Phenotype-driven molecular autopsy for sudden cardiac death.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

Update on cardiopulmonary resuscitation.

Adult cardiopulmonary resuscitation (CPR) has been shown to improve survival for individuals suffering cardiac arrest. Despite this, the delivery of basic life support to victims outside the clinical environment remains poor, particularly as only a minority receive resuscitation. In addition, research continues to examine the optimal techniques for CPR and guidelines have been modified to reflect the latest developments. These guidelines are a compromise between simplicity and effectiveness. While the core of the guidelines remains unchanged, the latest recommendations focus on minimising any delay in the assessment of the collapsed patient and the initiation of CPR. They also address the recent body of opinion promoting compression-only CPR as an alternative to the combined technique of compression and mouth-to-mouth ventilation. Throughout the guidelines a more pragmatic approach to resuscitation is adopted to try to encourage all individuals, whether trained healthcare professionals or lay people, to initiate resuscitation. An acknowledgement of the reasons why individuals may be reluctant to start resuscitation through fear or anxiety will hopefully help to encourage the instigation of these techniques. This overview will summarise the guidelines and highlight alterations or alternatives where appropriate.

Masquerade: a malignant arrhythmia masquerading as benign.

Pseudoatrial flutter has been reported to have benign causes, but this is the first report of a malignant arrhythmia presenting as a benign arrhythmia. An 82 year old patient presented with ventricular tachycardia and electrical artefact appearing as atrial flutter. In this case, comparing the morphology of the QRS complexes in the rhythm strip with those in lead II showed the arrhythmia to be ventricular in origin and points to the importance of comparing all leads of the ECG before arriving at a diagnosis.

Outcomes of permanent pacemaker implantation for carotid sinus hypersensitivity in a district general hospital with a Falls Fits Faints and Funny Turns Clinic.

UNLABELLED: Permanent pacemaker implantation is considered for carotid sinus hypersensitivity with asystolic pause of > 3 seconds during carotid sinus massage, with or without associated systolic blood pressure drop of > 50 mmHg. AIMS: To assess the outcome of treatment with dual chamber permanent pacemaker implantation for carotid sinus hypersensitivity in a district general hospital and to compare our practice with available national data. METHODS: Patients presenting with syncope, dizziness or unexplained falls were initially assessed as outpatient and investigations, commonly cardiovascular were performed including tilt table test with carotid sinus massage to look for carotid sinus hypersensitivity, vasovagal syncope and postural hypotension. A retrospective analysis was performed on patients who had pacemaker implantations for carotid sinus hypersensitivity. RESULTS: Fifty pacemaker implantations were performed, 14 (28%) were for carotid sinus hypersensitivity. Mean follow-up period was 10 months. Age range was 56-88 (mean = 71.9) years. In the eighteen months prior to pacemaker implantation, 71.4% of patients had syncope, 64% dizziness and 50% had unexplained falls. Following pacemaker implantations, only 2 (14.3%) had symptoms. Scottish national figures show 13.6% of all new pacemaker implants were for carotid sinus hypersensitivity, and in district general hospitals this was 16%. CONCLUSIONS: Health benefits for patients presenting with syncope dizziness and falls can be achieved by cardiovascular investigations including tilt table testing. We have shown carotid sinus hypersensitivity is successfully treated with pacemaker implantation in a district general hospital setting and this type of clinic has an impact on the rate and type of new pacemaker implantation.

Rate of change of left ventricular ejection fraction during exercise is superior to the peak ejection fraction for predicting functionally significant coronary artery disease.

OBJECTIVE: To detect and characterise rapid temporal changes in the left ventricular response to exercise in patients with ischaemic heart disease and to relate these changes to the functional severity of coronary artery disease. BACKGROUND: The gamma camera does not allow the detection of rapid changes in cardiac function during exercise radionuclide ventriculography, the monitoring of which may improve the assessment of patients with ischaemic heart disease. METHODS: A miniature nuclear probe (Cardioscint) was used to monitor continuously left ventricular function during exercise in 31 patients who had coronary angiography for suspected coronary artery disease. A coronary angiographic jeopardy score was calculated for each patient. RESULTS: The coronary jeopardy score ranged from 0 to 12 (median 4). Ejection fraction fell significantly during exercise from 46% to 34%. Patients were divided into two groups based on the response of their ejection fraction to exercise. In 14 patients (group I), the peak change in ejection fraction coincided with the end of exercise, whereas in the other 17 patients (group II) the peak change in ejection fraction occurred before the end of exercise, resulting in a brief plateau. The peak change in ejection fraction and the time to its occurrence were independent predictors of coronary jeopardy (r = -0.59, p < 0.001 for peak change and r = -0.69, p < 0.001 for time to that change). The rate of change in ejection fraction was the strongest predictor of coronary jeopardy (r = -0.81, p < 0.001). In group I the peak change in ejection fraction was a poor predictor severity of coronary disease (r = -0.28, NS), whereas the time to peak and the rate of change in ejection fraction were good predictors (r = -0.65 and r = -0.73, p < 0.01). In group II the peak, the time to the peak, and the rate of change in ejection fraction were good predictors of coronary jeopardy (r = -0.75, r = -0.61, and r = -0.83, p < 0.01). CONCLUSION: The rate of change of ejection fraction during exercise can be assessed by continuous monitoring of left ventricular function with the nuclear probe, and is the best predictor of functionally significant coronary artery disease.

Cardiac arrest in a young woman with the long QT syndrome and concomitant astemizole ingestion.

Ventricular fibrillation developed in a 19 year old woman taking the antihistamine astemizole. She was successfully resuscitated. QTc prolongation was found and persisted despite withdrawal of the drug. Aggravation of congenital long QTc syndrome by astemizole is postulated. More caution should be exercised with the use of this drug.

Intra-arterial monitoring of the antihypertensive effects of once-daily amlodipine.

Amlodipine is a dihydropyridine calcium antagonist with a long elimination half life making it suitable for once-daily dosing. This study used sphygmomanometric and intra-arterial ambulatory blood pressure (BP) monitoring to confirm the antihypertensive effect of a once-daily dose of amlodipine over the dosing interval. After a 2-week single-blind placebo run in, amlodipine was administered to 11 patients at a starting dose of 5 mg daily for 2 weeks increasing to 10 mg daily for a further 4 weeks if diastolic blood pressure (DBP) measured sphygmomanometrically was not < 90 mmHg or decreased by > 10 mmHg from baseline values. Intra-arterial blood pressure recordings for 24-hour periods were made at the end of the placebo run in and on completion of the active treatment phase. The effects of isometric and dynamic exercise and head-up tilting (60 degrees) on BP and heart rate were measured during ambulatory monitoring. Mean supine cuff BP was 169/104 mmHg (n = 11) at the end of the placebo treatment period and was reduced to 153/95 mmHg (n = 11) after 2 weeks of amlodipine treatment and 146/92 mmHg (n = 11) after 6 weeks of amlodipine treatment. There was no significant change in heart rate. Intra-arterial ambulatory monitoring showed that BP was controlled for the whole dosing interval with once-daily doses of amlodipine. The normal circadian pattern of BP changes was not altered. BP was reduced by amlodipine during exercise and physiological tests, but there was no postural hypotension and the BP and heart rate responses to exercise were not blunted.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure changes during the game of squash.

The extent and pattern of the blood pressure response to the playing of squash was studied in five healthy volunteers using intra-arterial blood pressure recordings. Systolic pressure increased more than diastolic, but by only 18% of basal, peaking 5.2 +/- 2.3 min into the game (mean game duration 49 +/- 4 min). Thereafter there was a progressive decline, with reducing pulse pressure towards basal. There was a marked and significant increase in beat-by-beat blood pressure variability (P less than 0.01) and systolic peaks of up to 200 mmHg were recorded. A peak heart rate of 171 +/- 25 beats min-1 occurred at 20 min. These findings do not support the concept of a disproportionate and prolonged pressor response induced by playing squash. The possibility of high single-beat systolic peaks still justifies some caution in subjects at risk of arterial rupture.

Spontaneous variability of left ventricular ejection fraction assessed with the Cardioscint.

A miniature, non-imaging caesium iodide nuclear probe optically coupled to a photodiode (the 'Cardioscint') has been developed which, in conjunction with a modified personal computer, is capable of continuous on-line monitoring of left ventricular function and ST-segment level at the bedside. The purpose of this study was to assess the variability in ejection fraction over periods of time and to compare this variability with that of equilibrium gamma camera radionuclide ventriculography. Ten normal volunteers (nine male) of mean (S.D.) age 49 (10) years underwent semisupine radionuclide ventriculography using both gamma camera and Cardioscint in randomized order. The gamma camera recorded four consecutive acquisitions (mean of 7.2 min each) and the Cardioscint, using a 20 s acquisition time, recorded left ventricular function over 35 min per subject. The mean ejection fraction of the group by gamma camera was 52 (7)% and by Cardioscint was 54 (5)%. When the variability in ejection fraction by gamma camera was compared with the Cardioscint averaged over corresponding time periods (i.e. an average of 7.2 min), the mean coefficient of variation of the camera was 5.0% versus 2.9% for the probe system. Individual 20-s probe acquisitions over the total study duration (reflecting the short-term variability of the system) had a coefficient of variation of 5.1%. Thus the Cardioscint provides a stable continuous recording of ejection fraction. These volunteer data provide a basis for interpretation of data acquired in the clinical situation.

Prolonged hypotensive effect of OPC-13340: a new, once-daily calcium channel blocking drug.

The duration and magnitude of the hypotensive effect of a new, once daily dihydropyridine calcium channel blocking drug, OPC-13340, was assessed in 14 patients with essential hypertension during normal daily activities and programmed exercise testing. Intra-arterial ambulatory blood pressure (BP) monitoring was performed before and after one month's treatment. Mean reduction in day-time BP was 27/14 mmHg and night-time BP 18/11 mmHg (P less than 0.001 and 0.05 respectively). There was no change in heart rate throughout the 24 h. Satisfactory day-time control of systolic and diastolic BP using the drug as monotherapy was achieved in 58% and 88% of patients respectively, although adequate control of nocturnal systolic and diastolic BP occurred in only 54% and 50% of patients respectively. No postural hypotension occurred during tilt testing, and there was a significant reduction in the peak BP observed during both dynamic and isometric exercise. Side effects were mild and transient. Thus OPC-13340, given once daily, is an effective and well tolerated anti-hypertensive drug, with a prolonged 24-h action.

Clinical validation of a miniature nuclear probe system for continuous on-line monitoring of cardiac function and ST-segment.

A new, miniature cesium iodide/photodiode nuclear probe (the "Cardioscint") has been developed for continuous on-line measurement of left ventricular function and the ST-segment. Ejection fraction (EF) measurements in 77 patients were compared with gated equilibrium radionuclide ventriculograms. The probe was positioned over the left ventricle by first using a blind positioning algorithm and then by using the gamma camera. Background was measured both manually and automatically. There was good correlation between probe (positioned blind) and gamma camera EF with both manual (r = 0.80, n = 65) and automatic (r = 0.78, n = 66) backgrounds. Use of the gamma camera did not significantly alter the results. Correlation between the probe stroke counts and thermodilution-derived stroke index during atrial pacing in six subjects was also satisfactory (r = 0.69, n = 102). Thus, the Cardioscint is able to provide a reliable estimate of EF and can track rapid changes in cardiac volumes.

The effects of intravenous carvedilol, a new multiple action vasodilatory beta-blocker, in congestive heart failure.

Recent studies have shown that beta-blockers may be effective in the management of heart failure. However, negative inotropic effects of these agents may offset the beneficial properties of up-regulation of the beta-receptors and reduction in myocardial oxygen demand. Carvedilol is a new drug which possesses a balanced combination of vasodilatation and beta-blockade. Previous studies have shown that carvedilol may have beneficial effects on left ventricular function in patients with ischemic heart disease. We have performed a preliminary study to address the safety and acute effects of intravenous carvedilol in 17 patients with chronic congestive heart failure secondary to ischemic heart disease. Acute hemodynamic changes were monitored by right heart catheterization and arterial cannulation. Ejection fraction was also monitored by radionuclide ventriculography. Significant reductions in heart rate (79 +/- 14 to 72 +/- 12 beats/min, p less than 0.001) systolic and diastolic blood pressure (137 +/- 20/72 +/- 8 to 119 +/- 19/66 +/- 8 mm Hg, p less than 0.001 and p less than 0.01), systemic vascular resistance (1766 +/- 367 to 1518 +/- 377 dynes/s/cm-5/m2, p less than 0.001) and pulmonary artery wedge pressure (20 +/- 8 to 15 +/- 7 mm Hg, p less than 0.001) were observed. Ejection fraction increased significantly from 24 to 28% (p less than 0.001) but there was little change in cardiac index or stroke volume index. The peak changes occurred at 10 min and the effect on pulmonary wedge pressure was maintained up to 30 min. No adverse effects were noted. The improvements in left ventricular filling pressure and systolic function, and the reduction in sympathetic activity may combine to produce an important therapeutic advantage in congestive heart failure. Further studies with this interesting agent are recommended.

Fibrinogen, factor VII clotting activity and coronary artery disease severity.

To asses the relationship between fibrinogen, factor VII coagulant (VIIc) activity and extent of coronary artery disease, we studied 43 white males shown to have greater than 50% stenosis of at least one major coronary artery. Thirty six had a definite history of myocardial infarction at least 3 months earlier and were classified as having 1, 2 or 3 vessel disease while 7 had 2 or 3 vessel disease, but no prior infarction. Groups were similar with regard to age, body mass index and blood pressure. In those with documented prior infarction, there was a significant relationship between the extent of atheroma and coagulation variables factor VIIc and fibrinogen. However, given a similar degree of atheroma, patients with prior infarction had significantly higher levels of factor VIIc activity compared with patients without such a history. These results corroborate those from prospective studies confirming a significant role for the coagulation system in the clinical manifestation of coronary artery disease.