Clinical Frailty Scale classes are independently associated with 6-month mortality for patients after acute myocardial infarction.

AIMS: Data on the prognostic value of frailty to guide clinical decision-making for patients with myocardial infarction (MI) are scarce. To analyse the association between frailty classification, treatment patterns, in-hospital outcomes, and 6-month mortality in a large population of patients with MI. METHODS AND RESULTS: An observational, multicentre study with a retrospective analysis of prospectively collected data using the SWEDEHEART registry. In total, 3381 MI patients with a level of frailty assessed using the Clinical Frailty Scale (CFS-9) were included. Of these patients, 2509 (74.2%) were classified as non-vulnerable non-frail (CFS 1-3), 446 (13.2%) were vulnerable non-frail (CFS 4), and 426 (12.6%) were frail (CFS 5-9). Frailty and non-frail vulnerability were associated with worse in-hospital outcomes compared with non-frailty, i.e. higher rates of mortality (13.4% vs. 4.0% vs. 1.8%), cardiogenic shock (4.7% vs. 2.5% vs. 1.9%), and major bleeding (4.5% vs. 2.7% vs. 1.1%) (all P < 0.001), and less frequent use of evidence-based therapies. In Cox regression analyses, frailty was strongly and independently associated with 6-month mortality compared with non-frailty, after adjustment for age, sex, the GRACE risk score components, and other potential risk factors [hazard ratio (HR) 3.32, 95% confidence interval (CI) 2.30-4.79]. A similar pattern was seen for vulnerable non-frail patients (fully adjusted HR 2.07, 95% CI 1.41-3.02). CONCLUSION: Frailty assessed with the CFS was independently and strongly associated with all-cause 6-month mortality, also after comprehensive adjustment for baseline differences in other risk factors. Similarly, non-frail vulnerability was independently associated with higher mortality compared with those with preserved functional ability.

Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin.

Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

Defective regulation of contractile function in muscle fibres carrying an E41K beta-tropomyosin mutation.

A novel E41K beta-tropomyosin (beta-Tm) mutation, associated with congenital myopathy and muscle weakness, was recently identified in a woman and her daughter. In both patients, muscle weakness was coupled with muscle fibre atrophy. It remains unknown, however, whether the E41K beta-Tm mutation directly affects regulation of muscle contraction, contributing to the muscle weakness. To address this question, we studied a broad range of contractile characteristics in skinned muscle fibres from the two patients and eight healthy controls. Results showed decreases (i) in speed of contraction at saturated Ca(2+) concentration (apparent rate constant of force redevelopment (k(tr)) and unloaded shortening speed (V(0))); and (ii) in contraction sensitivity to Ca(2+) concentration, in fibres from patients compared with controls, suggesting that the mutation has a negative effect on contractile function, contributing to the muscle weakness. To investigate whether these negative impacts are reversible, we exposed skinned muscle fibres to the Ca(2+) sensitizer EMD 57033. In fibres from patients, 30 mum of EMD 57033 (i) had no effect on speed of contraction (k(tr) and V(0)) at saturated Ca(2+) concentration but (ii) increased Ca(2+) sensitivity of contraction, suggesting a potential therapeutic approach in patients carrying the E41K beta-Tm mutation.

Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2).

OBJECTIVE: To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. PATIENTS: A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. RESULTS: Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the beta-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. CONCLUSIONS: The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.

[Heart failure in amyloidosis--a rare but treatable disease]. / Hjärtsvikt vid amyloidos--en ovanlig men behandlingsbar åkomma.

Cardiac amyloidosis is rare, but should be considered in the differential diagnosis of any patient with congestive heart failure who does not have evidence of ischemic heart disease. The diagnosis is more likely in patients with increased wall thickness and normal chamber size on echocardiogram, low voltage on the electrocardiogram, and evidence suggesting a multisystem disease. Amyloid proteins are varied; the most common are AA, AL and transthyretin. The clinical features differ and are largely determined by the underlying disease responsible for the amyloid infiltration and of the organs involved. The specific type of protein must be determined as the prognosis and treatment vary among the different types of amyloidoses. Systemic amyloidoses are life-threatening diseases but making an early diagnosis in connection with today's more specific treatment may modify the course of the disease.