Microvascular Dysfunction, Myocardial Ischemia, and Progression to Heart Failure in Patients with Hypertrophic Cardiomyopathy

Microvascular dysfunction can be demonstrated in most patients with hypertrophic cardiomyopathy (HCM), both in the hypertrophied and nonhypertrophied myocardial walls, mostly due to intimal and medial hyperplasia of the intramural coronary arteries and subsequent lumen reduction. As a consequence, regional myocardial ischemia may be triggered by exercise, increased heart rate, or arrhythmias, in areas which are unable to increase myocardial blood flow. In patients with HCM, microvascular dysfunction leading to severe myocardial hypoperfusion during maximal hyperemia represents a strong predictor of unfavorable outcome, left ventricular remodeling with progressive wall thinning, left ventricular dysfunction, and heart failure. Accurate quantitative assessment of microvascular dysfunction and myocardial ischemia is not easily feasible in clinical practice. Although signs of inducible myocardial ischemia may be detected by electrocardiogram, echocardiography, or myocardial scintigraphy, the vasodilator response to dipyridamole by positron emission tomography is considered the method of choice for the assessment of maximal regional and global flow. Cardiac magnetic resonance provides further information, by late gadolinium enhancement (LGE), which may show areas where replacement fibrosis has occurred following microvascular ischemia and focal necrosis. LGE areas colocalize with severe regional microvascular dysfunction, are associated with increased prevalence of ventricular arrhythmias, and show more extensive distribution in the late stages of the disease, when heart failure is the dominant feature. The present review aims to provide a concise overview of the available evidence of microvascular dysfunction and ischemia eventually leading to disease progression and heart failure in HCM patients.     

Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives

Hypertrophic cardiomyopathy (HCM) is entering a phase of intense translational research that holds promise for major advances in disease‐specific pharmacological therapy. For over 50 years, however, HCM has largely remained an orphan disease, and patients are still treated with old drugs developed for other conditions. While judicious use of the available armamentarium may control the clinical manifestations of HCM in most patients, specific experience is required in challenging situations, including deciding when not to treat. The present review revisits the time‐honoured therapies available for HCM, in a practical perspective reflecting real‐world scenarios. Specific agents are presented with doses, titration strategies, pros and cons. Peculiar HCM dilemmas such as treatment of dynamic outflow obstruction, heart failure caused by end‐stage progression and prevention of atrial fibrillation and ventricular arrhythmias are assessed. In the near future, the field of HCM drug therapy will rapidly expand, based on ongoing efforts. Approaches such as myocardial metabolic modulation, late sodium current inhibition and allosteric myosin inhibition have moved from pre‐clinical to clinical research, and reflect a surge of scientific as well as economic interest by academia and industry alike. These exciting developments, and their implications for future research, are discussed.     

Estimating wound age: looking into the future

A critical review is made of the studies on wound healing used for forensic purposes, focusing on the problem of which characteristics indicate that a parameter could be used as evidence in court. A panel analysing the more important information obtained by each marker is given, and a perspective of what might be expected from future research is discussed.     

Neonatal isolation alters stress hormone and mesolimbic dopamine release in juvenile rats

Rat pups were individually isolated from the mother and nest for 1 h/day from postnatal days (PND) 2 to 9 and tested as juveniles (PND 26-30) compared to nonhandled (NH) controls. In response to 1 h of restraint stress, NH rats increased locomotor activity and dopamine (DA) levels, but neonatally isolated (ISO) rats did not. Both groups had increased plasma corticosterone levels in response to restraint, but corticosterone levels were higher in ISO than in NH. Brain allopregnanolone (3alpha,5alpha-THP) levels also increased in response to stress, but NH and ISO did not differ. Sex of the rats was not a factor for any of the measures except plasma corticosterone levels, where females had higher levels than males. These data indicate that the effects of neonatal isolation persist postweaning and that the effects are most evident in response to stress as opposed to under baseline conditions.     

The effect of carbon tetrachloride and ultraviolet radiation on dolichol levels in liver cells isolated from 3- and 24-month-old male Sprague-Dawley rats

Dolichol (D) is a long-chain polyprenoid broadly distributed in the cell membranes, possibly endowed with a free-radical scavenging activity, whose concentration in tissues increases with increasing age. No enzyme pathway for D degradation has been discovered. In order to test the hypothesis that D might undergo a non-enzymatic free-radical mediated decomposition the effects of a xenobiotic agent (carbon tetrachloride, CCl(4)) and ultraviolet-B (UV-B) radiation on D levels were studied in liver cells isolated from male ad libitum fed Sprague-Dawley rats aged 3 or 24 months. Liver cells (90 mg/ml) were incubated in sealed flasks (6 ml cell suspension each) for 0, 5, 10 and 20 min after the addition of 25, 50 or 200 microl CCl(4) in the central well. 50 ml of a 6 mg/ml liver cell suspension were poured in a 120 cm(2) Petri dish and the sediment liver cell monolayer was exposed to UVB radiation for 0, 5, 10, 20 and 40 min. At the given time, cells were taken and D was extracted and assayed by the HPLC procedure. D levels were remarkably higher in older than in younger cells as expected ( P < 0.001). Treatment with CCl(4) and UVB caused a highly significant decrease in D ( P < 0.001) whose percentage was larger in younger than in older cells. The conclusions are that free-radicals generated either by chemical or by physical agents cause a very rapid depletion of D in liver cells, and that the effect of the free radical attack on D decomposition may be lower percentage wise in older than in younger cells, which might account at least in part for the accumulation of D in older tissues.     

Segmental vertebral motion in the assessment of neck range of motion in whiplash patients

The purpose of this study was to obtain comparative data concerning the relative contribution of segmental cervical vertebral motion to the cervical range of motion (ROM) in whiplash and healthy subjects in an effort to evaluate the usefulness of X-ray analysis in future forensic and research efforts. Each subjects neck ROM was measured with an optoelectronic system and also by X-ray measurements of the angular rotation in flexion and extension. The X-rays were examined to calculate the angular movement in the sagittal plane of each of the functional units C2–C3 to C6–C7. The chronic whiplash subjects showed reduced total neck range in all directions as compared to healthy subjects (p<0.001). There was a reduced total angular rotation from flexion to extension between these two groups (p<0.01), but no significant difference, however, between chronic whiplash subjects and controls in the percentage contribution of each of the functional units C2–C3 to C6–C7 to this rotation. This data will now allow a design of trials where healthy subjects are asked to simulate restricted neck ROM while undergoing optokinetic and X-ray evaluation of segmental vertebral motion. We will be able to determine if simulators produce a similar pattern to chronic whiplash and healthy, non-simulating subjects, and thus determine if, at least for forensic and research purposes, this technique is useful in validating reported restricted neck range.