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Purpose: Pathological changes of the peripheral pulmonary arteries induce pulmonary arterial hypertension (PAH). Aim of this study was to quantitatively assess the effect of PAH on pulmonary perfusion by 3D-MR-perfusion techniques and to compare findings to healthy controls. Furthermore, quantitative perfusion data were correlated with invasive pressure measurements., Material and Methods: Five volunteers and 20 PAH patients (WHO class II or III) were examined using a 1.5T MR scanner. Measurement of pulmonary perfusion was done in an inspiratory breathhold (FLASH3D; 3.5 mm x 1.9 mm x 4mm; TA per 3D dataset 1.5s). Injection of contrast media (0.1 mmol Gd-DTPA/kg BW) and image acquisition were started simultaneously. Evaluation of 3D perfusion was done using singular value decomposition. Lung borders were outlined manually. Each lung volume was divided into three regions (anterior, middle, posterior), and the following parameters were assessed: Time-to-Peak (TTP), blood flow (PBF), blood volume (PBV), and mean transit time (MTT). In 10 patients invasive pulmonary artery pressure measurements were available and correlated to the perfusion measurements., Results: In both, controls and patients, an anterior-to-posterior gradient with higher PBF and PBV posterior was observed. In the posterior lung region, a significant difference (p<0.05) was found for TTP (12s versus 16s) and MTT (4s versus 6s) between volunteers and patients. PBF and PBV were lower in patients than in volunteers (i.e. dorsal regions: 124 versus 180 ml/100 ml/min and 10 versus 12 ml/100 ml), but the difference failed to be significant. The ratio of PBF and PBV between the posterior and the middle or ventral regions showed no difference between both groups. A moderate linear correlation between mean pulmonary arterial pressure (mPAP) and PBV (r=0.51) and MTT (r=0.56) was found., Conclusion: The only measurable effect of PAH on pulmonary perfusion is a prolonging of the MTT. There is only a moderate linear correlation of invasive mPAP with PBV and MTT.

Background: Iloprost is a stable prostacyclin analogue that is associated with a longer duration of vasodilatation and has been approved for inhalative use with 6 or 9 inhalations during the daytime and a night pause. It is not known if during the night pause rebound pulmonary hypertension occurs. The aim of this study was to assess the hemodynamics in iloprost-treated patients during the daytime and at night., Methods: We enrolled 5 adult patients (aged 45 +/- 10 years) with idiopathic pulmonary arterial hypertension (IPAH) and chronic inhaled iloprost therapy for at least 12 months. Further medication remained unchanged during the study period. Hemodynamics were monitored by right heart catheterization., Results: After 30-60 min of nebulized iloprost, mean pulmonary arterial pressures (PAP) decreased from 68 +/- 15 to 51 +/- 18 mm Hg (p = 0.004). After 6 h off-medication sleeping time, mean PAP initially increased until 2 a.m. and decreased subsequently until wake-up time at 6 a.m. Mean PAP, cardiac index and pulmonary vascular resistance at night were not significantly different from the values during the day., Conclusions: In this study, patients with IPAH and chronic nebulized iloprost therapy did not reveal a rebound pulmonary hypertension during off-medication sleeping time., (Copyright 2007 S. Karger AG, Basel.)

Background: Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH., Methods and Results: Thirty patients with PH (21 women; mean age, 50+/-13 years; mean pulmonary artery pressure, 50+/-15 mm Hg; mean World Health Organization [WHO] class, 2.9+/-0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61+/-18 to 54+/-18 mm Hg) within the training group., Conclusions: This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.

Differentiation between different forms of pulmonary hypertension (PH) is essential for correct disease management. The goal of this study was to elucidate the clinical impact of high spatial resolution MR angiography (SR-MRA) and time-resolved MRA (TR-MRA) to differentiate between patients with chronic thromboembolic PH (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH). Ten PH patients and five volunteers were examined. Twenty TR-MRA data sets (TA 1.5 s) and SR-MRA (TA 23 s) were acquired. TR-MRA data sets were subtracted as angiography and perfusion images. Evaluation comprised analysis of vascular pathologies on a segmental basis, detection of perfusion defects, and bronchial arteries by two readers in consensus. Technical evaluation comprised evaluation of image quality, signal-to-noise ratio (SNR) measurements, and contrast-media passage time. Visualization of the pulmonary arteries was possible down to a subsegmental (SR-MRA) and to a segmental (TR-MRA) level. SR-MRA outperformed TR-MRA in direct visualization of intravascular changes. Patients with IPAH predominantly showed tortuous pulmonary arteries while in CTEPH wall irregularities and abnormal proximal-to-distal tapering was found. Perfusion images showed a diffuse pattern in IPAH and focal defects in CTEPH. TR-MRA and SR-MRA resulted in the same final diagnosis. Both MRA techniques allowed for differentiation between IPAH and CTEPH. Therefore, TR-MRA can be used in the clinical setting, especially in dyspneic patients.

Individuals susceptible to high-altitude pulmonary oedema (HAPE) are characterised by an abnormal increase of pulmonary artery systolic pressure (PASP) in hypoxia and during normoxic exercise, reduced hypoxic ventilatory response, and smaller lung volume. In 37 mountaineers with well-documented altitude tolerance, it was investigated whether any combination of these noninvasive measurements, including exercise in hypoxia, could improve the identification of HAPE-susceptible subjects at low altitude. HAPE-susceptible subjects showed a significant higher increase of PASP during hypoxia at rest (48+/-10 mmHg) compared with controls (38+/-3 mmHg), as well as during normoxic exercise (57+/-14 versus 38+/-7 mmHg) and hypoxic exercise (69+/-13 versus 49+/-8 mmHg). PASP could not be assessed in three and eight subjects during normoxic or hypoxic exercise, respectively, due to insufficient Doppler profiles or systemic arterial hypertension. Sensitivity (77-94%) and specificity (76-93%) were not significantly different between the various testing conditions. Additional assessment of hypoxic ventilatory response and lung function parameters did not improve identification of HAPE-susceptible subjects in a multivariate analysis. Due to the greater number of missing values in pulmonary artery systolic pressure measurements during hypoxic exercise, it was concluded that pulmonary artery systolic pressure measurements at rest during hypoxia or exercise in normoxia are most feasible for the identification of high-altitude pulmonary oedema-susceptible subjects.

Objective: This is the first study that investigates the prevalence and actual treatment of anxiety, depression, and other mental disorders in patients with pulmonary hypertension (PH). The prevalence of mental disorders in patients with PH was compared with parallel groups of primary care patients and patients with inflammatory rheumatic diseases, and the relationship between functional status and prevalence of mental disorders was determined., Methods: The patient group with PH (70.1% female; mean age, 47.8 +/- 12.7 years) and the two comparison groups, which were matched by age and sex, consisted of 164 patients each. Patients completed self-administered instruments, including the Patient Health Questionnaire for the diagnosis of mental disorders. New York Heart Association (NYHA) functional class was assessed in all patients with PH., Results: Thirty-five percent of the patients with PH suffered from mental disorders, with the most common being major depressive disorder (15.9%) and panic disorder (10.4%). Both panic disorder and panic attacks were significantly more prevalent in patients with PH than in either patients with inflammatory rheumatic diseases or primary care patients. The prevalence of mental disorders in patients with PH increased significantly with functional impairment, from 17.7% (NYHA class I) to 61.9% (NYHA class IV). Only 24.1% of the patients with PH with mental disorders were receiving psychopharmacological or psychotherapeutic treatment., Conclusions: Anxiety and depression are frequent in patients with PH and increase as the severity of disease progresses. Given the fact that safe and efficacious treatments of mental disorders are available, greater importance should be attached to the diagnosis and treatment of these conditions in patients with PH.

Mutations of the bone morphogenetic protein receptor II (BMPR2) gene on chromosome 2q33 can cause familial primary pulmonary hypertension (PPH) and may occur in 26% adult patients with sporadic disease. Other disease-related genes have been localized to chromosomes 2q31 (PPH2) and 12q13 (ALK1). The genetic background in affected children remains unclear. Thirteen children (age at diagnosis, 6 mo to 13 y; mean, 5.6 +/- 3.9 y) with invasively confirmed PPH were screened for BMPR2 mutations using denaturing HPLC and sequence analysis. In addition, all children were scanned for BMPR2 deletions by Southern blot analysis. Pulmonary artery pressure was assessed using echocardiography at rest and during exercise in 57 family members of six infants. The six families were subjected to linkage analysis. None of the 13 children had a BMPR2 mutation or deletion. Linkage to chromosome 2 or 12 could not be confirmed in any of the families investigated. In all assessed families, both parents of the index patient and/or members of both branches revealed an abnormal pulmonary artery systolic pressure (PASP)-response to exercise. PPH in children may have a different genetic background than in adults. We postulate a recessive mode of inheritance in a proportion of infantile cases.

Objectives: The aim of our study was to identify genetic causes of primary pulmonary hypertension (PPH), to estimate the proportion of families with mutations in the BMPR2 (bone morphogenetic protein receptor type 2) gene, and to examine whether genetic heterogeneity might play a role., Background: The BMPR2 mutations have been identified in a substantial portion of patients with familial or sporadic PPH. However, the genetic cause of PPH remains unclear in at least 45% of families., Methods: We investigated 130 members of 10 families with at least 1 PPH patient, recruited without selection for familial disease. Manifest PPH was documented in 21 individuals. An increase in pulmonary artery systolic pressure (PASP) above 40 mm Hg during supine bicycle exercise was found in 46 healthy individuals. Their PASP increased from 21.0 +/- 4.6 mm Hg at rest to 54.0 +/- 9.8 mm Hg during exercise. In 51 relatives, PASP values were normal at rest and during exercise, and 12 members were classified as status unknown., Results: Two families showed a mutation in the BMPR2 gene. Three families with no BMBR2 mutation showed evidence for linkage to a more proximal location on chromosome 2q31 (odds ratio [OR] for linkage 1.1.10(6):1). This locus, designated PPH2, maps in-between the markers D2S335 and D2S2314. We obtained significant support for heterogeneity in PPH with an OR of 2.8.10(11)., Conclusions: We conclude that PPH may be a genetically heterogeneous disorder with at least two-and possibly more-causative genes.

Objectives: This prospective study was performed to analyse whether routine clinical follow-up investigations at 12+/-6 months add to risk stratification and improve survival rates in patients with a first diagnosis of dilated cardiomyopathy (DCM)., Methods: Four hundred and eighty consecutive patients (mean age 53.4+/-12.3 years, 369 males, mean NYHA class 2.4+/-0.8) with invasively confirmed DCM were included and followed for 3.9+/-3.5 years. Patients were requested to adhere to a follow up investigation within 6-18 months either at the referring physicians or at our out patient department. Two hundred and eighty-one of the 480 patients presented for follow up which consisted of a detailed evaluation of symptoms, standardized physical examination, 12-lead-electrocardiogram recording and echocardiography. Seventeen patients were lost for follow up, 182 did not seek specialized medical follow up. Patients outcome was assessed by structured telephone interviews., Results: Independent predictors of death or transplantation at initial diagnosis were LV-ejection fraction <30% (P=0.0001, risk ratio 2.25), LV-end diastolic pressure >or=15 mmHg (P=0.002, risk ratio 2.0), age >or=54 years, (P=0.04, risk ratio 1.55), and presence of left bundle branch block (P=0.046, risk ratio 1.53). On follow up investigations only deterioration of clinical status by at least one NYHA-class (P=0.001, risk ratio 2.6) and new onset or worsening of mitral regurgitation (P=0.02, risk ratio 1.8), remained independent prognostic factors for cardiac death. Patients who presented for routine follow up revealed significant better 5-year survival rates (n=281, 70%) than those who did not (n=153, 55%, P=0.005)., Conclusions: Routine clinical follow up investigations within 6-18 months after first diagnosis of DCM adds to risk stratification and improves survival rates.

Background: Due to its higher diagnostic accuracy stress echocardiography (SE) has been advocated as a substitute for stress ECG to detect coronary heart disease (CAD). However, its contribution to clinical decision-making in unselected patients presenting to the ambulatory care centre for known or suspected coronary artery disease is unclear., Methods: To evaluate the clinical value of SE in unselected patients, we prospectively obtained SE and stress ECG in 221 consecutive patients (142 males; mean age 58+/-12 years) presenting to the ambulatory care centre with known or suspected CAD. Patients with acute coronary syndrome were not included., Results: Results of stress ECG and SE were concordant in 181 (82%) and discordant in 40 patients (18%). The clinical decision to recommend or to currently withhold coronary angiography was possible solely on the basis of clinical criteria and stress ECG findings in 191 (86.4%) patients but was guided by the results of SE in 30 patients (13.6%). Left heart catheterization and coronary angiography were conducted in 61 patients. In this population SE was more accurate (82.6%) than stress ECG (65.6%) in indicating significant coronary artery stenosis., Conclusion: Despite its higher accuracy, SE adds little to the information derived from dynamic stress ECG and symptom evaluation in unselected outpatients with known or suspected CAD. Thus, SE should not in general replace stress ECG as a screening method for detecting significant coronary artery disease, for both clinical and economic reasons.

The identification of several mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta receptor family, gives hope for new insights into the pathophysiology of pulmonary hypertension. Genetic predisposition might dictate the responses of pulmonary artery fibroblasts, smooth muscle cells, and endothelial cells, as well as platelets and leukocytes, or their specific interactions with different extrinsic factors. These cells possess distinct subtypes and interact with each other. Pulmonary hypertension is associated with vasoconstriction, remodeling, and in situ thrombosis of the pulmonary arteries, but the initial events and their relationship to the genetic background are presently unknown. Current therapeutic approaches are based on our knowledge of the physiologic regulation of pulmonary artery tone, pathophysiologic changes, and our clinical experience with different treatment strategies. Beyond diuretics and anticoagulants, prostaglandins are generally accepted therapeutic agents for primary pulmonary hypertension and related diseases, whereas high-dose calcium-channel blockers are reserved for a small subset of patients, those who respond favorably to vasodilators in an acute test. Long-term intravenous prostacyclin infusion has become the most important specific therapy for primary pulmonary hypertension and associated diseases. However, this therapy is hampered by catheter complications and systemic side effects. Alternative application routes of prostacyclin or its stable analogs may avoid these problems. Inhaled application of the prostacyclin analog iloprost results in predominant pulmonary vasodilation with few systemic side effects and may possess clinical efficacy similar to that of intravenous prostacyclin. Inhaled nitric oxide is widely accepted as a screening agent for active responders to vasodilators and has a similar hemodynamic profile as inhaled iloprost, although the percentage of responders is considerably lower. However, there are unsolved toxicologic questions and practical difficulties concerning the safe long-term application of nitric oxide. Combining inhaled vasodilators with phosphodiesterase inhibitors may prolong the duration of the effects and improve the convenience of inhaled therapy for pulmonary hypertension. Therapeutic approaches in the future may aim at the transforming growth factor beta pathway and at the identification of early stages of the disease to prevent further disease progression.

The most reliable prediction of high altitude tolerance can be derived from the clinical history of previous comparable exposures. Unfortunately, there are no reliable tests for prediction prior to first-time ascents. Although susceptibility to AMS is usually associated with a low hypoxic ventilatory response (HVR), there is too much overlap with the range of normal values, which precludes measuring HVR or O(2) saturation during brief hypoxia for reliable identification of susceptibility to AMS. A low HVR and an exaggerated rise in pulmonary artery pressure with (prolonged) hypoxia, or exercise in normoxia, are markers of susceptibility to high altitude pulmonary edema (HAPE). These tests can not be recommended for routinely determining high altitude tolerance because the prevalence of susceptibility to HAPE is low and because specificity and sensitivity of these tests are not sufficiently established. On the other hand, HAPE may be avoided in susceptible individuals by ascent rates of 300 m per day above an altitude of 2000 m. Since prediction of risk of mountain sickness is difficult, it is important during the physician consultation prior to ascent to consider the altitude profile, the type of ascent, the performance capacity, the history of previous exposures, and the medical infrastructure of the area.

An exaggerated hypoxic pulmonary vasoconstriction is essential for development of high-altitude pulmonary edema (HAPE). We hypothesized that susceptibility to HAPE may be related to decreased production of nitric oxide (NO), an endogenous modulator of pulmonary vascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure. Therefore, we investigated respiratory tract NO excretion by chemiluminescence and pulmonary artery systolic pressure (Ppa,s) by echocardiography in nine HAPE-susceptible mountaineers and nine HAPE-resistant control subjects during normoxia and acute hypoxia (fraction of inspired oxygen [FI(O2)] = 0.12). The subjects performed oral breathing. Nasally excreted NO was separated from respiratory gas by suction via a nasal mask. In HAPE-susceptible subjects, NO excretion in expired gas significantly decreased (p < 0.05) during hypoxia of 2 h in comparison with normoxia (28 +/- 4 versus 21 +/- 2 nl/min, mean +/- SEM). In contrast, the NO excretion rate of control subjects remained unchanged (31 +/- 6 versus 33 +/- 6 nl/ min, NS). Nasal NO excretion did not differ significantly between groups during normoxia (HAPE-susceptible group, 183 +/- 16 nl/ min; control subjects, 297 +/- 55 nl/min, NS) and was not influenced by hypoxia. The changes in Ppa,s with hypoxia correlated with the percent changes in lower respiratory tract NO excretion (R = -0.49, p = 0.04). Our data provide the first evidence of decreased pulmonary NO production in HAPE-susceptible subjects during acute hypoxia that may contribute among other factors to their enhanced hypoxic pulmonary vascular response.

Background: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise., Methods and Results: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected., Conclusions: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

Background: Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized., Methods and Results: Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified., Conclusions: A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.

Objective: This prospective single-blinded study was performed to quantitate noninvasive pulmonary artery systolic pressure (PASP) responses to prolonged acute hypoxia and normoxic exercise., Background: Hypoxia-induced excessive rise in pulmonary artery pressure is a key factor in high-altitude pulmonary edema (HAPE). We hypothesized that subjects susceptible to HAPE (HAPE-S) have increased pulmonary artery pressure response not only to hypoxia but also to exercise., Methods: PASP was estimated at 45, 90 and 240 min of hypoxia (FiO2 = 12%) and during supine bicycle exercise in normoxia using Doppler-echocardiography in nine HAPE-S and in 11 control subjects., Results: In the control group, mean PASP increased from 26+/-2 to 37+/-4 mm Hg (deltaPASP 10.3+/-2 mm Hg) after 90 min of hypoxia and from 27+/-4 to 36+/-3 mm Hg (deltaPASP 8+/-2 mm Hg) during exercise. In contrast, all HAPE-S subjects revealed significantly greater increases (p = 0.002 vs. controls) in mean PASP both during hypoxia (from 28+/-4 to 57+/-10 mm Hg, deltaPASP 28.7+/-6 mm Hg) and during exercise (from 28+/-4 to 55+/-11 mm Hg, deltaPASP 27+/-8 mm Hg) than did control subjects. Stress echocardiography allowed discrimination between groups without overlap using a cut off PASP value of 45 mm Hg at work rates less than 150 W., Conclusions: These data indicate that HAPE-S subjects may have abnormal pulmonary vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, Doppler echocardiography during supine bicycle exercise or after 90 min of hypoxia may be useful noninvasive screening methods to identify subjects susceptible to HAPE.

Objectives: This prospective study was performed to analyze the frequency and clinical characteristics of idiopathic dilated cardiomyopathy (DCM)., Background: Despite several previous reports on families with DCM, most cases are still believed to be sporadic, and specific clinical findings of the familial form are not well defined., Methods: In 445 consecutive patients with angiographically proven DCM, we obtained detailed family histories to construct pedigrees and examined 970 first- and second-degree family members., Results: Familial DCM was confirmed in 48 (10.8%) of the 445 index patients and was suspected in 108 (24.2%). The 156 patients with suspected or confirmed familial disease were younger at the time of diagnosis (p < 0.03) and more often revealed electrocardiographic changes (p = 0.0003) than patients with nonfamilial disease. Among the families of the 48 index patients with confirmed familial disease, five phenotypes of familial DCM could be identified: 1) DCM with muscular dystrophy; 2) juvenile DCM with a rapid progressive course in male relatives without muscular dystrophy; 3) DCM with segmental hypokinesia of the left ventricle; 4) DCM with conduction defects; and 5) DCM with sensorineural hearing loss., Conclusions: Up to 35% of patients with DCM may have an inherited disorder. Distinct clinical phenotypes can be observed in some families, suggesting a common molecular cause of the disease.

Although prognosis of dilated cardiomyopathy (DCM) has improved due to advances in diagnosis and therapy, still too many sudden cardiac deaths occur in DCM. Spontaneous ventricular ectopy is a very common finding in patients with DCM, but the prognostic significance of Holter monitoring remains controversial. Other noninvasive methods, e.g., late potentials and QT dispersion, have not yet contributed to the evaluation of prognosis for arrhythmogenic events in DCM. Programmed ventricular stimulation has been repeatedly used to stratify long-term prognosis, yet satisfactory data are still missing as many deaths occur in patients without inducible arrhythmias. Several prognostic studies are still in progress, and preliminary data for the use of ICDs already appear to be promising. In patients with poor left ventricular function and ICDs in situ, prognosis is determined by progression of heart failure. Heart transplantation may be the ultimate therapeutic instrument for end-stage heart failure patients. For patients with advanced DCM and increased risk for malignant arrhythmias who are unsuitable for orthotopic heart transplantation, the combined therapy with an ICD and dynamic cardiomyoplasty may be an alternative treatment.

The diagnosis of acute myocardial infarction is straightforward when anginal pain is accompanied by typical ECG changes and in these patients measurements of cardiac markers are unnecessary in deciding whether thrombolytic therapy is appropriate. Cardiac markers in patients with acute ischaemic coronary syndromes, however, may serve to identify a high risk subgroup of patients with small acute infarctions or minor myocardial damage. In many patients with chest pain a valid diagnosis of myocardial cell injury depends on the result of biochemical assays. In 30% of patients with unstable angina, troponin T is elevated although myocardial infarction was ruled out by cardiac enzymes and ECG recordings. The outcome of these patients at 4 weeks and 6 months follow-up is not different from that of patients with definite myocardial infarction. To guide therapeutic decisions on these patients a troponin T test result needs to be available rapidly. The rapid troponin T test strip assay, which allows the determination of troponin T levels in whole blood at the patient's bedside, can be performed conveniently in the emergency room or in laboratories with less sophisticated equipment and has the potential to aid in the triage of chest pain patients and the selection of therapeutic strategies.

We report on a family with a severe form of X-linked dilated cardiomyopathy (DCM). Two brothers, the elder requiring heart transplantation, and a maternal cousin presented elevated creatine kinase levels, increased right ventricular diameters and electrocardiographic abnormalities. All complained of exertional cramping myalgia, but none had muscle weakness or a pathological electromyogram. Muscle biopsies of these individuals revealed a mild myopathic picture with atrophic type I and hypertrophic type II fibers. Immunofluorescence using N- and C-terminal antibodies (dys-2, dys-3) against the dystrophin protein showed preserved, but reduced intensity of staining of the sarcolemmal membranes. Using the same two antibodies, Western blot analyses revealed a dystrophin molecule of the expected molecular weight, which was quantitatively reduced by 80%. However, the dys-1 antibody, directed against the mid rod region of the dystrophin protein, did not react with dystrophin both on Western blot and immunofluorescence. Linkage analysis with polymorphic markers of the dystrophin gene revealed an identical haplotype at the 5' region in all affected individuals (two point lod score of 1.93, phi = 0). A deletion of exons 48, 45-53, 2-7 and 1 including the promoter region of the dystrophin gene, as described in rare cases with similar clinical signs could be excluded by multiplex PCR and Southern blot analyses of this DCM family. In addition, a major splice-mutation of dystrophin mRNA was excluded by RT-PCR of skeletal and heart muscle tissue. Therefore, we conclude that a novel mutation in the 5' region of the dystrophin gene phenotypically leads to this severe form of DCM. Extensive analyses of the dystrophin gene, in particular of the sequences coding for the antigenic determinants of the dys-1 antibody in the mid rod region, may identify the molecular cause of this monogenetic form of DCM.

Dilative cardiomyopathy is a heterogeneous myocardial disease characterized by a depressed contractile function and ventricular dilation. The exercise intolerance of patients with dilative cardiomyopathy is partly explained by changes of metabolism and composition of skeletal muscle, whereas the physical findings result from progressive heart failure and cardiac remodeling. The clinical course of the disease is highly variable and prognostic indicators of progressive heart failure or cardiac arrhythmias are of little value in the assessment of cardiac risk in an individual patient. During recent years the mortality of patients with dilative cardiomyopathy was 5-15%, which appears to be lower than previously reported. The differences in mortality today and in previous years may be explained by a more precise and earlier diagnosis of the disease and possibly better treatment strategies. Patients with a severely depressed left ventricular function but a stable clinical course, a good hemodynamic response to therapy, and an oxygen uptake of > 12 ml/kg min can be followed without heart transplantation. It can be expected that the definition of the molecular causes of dilative cardiomyopathy will lead to a better classification of the patients and the development of more efficient treatment strategies.

Background: The purpose of this study was to derive indices of reperfusion and non-reperfusion after acute myocardial infarction (AMI) from changes in serum concentrations of cardiac troponin T and to test the predictive value of these indices., Methods: The indices were derived from a retrospective analysis of changes in serum troponin T concentration in 71 patients given thrombolytic treatment who had immediate and late angiography (group 1). These troponin T indices were first tested in a blinded and prospective study of 53 consecutive patients eligible for thrombolytic therapy (group 2). They were then used for the non-invasive assessment of reperfusion of AMI in 48 patients (group 3)., Results: In group 1 troponin T serum concentration curves were biphasic in patients who had reperfusion < or = 5.8 h after the onset of symptoms. Release of the cytosolic troponin T pool resulted in a peak at 14 h and ended at 38 h. The probability of reperfusion was > 95% when the ratio of peak cytosolic troponin T concentration to concentration at 38 h (PV1/38) exceeded 1.42 or the ratio of troponin T concentration at 14 h to that at 38 hours (14/38) exceeded 1.09. The probability of the presence of non-reperfused AMI was < 5% when troponin T PV1/38 and 14/38 ratios were < 0.99 and < 0.84 respectively. These discriminatory values of troponin T indices correctly classified (efficiency 96%) 48 of the 53 group 2 patients in whom immediate and late angiography were performed. When troponin T indices were used to classify 48 group 3 patients who were not studied by immediate angiography, thrombolytic therapy was deemed to have been successful in 82% of the treated patients, with spontaneous recanalisation in 11% and 23% of the non-treated patients assessed by PV1/38 and 14/38 respectively., Conclusion: The PV1/38 or 14/38 ratios of serum troponin T concentration indicated the effectiveness of thrombolytic therapy in achieving reperfusion of AMI.