Christer Backman

Epidemiology and Etiology of Ischemic Stroke in Young Adults Aged 18 to 44 Years in Northern Sweden

BACKGROUND AND PURPOSE The aim of this study was to conduct a population-based epidemiological survey among young adults aged 18 to 44 years in Northern Sweden and furthermore to gain further insight into the etiology of ischemic stroke in this age group. METHODS Two studies were done. In the first part, epidemiological data were collected to calculate incidence and mortality from 1991 through 1994. This was based on the World Health Organization Northern Sweden MONICA register of acute stroke events. Eighty-eight first-ever ischemic stroke patients were identified during that period. In the second part, 107 consecutive patients aged 18 to 44 years with ischemic stroke referred to a university hospital were studied prospectively during a 5-year period and were extensively evaluated according to a standardized protocol. On the basis of modified Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, the patients were classified into eight subtypes of ischemic stroke. RESULTS The average population-based annual incidence rate for ischemic stroke (cases per 100,000 per year) was 11.3 (95% confidence interval, 6.7 to 16.1). The case-fatality rate was 5.7%. According to the modified TOAST criteria, a probable cause of ischemic stroke was identified in 36% and remained unexplained in 21% of cases. Spontaneous cervical arterial dissection was the leading probable etiology (13%). Patent foramen ovale or atrial septal aneurysm was a possible cause of stroke in 28% of cases. The percentages of ischemic stroke attributed to IgG anticardiolipin antibodies (4.7%), atherothrombotic vasculopathy (3.7%), oral contraceptive use (7%), and migraine (1%) were lower than reported in recent clinical series. CONCLUSIONS The incidence rate for ischemic stroke was higher than previously reported from most countries in Western Europe. The higher incidence was not explained by a higher prevalence of premature atherosclerotic vasculopathy. Without the additional diagnostic information derived from advanced cardiac imaging, the proportion of indeterminate cases would have constituted 37% of the patients.

Progression of cardiomyopathy after liver transplantation in patients with familial amyloidotic polyneuropathy, Portuguese type

BACKGROUND Transthyretin amyloidosis is today an accepted indication for orthotopic liver transplantation (OLT). For several mutations progression of the cardiomyopathy has been observed after OLT. The aim of this study was to assess the course of cardiac involvement in Swedish familial amyloidotic polyneuropathy (FAP), Portuguese type, after OLT. By comparison of the echocardiographic findings before OLT with those obtained after, the course of the heart involvement was followed. METHODS Twenty-three patients, who had undergone OLT and were examined with echocardiography 1-12 months before OLT, were available for the study. Twenty-one patients were examined 12-27 months after OLT, and 12 were re-examined 52-71 months after OLT. Two-dimensional and M-mode echocardiography were performed in accordance with the standards of the American Society of Echocardiography. RESULTS A significantly increased septal and left ventricular posterior wall thickness and a significantly increased left atrial dimension was observed at the post-OLT examinations, indicating a progression of the amyloid heart disease. This increase of the cardiac involvement was neither correlated to waiting time for OLT or to pre-operative signs of cardiomyopathy. CONCLUSIONS Even though the production of the amyloidogenic-mutated transthyretin is stopped by OLT, the cardiomyopathy may progress after the operation even for the Portuguese type of FAP. The increase of the septal and left ventricular posterior wall thickness after OLT is not restricted to patients with signs of left ventricular hypertrophy before the transplantation. The findings have important implications for the follow-up of FAP patients after OLT.

Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis

Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine‐for‐valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post‐transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full‐length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full‐length transthyretin were associated with early age of onset (44.8 ± 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 ± 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy. Copyright

Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy

Heart complications are frequently encountered in hereditary transthyretin amyloidosis. Lately, reports of late onset familial amyloid polyneuropathy (FAP) cases presenting with a phenotype similar to that observed in senile systemic amyloidosis have emerged. The aim of the present study was to evaluate morphological and functional features of the heart by echocardiography including myocardial strain measurements, and to compare the outcome for early with those of late onset FAP cases. Eighty-one biopsy and genetically proven FAP, ATTR Val30Met patients were investigated with two-dimensional, M-mode echocardiography and myocardial strain with special attention to inter-ventricular septum (IVS) thickness. IVS thickness was closely related to the age at onset (P < 0.0001), but not to duration of disease. Seventeen percent of the patients had severe left ventricular hypertrophy (IVS > 15 mm). These patients were all late onset cases and represented 39% of all of the late onset cases. Strain measurements were also closely related to IVS thickness and age at onset thereby signifying a decreased function of the heart muscle in late onset cases. From the present investigation it appears that late onset Swedish FAP-cases more readily develop cardiomyopathy with an increased IVS thickness. Different pathways for amyloid formation in the heart may operate in early and late onset cases.

Impact of autonomic neuropathy on circulatory instability during liver transplantation for familial amyloidotic polyneuropathy

BACKGROUND Circulatory instability with severe hypotension frequently complicates liver transplantation in patients with familial amyloidotic polyneuropathy. Autonomic dysfunction is found early in the course of the disease by analysis of beat-to-beat heart rate variability (HRV). The aim of the present study was to investigate the impact of autonomic neuropathy on intraoperative circulatory instability during liver transplantation for familial amyloidotic polyneuropathy. METHODS Twenty-two patients were evaluated at the Department of Medicine, Umea University Hospital, by spectral analysis of HRV and later received liver transplants at Huddinge University Hospital. The low-and high-frequency bands obtained by spectral analysis of HRV in the supine and upright positions, respectively, were used as representative of sympathetic and parasympathetic activity. Circulatory instability during transplantation was defined as a fall in systolic arterial blood pressure below 70 mmHg for more than 5 min during the preanhepatic phase. RESULTS Both arrhythmia preventing spectral analysis of HRV and a sympathetic variability peak below 2.5 mHz2 were significantly more common among patients with intraoperative circulatory instability (P=0.03 and 0. 004, respectively). A diminished increase in pulse rate when tilting the patients from the supine to the upright position was also more pronounced among patients with circulatory instability (P<0.05). CONCLUSIONS The majority of patients who will develop circulatory instability with a pronounced fall in arterial blood pressure can be identified by Poincare plots of R-R intervals and spectral analysis of HRV. A low sympathetic peak or arrhythmia precluding spectral analysis of HRV is significantly related to operative circulatory instability.

The effects of GH replacement therapy on cardiac morphology and function, exercise capacity and serum lipids in elderly patients with GH deficiency

objectives  To assess effects of GH replacement therapy on cardiac structure and function, exercise capacity as well as serum lipids in elderly patients with GH deficiency (GHD).

Development of cardiomyopathy after liver transplantation in Swedish hereditary transthyretin amyloidosis (ATTR) patients

Background: Recent studies of liver transplanted (LTx) familial amyloidotic polyneuropathy (FAP) patients have shown a progression of cardiomyopathy in some patients after LTx, but knowledge of the underlying factors remains limited. Methods: Seventy-five patients, who had undergone LTx from 1996 to 2008, were included. They had all been examined by echocardiography 1–16 months before LTx. Fifty-four had been re-examined 7–34 months, and forty-two 36–137 months after LTx. Results: A significant increase in interventricular septum (IVS) thickness occurred after LTx (p < 0.01), particularly in males (p = 0.002) and late onset patients (p = 0.003). The development of post-LTx cardiomyopathy was related to patient’s age at onset of the disease, male gender and pre-LTx IVS thickness. On multivariate regression analysis, however, age at onset was the only significant predictor for the development of cardiomyopathy (odds ratio = 1.14, 95% confident interval 1.01–1.30, p = 0.04). Conclusion: An increase of IVS thickness can be observed in FAP patients after LTx. Age at onset of the disease is the main predictor for increased IVS thickness and for the development of cardiomyopathy after liver transplantation.

Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1

Abstract.  Mörner S, Lindqvist P, Mellberg C, Olofsson B‐O, Backman C, Henein M, Lundblad D, Forsberg H (Umeå University Hospital, Umeå; Umeå University, Umeå; Sunderby Hospital, Luleå; Sweden). Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1. J Intern Med 2010; 268:59–65.

Ventricular dysfunction in type 1 myotonic dystrophy: electrical, mechanical, or both?

BACKGROUND Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. METHODS Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. RESULTS Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR≥200 ms, 11 had QRS duration>120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. CONCLUSIONS In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials.

Cold Induced Vasospasm in Replanted Digits: A Comparison Between Different Methods of Arterial Reconstruction

Nineteen patients each of whom had had a single digit replanted were examined after replantation. The arterial reconstruction had been done with long grafts (n = 10) or short grafts or no graft (n = 9). The effect of local or whole body cooling on the replanted and uninjured opposite digits was monitored (9-46 months after the replantation), and the patients were given a questionnaire (9-95 months after replantation) designed to explore the development of their cold related symptoms in relation to time. All patients were troubled by cold intolerance, and improvement occurred in only 60% of the cases. Pathological (vasospastic) arterial reactions to cold measured as finger systolic pressure, were less common after replantation with long grafts. Perceived cold intolerance was significantly more pronounced in the group of patients (60%) who had evidence of cold induced arterial spasm in the replanted finger.