pathways. These results were compared with cardiac catheterization and Doppler echocardiography data. RESULTS: The study population (0.4 to 19.5 years) consisted of a study group (PV pathway obstruction, n = 7) and a control group (no PV obstruction, n = 26). No patients had any left-to-right shunt lesions. The MR imaging displayed precise anatomical detail of the pulmonary veins. Phase velocities in the control group ranged from 20 to 71 cm/s, whereas velocities in the study group ranged from 100 to 250 cm/s (p = 0.002). The MR phase velocities (154 +/- 0.53 cm/s) compared favorably with Doppler echocardiography (147 +/- 0.54 cm/s), (r = 0.76; p = 0.05). The MR velocity mapping was 100% specific and 100% sensitive in detecting PV obstruction, although the absolute gradient measurements among MR phase mapping, echocardiographic Doppler and catheterization did not show statistically significant correlation. CONCLUSIONS: In the absence of any associated left-to-right shunt lesions, PV velocities of 100 cm/s and greater indicated significant obstruction. The MR phase-shift velocity mapping, together with MR spin echocardiography and MR angiography, provides comprehensive anatomic and physiologic data that may obviate the need for further invasive studies.

A pregnancy following PGD for X-linked dominant [correction of X-linked autosomal dominant] incontinentia pigmenti (Bloch-Sulzberger syndrome): case report.

Incontinentia Pigmenti (Bloch-Sulzberger syndrome) is a rare multisystem, ectodermal disorder associated with dermatological, dental and ocular features, and in <10% of cases, severe neurological deficit. Pedigree review suggests X-linked dominance with lethality in affected males. Presentation in female carriers is variable. Following genetic counselling, a mildly affected female carrier diagnosed in infancy with a de novo mutation was referred for preimplantation sexing, unusually selecting for male gender, with an acceptance of either normality or early miscarriage in an affected male. Following standard in-vitro fertilization and embryo biopsy, fluorescence in situ hybridization (FISH) unambiguously identified two male and two female embryos. A single 8-cell, grade 4 male embryo was replaced. A positive pregnancy test was reported 2 weeks after embryo transfer, although ultrasonography failed to demonstrate a viable pregnancy. Post abortive fetal tissue karyotyping diagnosed a male fetus with trisomy 16. This is an unusual report of preimplantation genetic diagnosis (PGD) being used for selection of males in an X-linked autosomal dominant disorder and demonstrates the value of PGD where amniocentesis or chorion villus sampling followed by abortion is not acceptable to the patient. This case also demonstrates the importance of follow-up prenatal diagnosis.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Polypharmacy in a general surgical unit and consequences of drug withdrawal.

AIMS: To identify drug usage/withdrawal in surgical patients and the relative risk this imposes on postoperative surgical complications. METHODS: A prospective survey of patients' medicines, oral intake (food/fluids/ medicines) and postoperative complications was carried out in the General Surgical Unit, Dunedin Hospital, Dunedin, New Zealand. RESULTS: One thousand and twenty-five general surgical patients aged >/= 16 years, were entered into the study. Half of the patients were taking medicines unrelated to surgery. On average these patients received 9 different drugs (range 1-47) from a selection of 251, of which 21% were released in the last 10 years. The mean number of these drugs taken increased with age, vascular surgery and other major procedures. The majority of patients (53%) were taking drugs for cardiovascular problems. Only 8% of admissions were on the drugs more traditionally recognized to be of importance to the surgery, i.e. steroids and diabetic therapy. With respect to risk, taking a drug unrelated to surgery was associated with an increased relative risk of a postoperative complication by 2.7 (95% C.I. 1.76-4.04) compared with those who were not taking any drug. Cardiovascular drugs contributed significantly to this risk; when they were excluded from analysis, the risk dropped to 1.8 (95% C.I. 1.14-2.93). Death may be more common in those taking ACE inhibitors. Drug withdrawal and complications were analysed and as the time without medicines increased (range 1-42 days) so did the complication rate (chi2 = 14.7, DF = 2, P = 0.007). Of those patients who were taking a cardiovascular medicine and were without their normal medicines for a period of time postoperatively, 12% suffered a cardiac complication. CONCLUSIONS: Many patients admitted to a general surgical ward, are taking medicines unrelated to surgery. Drug therapy unrelated to surgery is a useful predictor for increased postoperative complications and one for which preventive action can be taken. This study provides evidence that withdrawal of regular medicines may add significant risk to the surgery and further complicate outcome. The longer patients were without their regular medicines the more nonsurgical complications they suffered. Reintroduction of patients' regular medicines early in their postoperative course may decrease morbidity and mortality in-patients.

Fluid mechanic assessment of the total cavopulmonary connection using magnetic resonance phase velocity mapping and digital particle image velocimetry.

The total cavopulmonary connection (TCPC) is currently the most promising modification of the Fontan surgical repair for single ventricle congenital heart disease. The TCPC involves a surgical connection of the superior and inferior vena cavae directly to the left and right pulmonary arteries, bypassing the right heart. In the univentricular system, the ventricle experiences a workload which may be reduced by optimizing the cavae-to-pulmonary anastomosis. The hypothesis of this study was that the energetic efficiency of the connection is a consequence of the fluid dynamics which develop as a function of connection geometry. Magnetic resonance phase velocity mapping (MRPVM) and digital particle image velocimetry (DPIV) were used to evaluate the flow patterns in vitro in three prototype glass models of the TCPC: flared zero offset, flared 14 mm offset, and straight 21 mm offset. The flow field velocity along the symmetry plane of each model was chosen to elucidate the fluid mechanics of the connection as a function of the connection geometry and pulmonary artery flow split. The steady flow experiments were conducted at a physiologic cardiac output (4 L/min) over three left/right pulmonary flow splits (70/30, 50/50, and 30/70) while keeping the superior/inferior vena cavae flow ratio constant at 40/60. MRPVM, a noninvasive clinical technique for measuring flow field velocities, was compared to DPIV, an established in vitro fluid mechanic technique. A comparison between the results from both techniques showed agreement of large scale flow features, despite some discrepancies in the detailed flow fields. The absence of caval offset in the flared zero offset model resulted in significant caval flow collision at the connection site. In contrast, offsetting the cavae reduced the flow interaction and caused a vortex-like low velocity region between the caval inlets as well as flow disturbance in the pulmonary artery with the least total flow. A positive correlation was also found between the direct caval flow collision and increased power losses. MRPVM was able to elucidate these important fluid flow features, which may be important in future modifications in TCPC surgical designs. Using MRPVM, two- and three-directional velocity fields in the TCPC could be quantified. Because of this, MRPVM has the potential to provide accurate velocity information clinically and, thus, to become the in vivo tool for TCPC patient physiological/functional assessment.

Prognostic value of thallium-201 single-photon emission computed tomography for patients with multivessel coronary artery disease after revascularization (the Emory Angioplasty versus Surgery Trial [EAST]).

The aim of this study was to investigate the relation between reversible thallium single-photon emission computed tomography (SPECT) myocardial perfusion defects at 1-year after revascularization and quantitative indexes in Emory Angioplasty versus Surgery Trial (EAST) and outcomes 3 years after revascularization in 336 patients. EAST was a randomized controlled trial assessing cardiac outcomes for angioplasty versus bypass surgery for patients with multivessel coronary artery disease. During this prospective trial, a substudy included the evaluation of the prognostic value of reversible defects on quantitative thallium SPECT. At 1-year after revascularization, 336 patients underwent SPECT thallium-201 stress myocardial perfusion and 3-hour delayed imaging. Subsequent events, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, myocardial infarction, and death, were recorded at 3 years. A stress-induced reversible thallium-201 defect was defined using a quantitative index of a reversibility score >30% and severity score >500. Reversible defects were observed more frequently in the percutaneous transluminal coronary angioplasty than in the coronary artery bypass graft surgery treatment groups (46% vs 27%, p <0.001). A total of 123 patients had stress-induced, reversible thallium defects and more events than patients with other perfusion results (freedom from all events was 81.3% vs 94% [p <0.001], and freedom from myocardial infarction and death 88.3% vs 95.5% [p = 0.031]). Quantitative thallium SPECT at 1 year after revascularization risk stratifies patients as to their likelihood of major cardiac outcomes.