Karl‐Josef Osterziel

This study introduces new methods of non-linear dynamics (NLD) and compares these with traditional methods of heart rate variability (HRV) and high resolution ECG (HRECG) analysis in order to improve the reliability of high risk stratification.Simultaneous 30 min high resolution ECG's and long-term ECG's were recorded from 26 cardiac patients after myocardial infarction (MI). They were divided into two groups depending upon the electrical risk, a low risk group (group 2, n = 10) and a high risk group (group 3, n = 16). The control group consisted of 35 healthy persons (group 1). From these electrocardiograms we extracted standard measures in time and frequency domain as well as measures from the new non-linear methods of symbolic dynamics and renormalized entropy.Applying discriminant function techniques on HRV analysis the parameters of non-linear dynamics led to an acceptable differentiation between healthy persons and high risk patients of 96%. The time domain and frequency domain parameters were successful in less than 90%. The combination of parameters from all domains and a stepwise discriminant function separated these groups completely (100%). Use of this discriminant function classified three patients with apparently low (no) risk into the same cluster as high risk patients. The combination of the HRECG and HRV analysis showed the same individual clustering but increased the positive value of separation.The methods of NLD describe complex rhythm fluctuations and separate structures of non-linear behavior in the heart rate time series more successfully than classical methods of time and frequency domains. This leads to an improved discrimination between a normal (healthy persons) and an abnormal (high risk patients) type of heart beat generation. Some patients with an unknown risk exhibit similar patterns to high risk patients and this suggests a hidden high risk. The methods of symbolic dynamics and renormalized entropy were particularly useful measures for classifying the dynamics of HRV.

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding β-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations.Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM.A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.

Studies on medical therapy in heart failure are focused on changes of left ventricular (LV) dimensions and function. These changes may be small, requiring a large study group. We measured LV parameters (LV volumes, LV ejection fraction (LV-EF), and left ventricular mass (LVM)) with two-dimensional echocardiography (2D-echo) and magnetic resonance imaging (MRI) in 50 patients. Based on the difference between the measurements, we determined the variance of the results and calculated the sample sizes needed to detect changes of baseline values. For the calculated and measured parameters we found significant differences between the two techniques: LV-EF and LVM were higher in 2D-echo, and LV dimensions were comparable. The sample size to detect relevant changes from baseline with MRI was significantly (P < 0.01) smaller than in 2D-echo. We conclude that MRI is superior in clinical studies on left ventricular dimensional and functional changes, since measurements are more reproducible and the required sample size is substantially smaller, thereby reducing costs.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC.

The referral of critically ill cancer patients to an intensive care unit (ICU) is a matter of controversial debate. This study was conducted by an interdisciplinary clinical group to evaluate the outcome of ICU treatment in cancer patients according to their characteristics at the time of referral. A retrospective analysis was used to identify relevant subgroups among 189 consecutive cancer patients referred as emergencies to one of four ICUs during a 2-year period. Reasons for ICU referral were pneumonia (29.6%), sepsis (27.0%), fungal infection (11.1%), another infection (9.5%), gastrointestinal emergency (16.9%), treatment-related organ toxicity (6.9%), or other, non-infectious complications (43.9%). Vasopressor support was required in 50.3%, mechanical ventilation in 49.7%, and haemodialysis/-filtration in 26.5% of the patients. Overall, 41.3% died during ICU treatment, 12.2% died after transfer from ICU to a non-ICU ward, and 35.4% were discharged alive. Sepsis, mechanical ventilation, vasopressor support, renal replacement therapy and neutropenia were independent risk factors for fatal outcome, but no single risk factor unequivocally predicted death. All patients with fungal infection who required vasopressor support and either had sepsis (n=13) or needed mechanical ventilation (n=14) died during ICU treatment, while all non-septic patients. who did not require mechanical ventilation, were younger than 74 years of age and had a non-infectious underlying complication (n=29), survived. This analysis may help to early identify relevant subgroups of cancer patients with different prognoses under ICU treatment. A prospective study to confirm the predictive usefulness of this approach is needed. Cancer patients should not be excluded from referral to the intensive care unit in an emergency solely due to their underlying malignant disease or a single unfavourable prognostic factor.

the effects of long-term administration of beta-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial.patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) < or =0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo.metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01).metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.

We examined the insertion/deletion polymorphism in the angiotensin-converting enzyme gene and identified polymorphisms in the heart chymase gene to test the hypothesis that these angiotensin II-producing enzymes are associated with a monogenic cardiac disease (50 patients and 50 control subjects) as a model of cardiac hypertrophy. We found that the angiotensin-converting enzyme DD genotype was present more often in patients than in control subjects and identified a possible interaction with 1 of the chymase polymorphisms.

Disease-causing mutations in cardiac myosin heavy chain (beta-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa(50)) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa(50), whereas those with the Ile736Thr mutation showed slightly increased mean pCa(50) with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa(50) between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences that were not observed in controls. While changes in mean pCa(50) may suggest specific pharmacological treatment (e.g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa(50) from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.

Invasive hemodynamic measurements and determination of baroreflex sensitivity were carried out in 12 mildly sodium-depleted normotensive volunteers in a randomized double-blind crossover study with a single dose of converting enzyme inhibitor, MK-421, and placebo.In supine humans at rest, MK-421 caused a reduction in blood pressure through a fall in total peripheral resistance and an increase in arterial compliance.Thus, MK-421 appears to dilate both resistance vessels and larger arteries.Cardiac output increased, but contrary to the effects of other vasodilators, the increase was due to a higher stroke volume with an unchanged heart rate.The lack of heart rate response may well reflect enhanced central parasympathetic cardiac inhibition.Head-up tilt on MK-421 caused an additional decrease in blood pressure in 65% of the subjects.The major determinant for the blood pressure fall during tilt and converting enzyme inhibition was a decrease in cardiac performance, while the reflex increase of arteriolar and venous tone was largely unimpaired.The decreased stroke volume may be secondary to elimination of a positive inotropic effect of angiotensin II (All).It is also conceivable that in the absence of AH the inotropic response to sympathetic activation is inadequate during tilt in these sodium-depleted normotensive individuals.Baroreflex sensitivity to blood pressure increase (i.v.phenylephrine) was enhanced after MK 421.Arterial compliance was increased, and this may explain the altered baroreceptor sensitivity.However, a possible central nervous enhancement of baroreceptor sensitivity after MK-421 could not be ruled out in this study.(Hypertension 5 (supp I): 1-184-1-191, 1983) KEY WORDS • hemodynamics adrenergic system • angiotensin II • baroreflex • blood pressureA NGIOTENSIN II (All) has been shown to fa- cilitate the cardiovascular effect elicited by stimulation of the sympathetic nervous system. 1 "-1 These effects of All are exerted on the peripheral as well as the central part of the adrenergic system 1 2 and involve a facilitation of ganglionic transmission through an increased norepinephrine release at the presynaptic level and to a minor degree by prevention of reuptake.Some data also suggest that All potentiates the effect of norepinephrine on postsynaptic receptors.' 4 Finally, All enhances the neuronally-mediated release of catecholamines from the adrenal medulla.

Assessment of fluctuations in heart rate (HR) following a premature ventricular complex (PVC) is valuable for identifying patients at high risk of sudden cardiac death. We hypothesised that postextrasystolic potentiation is the main determinant of the regulation patterns of blood pressure (BP) and HR following a PVC. Twelve patients with idiopathic dilated cardiomyopathy (IDC) and 13 control subjects with single PVCs (comparable coupling intervals) were investigated. Non‐invasive finger arterial BP and ECGs were analysed. Regulation patterns following a single PVC were quantified using the indices postextrasystolic amplitude potentiation (PEAP) and maximum turbulence slope of five consecutive mean BP values (MBP‐TS), and compared with the HR turbulence parameters turbulence slope (HR‐TS) and turbulence onset (HR‐TO). PEAP was significantly higher in IDC patients compared to controls (48.7 ± 32.6 vs . 9.8 ± 5.4 %, P &lt; 0.01), whereas MBP‐TS was lower (0.97 ± 0.60 vs . 2.07 ± 1.04 mmHg BBI −1 (BBI, beat‐to‐beat interval), P &lt; 0.05), as was HR‐TS (8.46 ± 7.90 vs . 30.73 ± 22.90 ms BBI −1 , P &lt; 0.01). HR‐TO was significantly higher in IDC patients (−0.56 ± 2.19 vs .−5.52 ± 4.13 %, P &lt; 0.01). In addition, the regulation patterns of BP and HR following a single PVC differed significantly between IDC patients and controls. Specifically, we observed pronounced PEAPs in IDC patients. The baroreflex response initiated by the low pressure amplitude of the PVC was suppressed in IDC patients due to the augmented potentiation of the first postextrasystolic blood pressure. Furthermore, IDC patients displayed impressive postextrasystolic pulsus alternans phenomena, whereas healthy subjects exhibited a typical baroreflex pattern. The pulsus alternans phenomenon seems to be triggered by a PVC.

Mutations in the gene encoding dysferlin (DYSF) cause the allelic autosomal recessive disorders limb girdle muscular dystrophy 2B and Miyoshi myopathy. It encompasses 55 exons spanning 150 kb of genomic DNA. Dysferlin is involved in membrane repair in skeletal muscle. We identified three families with novel sequence variants in DYSF. All affected family members showed limb girdle weakness and had reduced or absent dysferlin protein on immunohistochemistry. All exons of DYSF were screened by genomic sequencing. Five novel variants in DYSF were found: two missense mutations (c.895G>A and c.4022T>C), one 5' donor splice-site variant (c.855+1delG), one nonsense mutation (c.1448C>A), and a variant in the 3'UTR of DYSF (c.*107T>A). All alterations were confirmed by restriction enzyme analysis and not found in 400 control alleles. Nonsense mediated RNA decay or changes in the three-dimensional protein structure resulting in intracellular dysferlin aggregates and finally the lack of dysferlin protein were identified as consequences of the novel DYSF variants.

Baroreflex sensitivity (BRS) is an important parameter in the classification of patients with reduced left ventricular function. This study aimed at investigating BRS in patients with dilated cardiomyopathy (DCM) and in healthy subjects (controls), as well as comparing the values of BRS parameters with parameters of heart rate variability (HRV) and blood pressure variability (BPV). ECG, continuous blood pressure and respiration curves were recorded for 30min in 27 DCM patients and 27 control subjects. The Dual Sequence Method (DSM) includes the analysis of spontaneous fluctuations in systolic blood pressure and the corresponding beat-to-beat intervals of heart rate to estimate bradycardic, opposite tachycardic and delayed baroreflex fluctuations. The number of systolic blood pressure/beat-to-beat interval fluctuations in DCM patients was reduced in comparison with controls (DCM patients: male, 154.4±93.9ms/mmHg; female, 93.7±40.5ms/mmHg; controls: male, 245.5±112.9ms/mmHg; female, 150.6±55.8ms/mmHg, P &lt; 0.05). The average slope in DCM patients was lower than in controls (DCM, 5.3±1.9ms/mmHg; controls, 8.0±5.4ms/mmHg; P &lt; 0.05). Discriminant function analysis showed that, in the synchronous range of the standard sequence method, the DCM and control groups could be discriminated to only 76% accuracy, whereas the DSM gave an improved accuracy of 84%. The combination of six parameters of HRV, BPV and DSM gives an accuracy of classification of 96%, whereas six parameters of HRV and BPV could separate the two groups to only 88% accuracy. Thus the DSM leads to an improved characterization of autonomous regulation in order to differentiate between DCM patients and healthy subjects. BRS in DCM patients is significantly reduced and apparently less effective.

Although animal studies have shown that cardiopulmonary receptors regulate the release of antidiuretic hormone (ADH), human studies have produced conflicting results. Consequently, we studied 17 normal healthy men to determine the ADH response to selective unloading (decreased stretch) of cardiopulmonary low-pressure receptors by thigh cuff inflation in the supine position. Thigh cuff inflation of 30 to 40 mm Hg decreased the central blood volume and right atrial pressure (cardiopulmonary receptor load), while mean arterial pressure and pulse pressure were unchanged (arterial baroreceptor load). Thigh cuff inflation to this level did not alter plasma osmolality or cardiac output. Plasma ADH increased an average of 67% (p less than 0.01) following thigh cuff inflation compared to the preceding supine baseline. After thigh cuff deflation (n = 6), the ADH decreased toward preinflation values. We conclude that selective unloading of the cardiopulmonary receptors in humans increases plasma ADH levels.

Objective: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. Methods: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. Results: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P=0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 μmol/mmol creatinine (P=0.027) and 65 nmol/mmol creatinine (P=0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. Conclusion: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

The final clinical analysis of the REPAIR-AMI trial is disappointing to me. The authors state that the bone-marrow-derived progenitor cells (BMC) lead to an improvement of function in the infarcted zone, especially in patients with depressed left ventricular function at baseline,1 increasing the ejection fraction by 5% compared with placebo. In the recent article, they …

Effects of angiotensin-converting enzyme inhibition (ACEI) on autonomic responses and hemodynamics in patients with congestive heart failure (CHF) subjected to isometric exercise have not been studied. We tested whether acute ACEI might influence the effects of isometric exercise in patients with CHF. In the first part of the study we showed that isometric exercise increased blood pressure in the control group and in the CHF group, whereas cardiac output increased only in the control group. Stroke volume remained unchanged in the control group, whereas it decreased significantly in CHF group. We next analyzed the effect of acute ACEI (5 mg ramipril) on the decrease in cardiac output during isometric stress in patients with CHF. During isometric exercise mean blood pressure and heart rate increased similarly in both groups. However, cardiac output decreased during placebo by -0.48 +/- 0.12 L/min (p < 0.01) but not during ACEI. Spectral analysis of blood pressure showed an increase (p < 0.01) in the high-frequency parasympathetic component from 7.3% +/- 3.6% to 18.1% +/- 9.5% after ACEI. norepinephrine plasma levels increased after isometric stress in the placebo group, whereas other hormones did not change. ACEI prevented the norepinephrine increase after isometric stress. Thus the decrease in cardiac output during isometric exercise in patients with CHF was prevented by acute ACEI. The effect of ACE inhibition may be related to reduced sympathetic activity.

The discovery of new properties of angiotensin converting enzyme (ACE) inhibitors in addition to their well-known ability to lower blood-pressure, such as antiproliferative actions and antiadrenergic and vagal-stimulating effects, has contributed to the usefulness of this class of agents in the prevention and treatment of cardiovascular diseases.The contribution of an activated endocrine and/or cardiac paracrine renin-angiotensin system to the progression of cardiovascular diseases with the exception of renovascular hypertension is not fully understood. In particular, the following questions were addressed: 1) Is the facilitation of noradrenaline release in the genesis of arrhythmias a target for ACE inhibition? 2) Is an impaired nutritional cardiac blood flow in heart failure a target for ACE inhibition? 3) Is the intimal hyperplasia that results from coronary angioplasty a target for ACE inhibition? 4) Is the diastolic dysfunction associated with left ventricular hypertrophy in essential hypertension a target for ACE inhibition? In an isolated rat heart preparation with ischemia-induced arrhythmias, none of the ACE inhibitors nor an angiotensin II antagonist was able to significantly suppress the incidence or severity of arrhythmias. In 12 patients with New York Heart Association functional class II-IV heart failure, a fall in cardiac filing pressures after ACE inhibition was associated with an immediate rise in cardiac output and an increase in coronary blood flow of almost 30%. In 24 patients with angina at rest, a preceding percutaneous transluminal coronary angioplasty, and a second angioplasty, control angiograms at 6 months revealed a high degree of restenosis in both ACE inhibitor-treated and placebo patients. Luminal narrowing amounted to 72% in the placebo group and 61% in the ACE inhibitor group. The differences between placebo and enalapril were statistically not significant. In 12 patients with essential hypertension treated with 5 mg cilazapril, left ventricular mass was reduced by 30%, which was closely related to the change in mean arterial blood pressure. The concomitant normalization of the diastolic filling pattern by ACE inhibition, however, was not related to the respective changes in blood pressure.Promising experimental data regarding the antiproliferative effects of ACE inhibitors in preventing restenosis could not be transferred into clinical benefits for patients who underwent repeat coronary angioplasty. Possible antiarrhythmic effects of ACE inhibitors are not likely to be caused by their suppression of noradrenaline release during myocardial ischemia. ACE inhibition was effective in reducing coronary resistance in patients with severe heart failure, thereby augmenting nutritional cardiac blood flow. ACE inhibition also effectively induced a regression of left ventricular hypertrophy in essential hypertension. The associated normalization of diastolic filling pattern may represent an important goal in the treatment of hypertension.

A previously healthy 40-year-old varnisher was admitted because of increasing dyspnoea. His clinical status rapidly deteriorated. He was referred to a cardiology intensive care unit but had to be resuscitated during transport. His condition became stable under controlled ventilation and analgesics. There were no other contributory abnormal findings.The concentration of D-dimers was raised. Pulmonary angiography demonstrated multiple bilateral occlusions of the segmental arteries.Extubation became possible after thrombolysis with recombinant tissue plasminogen activator (rTPA). There was no evidence of leg or pelvic vein thrombosis. But a hard mass was palpated in the left popliteal fossa and extensively thrombosed saccular aneurysm of the popliteal vein was found. The aneurysm was resected and a venous graft was interposed. There were no further thromboemboli under oral anticoagulation. Two years later the venous graft was occluded with adequate collateral circulation.Aneurysm of the popliteal vein is a rare vascular anomaly of unknown pathogenesis. In patients with repetitive episodes of lung embolism peripheral aneurysms must be taken into consideration.

Tachograms of two groups, one consisting of 16 cardiac patients with dilated cardiomyopathy (DCM) and the second group consisting of 18 healthy persons as a control group, were investigated. The tachograms were obtained from a commercial Holter ECG system. Artefacts and recognized misclassifications were manually edited and removed. In this study we confirm the effectiveness of methods from non-linear dynamics in the 24 hours analysis of heart rate variability. The methods from symbolic dynamics are useful approaches for classification of the dynamics of heart rate time series. With the help of these methods we can investigate the inner motions of the time series. One interesting aspect of this study is the surprising stability of the renormalized entropy in controls and in DCM patients.

Hypertrophic cardiomyopathy (HCM) is a relatively frequent, genetically determined primary cardiomyopathy, characterized by most often asymmetric hypertrophy of the ventricular septum with or without systolic obstruction of the left ventricular outflow tract. HCM is a genetically heterogeneous disease, with 12 different disease-causing genes beeing indentified to date. Histologically the disease is characterized by hypertophy and disarray of myofibrils as well as by an increase in myocardial fibrosis. Clinically, these changes may lead to palpitations, dyspnoe on exertion, and/or angina pectoris. However, they also lead to an increased propensity to the development of severe ventricular tachyarrhythmias and sudden cardiac death. The incidence of sudden death is significantly increased in HCM, particularly in affected young subjects. Risk stratification in HCM should include a complete clinical-cardiological evaluation that should also consider new diagnostic features, e. g. MR imaging. Major risk factors for sudden cardiac death include a survived cardiac arrest (ventricular fibrillation), non-sustained and sustained ventricular tachycardia, a history of premature familial sudden death, unexplained syncope, an abnormal blood pressure response on exercise, and left ventricular thickness greater than or equal to 3 cm. Ideally, risk stratification should also include genetic testing, since some gene mutations seem to be associated with a higher risk for sudden cardiac death than others. However, genetic testing in HCM in not yet available on a routine basis. The implantation of a cardioverter/defibrillator is first-line therapy in patients with documented ventricular tachycardia/fibrillation or patients who have survived sudden cardiac death. These devices also play an important role in the primary prevention of sudden cardiac death in HCM. Algorithms and scores are available to estimate the risk of sudden death, however, the decision to implant a cardioverter/defibrillator remains an individual decision in every single patient.

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease of the heart. The severity of the disease ranges from mild cases to sudden cardiac death or progression to heart failure. FHC is mostly caused by mutations in genes encoding for sarcomeric proteins, 30-40% of the patients are affected by missense mutations in one allele of the β-myosin heavy chain (MYH7). To gain further insights into the mechanisms of FHC-progression in heterozygous patients we performed a comparative expression analysis of the wildtype and the mutated MYH7 allele. We have analyzed samples from Musculus soleus and myocardium of genotyped and clinically well-characterized FHC-patients with different MYH7-mutations. We demonstrated an unequal allelic mRNA expression for each mutation analysed. The ratios of the mutated mRNA ranged from 29% to 66% in a mutation-specific manner. They were comparable in myocardium and soleus muscle and, importantly, were essentially the same at the protein level. Intriguingly, we observed a correlation between life expectancy and fraction of mutated mRNA or protein. Thus, the allelic imbalance may provide a novel factor underlying the progression of FHC. Our results suggest that the allelic imbalance is induced by differential regulation of the mutated MYH7 mRNA-expression. Thus we aimed to identify molecular mechanisms that may account for the mutation-related different mRNA levels. Bioinformatical analysis revealed that mutation V606M disrupts an exonic splicing enhancer site. Additionally, for the mutation R723G severe changes in the mRNA secondary structure were predicted. Alternative splicing variants of the V606-allele and a structure-related increased stability of the R723G-allele thus may provide potential factors inducing altered levels of mutated MYH7-mRNA.

Mutations in the human cardiac troponin T gene (TNNT2) are associated with familial hypertrophic cardiomyopathy (FHC) linked to chromosome 1q3 (CMH2). Mutation analyses of TNNT2 have been restricted to RNA-based screening methods because only the TNNT2 cDNA sequence was known. We characterized the genomic structure of 15 TNNT2 exons spliced into the adult isoform. A protocol for rapid mutation detection based on direct sequencing of large PCR-amplified genomic DNA fragments revealed a known TNNT2 mutation (Phe110Ile) in one of 30 FHC probands. Three polymorphic short tandem repeat elements (D1S477, D1S2622, and D1S1723), useful for FHC pedigree analyses at CMH2, were shown to be physically tightly linked to TNNT2. Hum Mutat 11:179–182, 1998. © 1998 Wiley-Liss, Inc.

Dear Editor, Recently, Lodi et al. described a deficiency of cardiac energetics in Friedreich's ataxia (FRDA) patients in the absence of cardiac dysfunction and hypertrophy [1]. The authors concluded that cardiac metabolic dysfunction proceeds the development of myocardial hypertrophy. In this manuscript left ventricular hypertrophy (LVH) was …

This study aims to estimate the spontaneous baroreflex sensitivity (BRS) with two different methods in patients with dilated cardiomyopathy (DCM). The new Dual Sequence Method (DSM) contains the analysis of spontaneous fluctuations of systolic blood pressure (SEP) and the corresponding beat-to-beat intervals (BBI) of heart rate (HR). Bradycardic as well as tachycardic fluctuations were considered for synchronized and a three beats shifted BBI-sequence. Whereas the established Z-coefficient method investigates the statistical dependence between SEP and HR values. The BRS and the number of fluctuations with a slope >5 msec/mmHg calculated by the DSM are significant lower (p<0.05) in DCM patients than in controls. Thus, the DSM leads in contrast to the Z-coefficient method to an improved precision in characterizing DCM patients.

This study was designed to improve the prognostic value of heart rate variability (HRV) in patients with dilated cardiomyopathy (DCM) using a new method of long-term symbolic dynamics. DCM patients show a decreased HRV in comparison to healthy subjects (p<0.03). A lower ejection fraction leads to a further reduction in HRV (p<0.01). Moreover, the DCM patients exhibit a decreased low frequency component (p<0.001). The Renyi-entropy of the word distribution as a method of long-term symbolic dynamics show the most significant differences between the LVEF<27% and >27% group (p<0.001). The new non-linear method of symbolic dynamics leads to an increased diagnostic precision in characterizing DCM patients.

At the beginning of the 21st century, we are faced with a discrepancy between the favourable results produced by a series of large randomised controlled trials on heart failure and their poor implementation into clinical practice. (ACE-inhibition, beta-blockade, aldosterone antagonism). The organisation of care for patients with heart failure needs improvement. This is why the first large international survey was initiated to evaluate perception and practice of primary care physicians (PCPs) in the management of heart failure. In general, PCPs appeared well-informed about diagnostic steps and therapeutic interventions. In practice, most patients received appropriate diagnostic tests. The uptake of ACE inhibitors was high, but few patients were receiving recommended doses. Beta-blockers are currently underused but this situation may be changing rapidly. Though "IMPROVEMENT" might suggest we get it right fairly often, it does also indicate that the process is haphazard and that we could be much more efficient.

Symbolic dynamics did start with Hadamard [1] ideas to more complicated systems in 1898. The most important point of this work is the simple description of the possible sequences that can arise in geodesic flows on surfaces of negative curvature. He introduced a finite set of forbidden symbol pairs and defined possible sequences as those that do not contain any forbidden symbol pair. Later on, Hedlund and Morse [2, 3] used this method to prove the existence of periodic and other dynamics in different classical dynamical systems. They showed that in many circumstances such a finite description of a system’s dynamics is possible and performed their investigations by finding interesting sequences satisfying the constraints defined by the corresponding symbolic dynamical system.

Susan Hankinson and colleagues1Hankinson SE Willett WC Colditz GA et al.Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.Lancet. 1998; 351: 1393-1396Summary Full Text Full Text PDF PubMed Scopus (1591) Google Scholar describe an increased risk for breast cancer in premenopausal women with raised serum IGF-I concentrations. This increased risk was not shown in postmenopausal women. Raised circulating insulin and IGFBP-3 values are present in premenopausal women2Del Giudice ME Fantus IG Ezzat S McKeown Eyssen G Page D Goodwin PJ Insulin and related factors in premenopausal breast cancer risk.Breast Cancer Res Treat. 1998; 47: 111-120Crossref PubMed Scopus (271) Google Scholar and can be explained by an underlying syndrome of insulin resistance. IGF-I is secreted in a circadian fashion, introducing variability in single-point measurements, which were used in Hankinson's study. The total serum concentration of IGF-I, as well as in growth hormone and IGFBP-3, depend on body mass, age, and time of menstrual cycle.3Juul A Dalgaard P Blum WF et al.Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation.J Clin Endocrinol Metab. 1995; 80: 2534-2542Crossref PubMed Google Scholar, 4Zanker CL Swaine IL Bone turnover in amenorrhoeic and eumenorrhoeic women distance runners.Scand J Med Sci Sports. 1998; 8: 20-26Crossref PubMed Scopus (54) Google Scholar Hankinson and colleagues adjusted their analysis for body-mass index but not for age and time of menstrual cycle. It would be of interest to know how the risk ratio for breast cancer would change if adjusted for these indices. Women younger than age 35 with a higher normal range of IGF-I seem to have more aggressive breast carcinoma.5Winchester DP Osteen RT Menck HR The National Cancer Data Base report on breast carcinoma characteristics and outcome in relation to age.Cancer. 1996; 78: 1838-1843Crossref PubMed Scopus (164) Google Scholar Is the risk of breast cancer in premenopausal women also increased when the age-adjusted standard-deviation scores of IGF-I (SDS IGF-I) are used in the regression analysis? Insulin-like growth factor-l and risk of breast cancerAuthors' reply Full-Text PDF

Aims: Single nucleotide polymorphisms (SNPs) in the cardiac ryanodine receptor (RYR2) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). The molecular mechanisms, however, by which genetic modifications lead to this cardiomyopathy, are still not well understood.

Cardiovascular diseases are often associated with increased activity of the systemic and/or local renin-angiotensin systems. Hence, with respect to the coronary vessels, it has been demonstrated that in patients with severe heart failure inhibition of the renin-angiotensin system with an angiotensin converting enzyme (ACE) inhibitor clearly reduces resistance in the systemic, renal and cardiovascular systems. This reduction in resistance improves the blood supply to the failing heart while, at the same time, diminishing the external workload. It is most likely this effect that contributes towards the improved progression of the underlying disease observed after ACE inhibitor administration. The clinical efficacy of ACE inhibitors in patients who had been subjected to repeated coronary angioplasty has, however, been disappointing. Although these agents exerted a clear inhibitory effect on neo-intima proliferation after balloon dilatation performed on animals, it was not observed in patients with coronary artery disease and did not prevent restenosis. In patients suffering from heart failure there is an increase in sympathetic tone and a decrease in parasympathetic tone. An increase in activity of the renin-angiotensin system produces an increase in sympathetic activity at the level of the peripheral sympathetic synapses and vagus blockage via its effect on the vagal centres in the postremal area. Both effects can be clearly diminished by administering ACE inhibitors. Although high sympathetic tone and low parasympathetic activity are indicators of low life expectancy in heart failure, a clear correlation between the incidence of sudden cardiac death and the changes in autonomic nervous system activity has not yet been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Der Einsatz von β-Blockern zur Behandlung von Patienten mit Herzinsuffizienz erschien zunächst paradox. Dementsprechend hat die kardiologische Gemeinschaft sehr zurückhaltend auf die erste Veröffentlichung von Waagstein et al. (1975 im British Heart Journal) reagiert. Die Zurückhaltung gegenüber dem Einsatz von β-Blockern bei der Herzinsuffizienz wurde in der folgenden Zeit noch dadurch bestärkt, dass Berichte verschiedener Gruppen über eine Verschlechterung des klinischen Zustandes der Patienten unter β-Blockade erschienen. Dies war insbesondere dann der Fall, wenn die Studien nur über eine kurze Beobachtungszeit (1 Monat und weniger) angelegt waren, während Studien mit Beobachtungszeiten von mehr als 3 Monaten in der Regel über eine Verbesserung von Belastungsdauer und linksventrikulärer Austreibungsfraktion berichteten. Wir haben jetzt im Jahr 2000 den Beleg dafür, dass β-Blocker in der Lage sind, nicht nur die Symptome der Patienten mit Herzinsuffizienz zu verbessern, sondern auch die Lebenserwartung dieser Patienten zu verlängern. Drei große plazebo-kontrollierte klinische Studien mit insgesamt mehr als 9000 Patienten haben gezeigt, dass Carvedilol, Bisoprolol und Metropolol Morbidität und Mortalität bei dem klinischen Bild der Herzinsuffizienz signifikant vermindern können. Diese Substanzen sollten daher für die Mehrzahl dieser Patienten in Zukunft zur Basistherapie gehören.

The objective of this study was to determine the clinical feasibility of continuous, non-invasive blood pressure recordings for characterizing pathological changes in cardiovascular diseases. Tachograms (interbeat intervals and systolic pressure over the time) of two groups, one consisting of 26 cardiac patients with dilated cardiomyopathy (DCM) and the second group consisting of 24 healthy persons as a control group, were investigated. The tachograms were obtained from a Portapres noninvasive blood pressure monitor device. Artifacts and misclassifications were automatically detected and removed. From these corrected tachograms the authors extracted 41 parameters from different domains. Two (of 10) time domain, 4 (10) frequency domain and 4 (10) NLD parameters did separate significantly (p<0.01) the controls from the DCM patients. In this multiparametric and multidimensional approach the combination of 6 parameters from heart rate and mainly blood pressure variability improves the classification result of the discriminant function techniques to 90%. Furthermore, the authors confirmed the effectiveness of the measures from symbolic dynamics as a useful approach to classify the dynamics and intermittent variability change in blood pressure time series.

Mutations in the human cardiac troponin T gene (TNNT2) are associated with familial hypertrophic cardiomyopathy (FHC) linked to chromosome 1q3 (CMH2). Mutation analyses of TNNT2 have been restricted to RNA-based screening methods because only the TNNT2 cDNA sequence was known. We characterized the genomic structure of 15 TNNT2 exons spliced into the adult isoform. A protocol for rapid mutation detection based on direct sequencing of large PCR-amplified genomic DNA fragments revealed a known TNNT2 mutation (Phe110Ile) in one of 30 FHC probands. Three polymorphic short tandem repeat elements (D1S477, D1S2622, and D1S1723), useful for FHC pedigree analyses at CMH2, were shown to be physically tightly linked to TNNT2. Hum Mutat 11:179–182, 1998. © 1998 Wiley-Liss, Inc.

Übergewicht führt zu einer Zunahme des Schlagvolumens und induziert eine linksventrikuläre Hypertrophie und Dilatation [9]. Da das Herzzeitvolumen bei Übergewichtigen parallel zur Körperoberfläche zunimmt, kann eine effektive Entlastung des Herzens durch einfache Gewichtsreduktion mittels einer Reduktionsdiät erzielt werden [14]. Gewichtsreduktion führt zu einer Regression der Hypertrophie und vermindert Vor- und Nachlast [9]. Allerdings sollte darauf geachtet werden, daß während der Diät keine Depletion an Magnesium und Kalium erfolgt, denn beides führt zu vermehrten ventrikulären Rhythmusstörungen.