Identification of mtDNA mutation in a pedigree with gestational diabetes, deafness, Wolff-Parkinson-White syndrome and placenta accreta.

Mitochondrial DNA (mtDNA) defects are associated with a number of human disorders. Although many occur sporadically, maternal transmission is the hallmark of diseases due to mtDNA point mutations. The same mutation may manifest strikingly different phenotypes; for example, the A to G substitution at np 3243 was first reported in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (the MELAS syndrome), but is also found in patients with diabetes and deafness. Here we present a case of gestational diabetes, deafness, premature greying, placenta accreta and Wolff-Parkinson-White (WPW) syndrome associated with a mtDNA mutation. Although this is the first report of such an association, study of 27 other patients with WPW syndrome failed to confirm that this mtDNA mutation is a common cause of such pre-excitation disorders.

What do we do when thrombolysis fails? A United Kingdom survey.

We conducted a postal survey amongst members of the British Cardiac Society to determine current strategies for the detection and management of failed thrombolysis for acute myocardial infarction. The response rate was 290/387 (75%). On-site cardiac catheterisation facilities are available to 162 (60%), 112 (41%) of which are prepared for urgent angiography +/- angioplasty. Streptokinase is the preferred routine thrombolytic agent (n = 242, 90%). After thrombolysis, 121 (45%) respondents rarely search for evidence of reperfusion; a further 55 (20%) confine their search to selected cases. Practice varies amongst those with an active management strategy following proven failed thrombolysis (n = 149, 55%): 50 (19%) perform urgent angiography +/- angioplasty, 49 (18%) administer another thrombolytic agent, 6 (2%) administer another dose of the same agent and 44 (16%) combine these approaches. Transfer to an interventional centre is considered by only 11/106 (10%) without on-site access to cardiac catheterisation. These data indicate considerable variation in the management of failed thrombolysis. Randomised, controlled trials are required to elucidate optimal treatment for this common and important clinical situation.

Systemic lytic state is not a predictor of coronary reperfusion in acute myocardial infarction.

To investigate why approximately one third of patients thrombolysed with streptokinase fail to reperfuse, we assessed the lytic status, antistreptokinase antibody and non invasive parameters of reperfusion in 95 consecutive patients with acute myocardial infarction treated with streptokinase for the first time. The lytic status was assessed by Clauss fibrinogen assay and thrombin clotting time before and 2 h after streptokinase infusion. Antistreptokinase antibody was measured prior to the infusion. Reperfusion was assessed by measurement of the 24:96 h troponin-T ratio (a ratio > 1 indicating reperfusion) and ST segment resolution 2 h post streptokinase. Ninety-two (97%) patients achieved a systemic lytic state with a fibrinogen titre of less than 1.0 g/l and thrombin clotting time ratio of > 2.5. Despite this, 27% failed to reperfuse with a mean 24:96 h troponin-T of 0.9, SD 0.6 vs. 3.4 +/- 3.2 in the reperfused group, (P < 0.0001). 83% of the reperfused group but none of the non reperfused group had ST segment resolution. No difference was observed in the levels of fibrinogen and thrombin clotting time between the reperfused 0.25 +/- 0.3 g/l; 6.9 +/- 4, and the non reperfused group 0.4 +/- 0.6 g/l; 7.9 +/- 2.6. No difference was observed in the levels of antistreptokinase antibody between the reperfused (median = 168 U/ml and the non reperfused (median = 177 U/ml). Failure to reperfuse with Streptokinase is not due to failure to achieve a lytic state. Therefore increased or accelerated dosages of streptokinase are unlikely to increase the rate of reperfusion.

Inadequate management of hyperlipidaemia after coronary bypass surgery shown by medical audit.

OBJECTIVE: To audit the detection and management of hyperlipidaemia in patients who have had coronary bypass surgery. PATIENTS: 100 consecutive patients (81 men), mean age 61, who had survived at least 3 months after coronary bypass surgery. METHODS: Retrospective review of case notes and computerised biochemistry records. RESULTS: 83 patients had at least one lipid measurement in the hospital, and of the remaining 17 patients, 10 had undergone urgent or emergency surgery. The median (range) total cholesterol was 6.7 (4.0-11.7) mmol/l and the triglyceride concentration was 2.1 (0.6-18.4) mmol/l. Only 30 patients were referred to a dietician, and 12 were given a lipid lowering drug--these interventions were no more frequent in patients with a cholesterol concentration above than below the median. CONCLUSIONS: Although a high proportion of patients who undergo routine coronary bypass surgery have their plasma lipid concentrations measured, many patients with raised cholesterol concentrations, who would benefit from lipid lowering interventions, are not offered them.

Rotational deformation of the canine left ventricle measured by magnetic resonance tagging: effects of catecholamines, ischaemia, and pacing.

OBJECTIVE: The aim was to investigate the generation of rotation of the left ventricular apex with respect to the base by magnetic resonance tagging, a non-invasive method of labelling the myocardium, in a canine model. METHODS: 18 dogs were imaged at baseline and during: (1) inotropic stimulation with dobutamine; (2) chronotropic stimulation with atrial pacing; (3) anterior wall ischaemia; (4) posterior wall ischaemia; and (5) varying left ventricular activation site; six dogs underwent each intervention. Apical rotation of the apex (torsion) was quantified. The epicardium and the endocardium were considered separately, as were the anterior and posterior walls. RESULTS: Mean torsion of the epicardium [anterior 3.1(SEM 1.2) degrees, posterior 9.9(1.0) degrees] was less than that of the endocardium [anterior 8.1(2.6) degrees, posterior 14.9(2.0) degrees, p < 0.05 for both]. Anterior torsion was less than posterior torsion for both the epicardium, p < 0.05, and the endocardium, p < 0.05. Dobutamine increased torsion of both the epicardium [anterior 13.3(2.2) degrees, posterior 12.6(1.7) degrees, p < 0.05 for both] and the endocardium [anterior 24.6(2.3) degrees, posterior 16.5(2.1) degrees, p < 0.05 for both]. Atrial pacing at 160% baseline rate increased torsion of both the anterior wall [epicardium 6.6(1.0) degrees, endocardium 11.3(1.2) degrees, p < 0.05] and the posterior wall [epicardium 13.0(1.3) degrees, endocardium 19.4(1.9) degrees, p < 0.05]. Anterior wall ischaemia reduced torsion of the anterior wall only [epicardium -2.0(1.0) degrees, endocardium 6.7(2.3) degrees, both p < 0.05]. Posterior wall ischaemia reduced torsion of the posterior wall of the epicardium only [7.1(1.2) degrees, p < 0.05] but also reduced torsion of the anterior wall [epicardium 0.7(1.0) degrees, endocardium 2.4(1.6) degrees, p < 0.05 for both]. Altering the pattern of left ventricular activation by atrioventricular pacing reduced torsion of the posterior wall of the epicardium [6.6(1.2) degrees, p < 0.05] and of the anterior [3.6(1.9) degrees, p < 0.05] and posterior [7.1(1.6) degrees, p < 0.05] walls of the endocardium. CONCLUSIONS: Rotational deformation of the left ventricle is dependent on the pattern of left ventricular activation and the contractile state. That a decrease in the contractile state in one area (by ischaemia) can cause a decrease in rotation in another suggests that this rotation depends on the complex fiber arrangement of the whole ventricle.

Accurate systolic wall thickening by nuclear magnetic resonance imaging with tissue tagging: correlation with sonomicrometers in normal and ischemic myocardium.

OBJECTIVES: This study examined whether the correlation of systolic wall thickening (%WT) by nuclear magnetic resonance (NMR) imaging with wall thickening by sonomicrometry (SM) is improved by using a three-dimensional volume element model of the left ventricular wall. BACKGROUND: Left ventricular wall obliquity with respect to the imaging plane causes overestimation of wall thickness by planar imaging techniques. Wall thickness perpendicular to the endocardial surface can be accurately calculated by three-dimensional reconstruction of left ventricular wall segments. METHODS: Sonomicrometers were placed transmurally in 11 dogs (left anterior descending artery territory) with an imaging marker, visible on NMR imaging, sewn to the epicardial crystal. Two adjacent NMR short-axis image planes were radially segmented by four perpendicular spin-saturated planes (tags), dividing the myocardium into eight volume elements, one of which contained the sonomicrometer crystal pair. Left ventricular thickness and thickening were calculated by four methods: 1) linear = distance between epicardium and endocardium at midpoint in the segment with the sonomicrometer; 2) planar = area of that segment divided by the mean of the endocardial and epicardial arc lengths; 3) biplanar = average of wall thicknesses calculated by the planar method from the segment with sonomicrometers and the corresponding segment located in the adjacent short-axis imaging plane; and 4) three-dimensional = volume of the element with the sonomicrometers divided by the mean of the endocardial and epicardial surface areas. RESULTS: Regressions for all methods using pooled data from control periods and during ischemia: Linear %WT = 0.59 + 1.31 SM%WT (r = 0.71, SEE = 0.28, p < 0.0002) Planar %WT = 1.43 + 1.62 SM%WT (r = 0.87, SEE = 0.19, p < 0.0001) Biplanar %WT = 2.09 + 1.46 SM%WT (r = 0.90, SEE = 0.15, p < 0.0001) Three-dimensional %WT = 0.19 + 1.49 SM%WT (r = 0.95, SEE = 0.10, p < 0.0001) CONCLUSIONS: Nuclear magnetic resonance imaging with tissue tagging allows accurate noninvasive assessment of systolic wall thickening. The three-dimensional volume element approach, by accounting for obliquity between the image plane and the left ventricular wall, provides the strongest correlation between NMR imaging and percent systolic wall thickening by sonomicrometer crystals.

Streptokinase resistance: when might streptokinase administration be ineffective?

OBJECTIVE: (a) To develop an assay for streptokinase resistance. (b) To determine the prevalence of streptokinase resistance in patients presenting with acute myocardial infarction for the first time. (c) To determine the prevalence of streptokinase resistance in patients after exposure to streptokinase or streptococcal infection. DESIGN: Open, prospective. PATIENTS: 30 healthy volunteers. 40 patients admitted to the coronary care unit at Addenbrooke's Hospital with suspected acute myocardial infarction, 12 patients 12 months after streptokinase treatment, eight patients 24 months after streptokinase treatment, and sera from 12 patients with raised anti-streptolysin O (ASO) titres. METHODS: Three assays were used; a dilution neutralisation assay, an enzyme linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) anti-streptokinase antibodies, and an in vitro fibrin plate lysis assay. All measurements were performed on venous blood samples. RESULTS: Neutralisation and IgG antibody titres were positively correlated. Mean (SEM) antistreptokinase concentrations in the 30 controls were 87 (10) U/ml (neutralisation assay) and 28 (6.3) U/ml (ELISA). Corresponding concentrations in patients before streptokinase were 68 (6.1) U/ml and 18 (4.5) U/ml with a mean fibrin plate assay 117 (7.1)% that of controls. Resistance to streptokinase was detectable in one patient after 72 hours and in all patients by day 10. By day 10 concentrations were 4388 (919) U/ml, 773 (109) U/ml, and 17 (5.4)%. At both 12 and 24 months resistance was present in 75% of patients. Similarly 66% of high ASO titre sera showed resistance. The fibrin plate lysis assay detected significantly reduced streptokinase dependent fibrinolysis in vitro in the absence of raised total concentrations of antistreptokinase antibodies. CONCLUSIONS: The prevalence of streptokinase resistance in patients presenting with their first myocardial infarction is low. Resistance develops early after treatment and is still present in 75% of patients after 24 months. Retreatment with streptokinase is likely to be suboptimal even after 24 months. The fibrin plate lysis assay detects resistance in patients with normal concentrations of streptokinase antibodies. Streptococcal infection is associated with a high incidence of streptokinase resistance.

The occurrence of early sudden coronary artery occlusion following angioplasty may be predicted from the clinical characteristics of the patients and their coronary lesion morphology.

The aim of this study was to assess whether the incidence of early occlusion following angioplasty was greater among patients with unstable angina and whether the coronary lesions prone to early occlusion could be predicted from their angiographic appearance. Seventy-seven patients who had had a first angioplasty of a native vessel for stable or unstable angina in one twelve month period were included. The angiographic appearances of the angioplastied lesions were classified as either Type 1, which were smooth and unlikely to have thrombus or intimal rupture, or Type 2, which were irregular due to thrombus or intimal rupture. The lesion classification was compared to the patients' clinical features, i.e. stable or unstable angina, and the outcome of the angioplasty. Type 2 lesions occurred in 25% of patients with stable angina but 49% of patients with unstable angina (p less than 0.05). Early sudden occlusion of the angioplastied vessel occurred in 24% of patients with unstable angina but in only 3% of patients with stable angina (p less than 0.05) and in 6% of Type 1 lesions compared with 24% of Type 2 lesions (p less than 0.05). Thus it is possible to identify the clinical characteristics and angiographic appearances of those patients undergoing angioplasty who are most likely to experience early vessel occlusion.

Dissociation between left ventricular untwisting and filling. Accentuation by catecholamines.

BACKGROUND: Efficient early diastolic filling is essential for normal cardiac function. Diastolic suction, as evidenced by a decreasing left ventricular pressure during early filling, could result from restoring forces (the release of potential energy stored during systolic deformation) dependent on myofilament relaxation. Although these restoring forces have been envisioned within individual myofibers, recent studies suggest that gross fiber rearrangement involving the connective tissue network occurs easy in diastole. This may lead to the release of potential energy stored during systole and suction-aided filling. METHODS AND RESULTS: To establish precisely the timing and extent of restoration of the systolic torsional deformation of the left ventricle with respect to early filling at baseline and with enhanced relaxation, we studied untwisting during control conditions and with catecholamine stimulation. Using noninvasive and nondestructive magnetic resonance tagging, torsional deformation of the left ventricle was measured at 20-msec intervals in 10 open-chest, atrially paced dogs, starting at aortic valve closure. Eight equiangular tags intersected the epicardium and endocardium in three short-axis imaging planes (base, mid, and apex). From the intersection points, epicardial and endocardial circumferential chord and arc lengths were measured and angular twist of mid and apical levels with respect to the base (maximal torsion and its reversal, untwisting) was calculated. Echo-Doppler provided timing of aortic valve closure and of mitral valve opening. Zero torsion was defined at end diastole. Torsion at the apical level reversed rapidly between its maximum and the time immediately after mitral valve opening: from 7.0 +/- 5.8 degrees to 3.2 +/- 5.4 degrees and 12.0 +/- 8.5 degrees to 6.9 +/- 7.8 degrees (mean +/- SD, both p less than 0.01) at the epicardium and endocardium, respectively. During the same period, no significant circumferential segment length changes occurred. As expected, after mitral valve opening, filling resulted in significant circumferential segment lengthening, whereas further reversal of torsion was small and nonsignificant. During dobutamine infusion, torsion at end systole was greater and reversal during isovolumic relaxation was much more rapid and greater in extent (p less than 0.01). Torsion reversed from 11.5 +/- 4.3 degrees to 5.7 +/- 4.8 degrees and 17.4 +/- 6.4 degrees to 6.9 +/- 7.7 degrees at epicardium and endocardium. CONCLUSIONS: Untwisting occurs principally during isovolumic relaxation before filling and is markedly enhanced in speed and magnitude by catecholamines. This partial return of the left ventricle to its preejection configuration before mitral valve opening could represent an important mechanism for the release of potential energy stored in elastic elements during the systolic deformation. These myocardial restoring forces would be markedly enhanced by physiological changes consequent to catecholamines such as during exercise, offsetting the concomitant shortening of the filling period.

Measurement of regional left ventricular function using labelled magnetic resonance imaging.

A technique for assessing regional left ventricular function using magnetic resonance imaging is described. Spatial modulation of magnetization (SPAMM) is effected immediately before images are obtained at various intervals during the cardiac cycle using a modified field echo even rephasing technique (FEER). By performing such modulation in two planes, a grid pattern of labelling can be produced across the image. On the resulting labelled short axis images of the left ventricle, the systolic increase in thickness (thickening) and decrease in length (shortening) of different regions of myocardium can then be measured. The findings in five normal volunteers are presented. Radial shortening was twice as great in the endocardium (mean 20.4%, standard deviation (SD) 5.7) than in the epicardium (mean 10.2%, SD 5.5) and appears to offer more promise as a marker of regional function than simple thickening (mean 9.8%, SD 13.6).

Quantification of and correction for left ventricular systolic long-axis shortening by magnetic resonance tissue tagging and slice isolation.

BACKGROUND: Measurement of regional left ventricular (LV) function is predicted on the ability to compare equivalent LV segments at different time points during the cardiac cycle. Standard techniques of short-axis acquisition in two-dimensional echocardiography, cine computed tomography, and standard magnetic resonance imaging (MRI) acquire images from a fixed plane and fail to compensate for through-plane motion. The shortening of the left ventricle along its long axis during systole results in planar images of two different levels of the ventricle, leading to error in any derived functional measurements. LV systolic long-axis motion was measured in 19 normal volunteers using MRI. METHODS AND RESULTS: With a selective radio frequency (RF) tissue-tagging technique, three short-axis planes were labeled at end diastole and standard spin-echo images were acquired at end systole in the two- and four-chamber orientations. Persistence of the tags through systole allowed visualization of the intersecting short-axis tags in the long-axis images and allowed precise quantification of long-axis motion of the septum, lateral, anterior, and inferior walls at the base, mid, and apical LV levels. The total change in position along the long axis between end diastole and end systole was greatest at the base, which moved toward the apex 12.8 +/- 3.8 mm. The mid left ventricle moved 6.9 +/- 2.6 mm, and the apex was nearly stationary, moving only 1.6 +/- 2.2 mm (p less than 0.001). Having quantified the normal range of long-axis shortening, we developed a technique that isolates a slice of tissue between selective RF saturation planes at end diastole. Combining this with a wide end-systolic image slice, end-systolic images were acquired without contamination of signal from adjacent tissue moving into the imaging plane. This technique was validated in a moving phantom and in normal volunteers. CONCLUSIONS: Significant LV systolic long-axis shortening exists, and this effect is seen the most at the base and the least at the apex. At a given ventricular level, shortening varied significantly according to location. A method using selective saturation pulses and gated spin-echo MRI automatically corrects for this motion and thus eliminates misregistration artifact from regional function analysis.

Dipyridamole echocardiography: the bedside stress test for coronary artery disease.

Identification of dipyridamole-induced regional wall motion abnormalities by echocardiography has recently been proposed as an alternative diagnostic stress test for coronary artery disease. This study evaluates this new technique by comparing the results obtained (overall, regionally and by abnormality type) with those of thallium-201 myocardial imaging after dipyridamole stress in 25 patients. Acceptable echocardiograms were obtained in 20 patients (80%). Concordance of echocardiographic abnormalities for both overall and regional thallium abnormalities was 85%. Sensitivity, specificity and predictive value of dipyridamole echocardiography for overall and regional thallium defects were 92%, 71% and 85%, and 91%, 81% and 85% respectively. However, concordance between the two for abnormality type (i.e. ischaemia versus infarction) was only 66% and the sensitivity, specificity and predictive value of dipyridamole echocardiography for identifying ischaemia as opposed to infarction were only 43%, 82% and 63%, respectively. There was substantial agreement between thallium and echocardiographic imaging after dipyridamole infusion in the diagnosis of coronary artery disease. Echocardiography appears less well able to distinguish infarction from active ischaemia. Dipyridamole echocardiography provides a highly versatile, noninvasive bedside stress test for the detection and localization of coronary artery disease.

Noninvasive quantification of left ventricular rotational deformation in normal humans using magnetic resonance imaging myocardial tagging.

It has been postulated that rotation of the left ventricular apex with respect to the base is a component of normal systolic function in humans, but it has been difficult to measure it noninvasively. Tagging is a new magnetic resonance imaging technique that labels specific areas of myocardium by selective radio-frequency excitation of narrow planes orthogonal to the imaging plane before acquiring an image. Tags appear as black lines and persist in myocardium for 400-500 msec and, if applied at end diastole, will move with the myocardium through systole. Tagging was used to noninvasively quantify left ventricular torsion and circumferential-longitudinal shear (shearCL) in humans. Eight normal volunteers, aged 24-38 years, were imaged in a 0.38-T iron-core resistive magnet. Five short-axis left ventricular images, positioned to encompass the entire left ventricle (LV), were obtained separately at end systole. Four equiangular radial tags had been applied at end diastole, intersecting the myocardium at eight locations. We calculated the difference in angular displacement of each epicardial and endocardial tag point (a tag point being where the tag crossed the epicardium or endocardium) at end systole from the systolic position of the corresponding tag point on the basal plane. This value was called the torsion angle. From this, shearCL, the angle inscribed on the epicardial or endocardial surface between the systolic tag position, the corresponding basal tag position, and its projection onto the slice of interest could be calculated at 32 points in the left ventricular wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance imaging as a noninvasive standard for the quantitative evaluation of left ventricular mass, ischemia, and infarction.

Because magnetic resonance imaging (MRI) acquires data in a spatially unambiguous fashion and the three-dimensional interrelationships of one image plane to another are easily ascertained, there are far fewer technical restrictions imposed on this method than on other imaging techniques. Furthermore, the multiplanar nature of MRI image acquisition, in any plane desired, is a feature unique to this imaging technology. MRI is thus well suited to the highly accurate quantification of global and regional left ventricular (LV) size and function, and can be used as a standard for comparison to other techniques, once validated. Because the determination of LV mass by MRI requires no assumptions about ventricular shape, it should be well suited to the evaluation of both normal hearts and those distorted by infarction. We performed gated MRI on 15 dogs before and after myocardial infarction. LV mass was calculated with 5 short axis planes. The correlation was excellent between actual mass before infarction and after MI. Accuracy was similar for both end-diastole and end-systole. Thus, MRI accurately determines LV mass in both distorted and normal hearts. We have also developed a method for quantification and mapping of regional wall thickening throughout the LV as an index of regional ischemia by utilizing the 3D geometry to calculate the perpendicular wall thickness of a 3D volume element of tissue. This 3D volume element results in less variability of normal wall thickening and provides a better discriminator of ischemic from nonischemic zones in a canine model of acute ischemia, whereas there is considerably greater overlap between ischemic and normal zones with standard planar MRI techniques. The 3D method is more accurate than planar methods in avoiding biases resulting from the oblique course of an image plane through the LV wall, resulting in better distinction of ischemic from nonischemic tissue. Finally, the accurate assessment of regional LV function for the identification of ischemic or infarcted myocardium has been enhanced greatly by a new technique, myocardial tissue tagging, in which an electronic marker is applied to the myocardium which persists through ejection, enabling the accurate tracking of specific areas of the heart as they move and rotate through the cardiac cycle.

The effect of thrombolytic therapy with anisoylated plasminogen streptokinase activator complex on the indicators of myocardial salvage.

The role of anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction, in effecting thrombolysis, in limiting infarct size and in preserving myocardial function, was assessed by comparing APSAC and placebo in a double-blind, randomised trial. Between October 1984 and April 1985, 43 patients (mean age 57.3 years) with evolving infarctions (19 anterior/24 inferior) were randomised. All patients received treatment within 3 hours of the onset of pain. Patients over 70 years of age or with contraindications to thrombolytic therapy were excluded. Response to therapy was assessed by comparing reductions in summated ECG R wave amplitude and changes in QRS score at 24 hours and 7 days in the leads with ST abnormalities on admission. Radionuclide ejection fractions (EF) were performed 2 to 6 months after infarction. Evidence of successful reperfusion was based on non-invasive parameters. Mean time to peak cardiac enzyme release was shorter in the active treatment group, indicating effective thrombolysis (11.5 hours vs 17.6 hours; p less than 0.01). No differences were found in R wave reduction or QRS score at either 24 hours or 7 days, between active and placebo groups in total or when divided by infarct site. No difference was seen between the EFs of the groups in total or between inferior infarct groups. The mean EF of the treated anterior group was higher than that of the untreated group (p less than 0.05). Successful thrombolysis was seen in the actively treated group. Evidence of myocardial salvage and preservation was seen among treated patients with anterior infarcts only.