The German Aortic Valve Registry (GARY): a nationwide registry for patients undergoing invasive therapy for severe aortic valve stenosis.

Background The increasing prevalence of severe aortic valve defects correlates with the increase of life expectancy. For decades, surgical aortic valve replacement (AVR), under the use of extracorporeal circulation, has been the gold standard for treatment of severe aortic valve diseases. In Germany ~12,000 patients receive isolated aortic valve surgery per year. For some time, percutaneous balloon valvuloplasty has been used as a palliative therapeutic option for very few patients. Currently, alternatives for the established surgical procedures such as transcatheter aortic valve implantation (TAVI) have become available, but there are only limited data from randomized studies or low-volume registries concerning long-time outcome. In Germany, the implementation of this new technology into hospital care increased rapidly in the past few years. Therefore, the German Aortic Valve Registry (GARY) was founded in July 2010 including all available therapeutic options and providing data from a large quantity of patients.Methods The GARY is assembled as a complete survey for all invasive therapies in patients with relevant aortic valve diseases. It evaluates the new therapeutic options and compares them to surgical AVR. The model for data acquisition is based on three data sources: source I, the mandatory German database for external performance measurement; source II, a specific registry dataset; and source III, a follow-up data sheet (generated by phone interview). Various procedures will be compared concerning observed complications, mortality, and quality of life up to 5 years after the initial procedure. Furthermore, the registry will enable a compilation of evidence-based indication criteria and, in addition, also a comparison of all approved operative procedures, such as Ross or David procedures, and the use of different mechanical or biological aortic valve prostheses.Results Since the launch of data acquisition in July 2010, almost all institutions performing aortic valve procedures in Germany joined the registry. By now, 91 sites which perform TAVI in Germany participate and more than 15,000 datasets are already in the registry.Conclusion The implementation of new or innovative medical therapies needs supervision under the conditions of a well-structured scientific project. Up to now relevant data for implementation of TAVI and long-term results are missing. In contrast to randomized controlled trials, GARY is a prospective, controlled, 5-year observational multicenter registry, and a real world investigation with only one exclusion criterion, the absence of patients' written consent.

Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI) : Joint Consensus Document of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V. (ALKK) and cooperating Cardiac Surgery Departments.

Indications for TF-TAVI (transfemoral transcatheter aortic valve implantation) are rapidly changing according to increasing evidence from randomized controlled trials. Present trials document the non-inferiority or even superiority of TF-TAVI in intermediate-risk patients (STS-Score 4-8%) as well as in low-risk patients (STS-Score < 4%). However, risk scores exhibit limitations and, as a single criterion, are unable to establish an appropriate indication of TF-TAVI vs transapical TAVI vs SAVR (surgical aortic valve replacement). The ESC (European Society of Cardiology)/EACTS (European Association for Cardio-Thoracic Surgery) guidelines 2017 and the German DGK (Deutsche Gesellschaft für Kardiologie)/DGTHG (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie) commentary 2018 offer a framework for the selection of the best therapeutic method, but the individual decision is left to the discretion of the heart teams. An interdisciplinary TAVI consensus group of interventional cardiologists of the ALKK (Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V.) and cardiac surgeons has developed a detailed consensus on the indications for TF-TAVI to provide an up-to-date, evidence-based, comprehensive decision matrix for daily practice. The matrix of indication criteria includes age, risk scores, contraindications against SAVR (e.g., porcelain aorta), cardiovascular criteria pro TAVI, additional criteria pro TAVI (e.g., frailty, comorbidities, organ dysfunction), contraindications against TAVI (e.g., endocarditis) and cardiovascular criteria pro SAVR (e.g., bicuspid valve anatomy). This interdisciplinary consensus may provide orientation to heart teams for individual TAVI-indication decisions. Future adaptations according to evolving medical evidence are to be expected. Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI).

Image reconstructions of microtubules decorated with monomeric and dimeric kinesins: comparison with x-ray structure and implications for motility.

We have decorated microtubules with monomeric and dimeric kinesin constructs, studied their structure by cryoelectron microscopy and three-dimensional image reconstruction, and compared the results with the x-ray crystal structure of monomeric and dimeric kinesin. A monomeric kinesin construct (rK354, containing only a short neck helix insufficient for coiled-coil formation) decorates microtubules with a stoichiometry of one kinesin head per tubulin subunit (alpha-beta-heterodimer). The orientation of the kinesin head (an anterograde motor) on the microtubule surface is similar to that of ncd (a retrograde motor). A longer kinesin construct (rK379) forms a dimer because of the longer neck helix forming a coiled-coil. Unexpectedly, this construct also decorates the microtubule with a stoichiometry of one head per tubulin subunit, and the orientation is similar to that of the monomeric construct. This means that the interaction with microtubules causes the two heads of a kinesin dimer to separate sufficiently so that they can bind to two different tubulin subunits. This result is in contrast to recent models and can be explained by assuming that the tubulin-kinesin interaction is antagonistic to the coiled-coil interaction within a kinesin dimer.

[Position paper telemonitoring : From the Nucleus Members of the AG33 Telemonitoring of the DGK and associated members]. / Positionspapier Telemonitoring : Von den Nukleusmitgliedern der AG33 Telemonitoring in der DGK und assoziierten Mitgliedern.

The position paper of the working group 33/Telemonitoring in the German Society for Cardiology e. V. (DGK) discusses the importance of digital solutions in the German health care system and highlights the application possibilities and potentials of telemonitoring in the treatment of patients with cardiac diseases. In addition to telemonitoring of acute ischaemic diseases, acute coronary syndrome and acute cardiac arrhythmias, telemonitoring of chronic cardiac diseases is discussed. Chronic diseases, such as chronic heart failure, are age-associated and present society with the great challenge of providing high-quality, yet cost-efficient care to an increasing number of patients in the future. Telemonitoring offers an opportunity to meet this challenge. However, the introduction of telemonitoring and the associated changes for patients, doctors and other service providers must be accompanied by measures to ensure the acceptance of telemonitoring and the secure handling of sensitive data as well as the quality of telemonitoring services.

[Constellations of findings and derived treatment interventions in telemedical monitoring of patients with heart failure, cardiac arrhythmia or increased risk for sudden cardiac death : Recommendations of the working group 33 telemonitoring of the German Cardiac Society]. / Befundkonstellation und abgeleitete Behandlungsinterventionen bei telemedizinisch überwachten Patienten mit Herzinsuffizienz, Herzrhythmusstörungen oder erhöhtem Risiko für den plötzlichen Herztod : Empfehlungen der Arbeitsgruppe 33 Telemonitoring der Deutschen Gesellschaft für Kardiologie, Herz- und Kreislaufforschung e. V.

The specification of standard operating procedures (SOPs) is a basic requirement for a successful implementation of telemonitoring with implanted cardiac devices and with external measuring devices in patients with heart failure, cardiac arrhytmia or increased risk of sudden cardiac death. The following article summarizes the possibilities of telemonitoring from a technical and organizational point of view and descibes basic requirements on SOPs. these basic requirements should be further specified and anchored in the organizational structure of the individual telemonitoring concept. Moreover, they should de understood as a basic guideline fpr the actions of telemonitoring center (TMC) employees.

[Basic structural features of a cardiac telemedicine center for patients with heart failure and implanted devices, cardiac arrhythmias, and increased risk of sudden cardiac death : Recommendations of the working group 33 Telemonitoring of the German Cardiac Society]. / Grundlegende Strukturmerkmale eines kardiologischen Telemedizinzentrums für Patienten mit Herzinsuffizienz und implantierten Devices, Herzrhythmusstörungen und erhöhtem Risiko für den plötzlichen Herztod : Empfehlungen der Arbeitsgruppe 33 Telemonitoring in der Deutschen Gesellschaft für Kardiologie, Herz- und Kreislaufforschung e. V.

Heart failure is one of the most common diseases. It is associated with high morbidity and mortality. Since heart failure is age-associated, the number of patients with heart failure is constantly increasing. At the same time, the imbalance between the need for treatment and the provision of care is growing. Telemonitoring/telemedicine offers patients in rural or remote areas access to high-quality health care and enables fast access to specialists. The working group 33 Telemonitoring of the German Cardiac Society describes the characteristics and possible applications of telemonitoring/telemedicine in the treatment of patients with heart failure. Furthermore, quality criteria for cardiological telemedicine centres are defined. In addition to the personnel structure of a telemedicine centre and the competencies of employees, requirements for the technical infrastructure and the management of incoming data and alarms are described.

Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome.

The aim of our study was to evaluate the prevalence of the metabolic syndrome (MBS) according to the current International Diabetes Federation definition in German PCOS women. Four hundred and eleven PCOS patients (age 28+/-6.3 years) and 82 controls (age 28+/-7.5 years) were evaluated for anthropometric and metabolic parameters by physical examination, blood testing and a personal interview including family history. A subgroup analysis of controls with BMI-matched PCOS women (BMI 22.9+/-2.8 kg/m (2)) was performed to detect PCOS specific differences in metabolic variables between the groups. The MBS was found in 33.8% of PCOS women compared to 7.3% in the control group. Parameters of insulin resistance, lipid-and glucose metabolism, mean values of all criteria of the MBS as well as the prevalence of the MBS were significantly different between the entire PCOS cohort and controls, but did not differ between BMI-matched PCOS women and controls. In addition, the prevalence of the MBS increased with age. Moreover, in PCOS women an increase in BMI and insulin resistance was accompanied by a further significant increase in the severity of clinical and biochemical hyperandrogenism. In PCOS women, while one out of three PCOS women had the MBS, the presence of metabolic abnormalities did not appear to be associated with PCOS per se, but rather correlated with age and the degree of obesity.

[The telemedical service centre as an essential element of the conceptual approach for telemonitoring of cardiac patients : Requirements on the service, quality, and technical realization of telemonitoring]. / Das Telemedizinische Zentrum als essenzieller Baustein konzeptioneller Ansätze zum Telemonitoring kardialer Patienten : Anforderungen an Leistungen, Qualität und technische Umsetzung von Telemonitoring.

Telemonitoring as part of a treatment strategy supports and facilitates the monitoring, disease management and education of patients with heart failure and cardiac arrhythmias. Therefore, telemonitoring affects quality and success of the therapy. Thus, meeting the needs of the patients and of the involved health care professionals is important for the success of the telemonitoring service. Moreover, a high quality of the service has to be ensured. The following article describes several configuration options for telemonitoring services considering technical as well as quality- and service-related aspects.

Crystal structure of UDP-N-acetylglucosamine enolpyruvyltransferase, the target of the antibiotic fosfomycin.

BACKGROUND: The ever increasing number of antibiotic resistant bacteria has fuelled interest in the development of new antibiotics and other antibacterial agents. The major structural element of the bacterial cell wall is the heteropolymer peptidoglycan and the enzymes of peptidoglycan biosynthesis are potential targets for antibacterial agents. One such enzyme is UDP-N-acetylglucosamine enolpyruvyltransferase (EPT) which catalyzes the first committed step in peptidoglycan biosynthesis: the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 3-hydroxyl of UDP-N-acetylglucosamine (UDPGlcNAc). EPT is of potential pharmaceutical interest because it is inhibited by the broad spectrum antibiotic fosfomycin. RESULTS: The crystal structure of substrate-free EPT has been determined at 2.0 A resolution. The structure reveals a two-domain protein with an unusual fold (inside out alpha/beta barrel) which is built up from the sixfold repetition of one folding unit. The only repetitive element in the amino acid sequence is a short motif, Leu-X3-Gly(Ala), which is responsible for the formation of hydrogen-bond interactions between the folding units. An enzyme which catalyzes a similar reaction to EPT, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), has a very similar structure despite an amino acid sequence identity of only 25%. To date, only these two enzymes appear to display this characteristic fold. CONCLUSIONS: The present structure reflects the open conformation of the enzyme which is probably stabilized through two residues, a lysine and an arginine, located in the cleft between the domains. Binding of the negatively charged UDPGlcNAc to these residues could neutralize the repulsive force between the two domains, thereby allowing the movement of a catalytically active cysteine residue towards the cleft.

Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group.

BACKGROUND: Previous studies of pacing therapy for dilated congestive heart failure (CHF) have not established the relative importance of pacing site, AV delay, and patient heterogeneity on outcome. These variables were compared by a novel technique that evaluated immediate changes in hemodynamic function during brief periods of atrial-synchronous ventricular pacing. METHODS AND RESULTS: Twenty-seven CHF patients with severe left ventricular (LV) systolic dysfunction and LV conduction disorder were implanted with endocardial pacing leads in the right atrium and right ventricle (RV) and an epicardial lead on the LV and instrumented with micromanometer catheters in the LV, aorta, and RV. Patients in normal sinus rhythm were stimulated in the RV, LV, or both ventricles simultaneously (BV) at preselected AV delays in a repeating 5-paced/15-nonpaced beat sequence. Maximum LV pressure derivative (LV+dP/dt) and aortic pulse pressure (PP) changed immediately at pacing onset, increasing at a patient-specific optimal AV delay in 20 patients with wide surface QRS (180+/-22 ms) and decreasing at short AV delays in 5 patients with narrower QRS (128+/-12 ms) (P<0.0001). Overall, BV and LV pacing increased LV+dP/dt and PP more than RV pacing (P<0.01), whereas LV pacing increased LV+dP/dt more than BV pacing (P<0.01). CONCLUSIONS: In this population, CHF patients with sufficiently wide surface QRS benefit from atrial-synchronous ventricular pacing, LV stimulation is required for maximum acute benefit, and the maximum benefit at any site occurs with a patient-specific AV delay.

Changes in QRS voltage in cardiac tamponade and pericardial effusion: reversibility after pericardiocentesis and after anti-inflammatory drug treatment.

OBJECTIVES: The goal of this study was to define the association between low QRS voltage and cardiac tamponade or pericardial effusion and to assess the reversibility of low QRS voltage after therapeutic procedures. BACKGROUND: It is unclear whether low QRS voltage is a sign of cardiac tamponade or whether it is a sign of pericardial effusion per se. METHODS: In a prospective study design, we recorded consecutive 12-lead electrocardiograms and echocardiograms in 43 patients who were referred to our institution for evaluation and therapy of a significant pericardial effusion. Cardiac tamponade was present in 23 patients (53%). Low QRS voltage (defined as maximum QRS amplitude <0.5 mV in the limb leads) was found in 14 of these 23 subjects (61%). Nine of these 14 patients were treated by pericardiocentesis (group A). Five patients received anti-inflammatory medication (group B). Group C consisted of nine patients with pericarditis and significant pericardial effusion who had no clinical evidence of tamponade. RESULTS: In group A, low QRS voltage remained largely unchanged immediately after successful pericardiocentesis (0.36 +/- 0.17 mV before vs. 0.42 +/- 0.21 mV after, p = NS), but QRS amplitude recovered within a week (0.78 +/- 0.33 mV, p < 0.001). In group B, the maximum QRS amplitude increased from 0.40 +/- 0.20 mV to 0.80 +/- 0.36 mV (p < 0.001) within six days. In group C, all patients had a normal QRS amplitude initially (1.09 +/- 0.55 mV) and during a seven-day follow-up (1.10 +/- 0.56 mV, p = NS). CONCLUSIONS: Low QRS voltage is a feature of cardiac tamponade but not of pericardial effusion per se. Our findings indicate that the presence and severity of cardiac tamponade, in addition to inflammatory mechanisms, may contribute to the development of low QRS voltage in patients with large pericardial effusions.

Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances.

OBJECTIVES: We sought to investigate the impact of six months of cardiac resynchronization therapy (CRT) on echocardiographic variables of left ventricular (LV) function. BACKGROUND: Cardiac resynchronization therapy has recently been introduced as a new therapeutic modality in patients with advanced heart failure (HF) and conduction abnormalities. However, most studies have only investigated the early hemodynamic effects of CRT. METHODS: Twenty-five patients (12 women and 13 men; 59.8 +/- 5.1 years old) with advanced HF caused by ischemic (n = 7) or idiopathic dilated cardiomyopathy (n = 18) and a prolonged QRS complex were analyzed. All patients underwent early hemodynamic testing with a randomized testing protocol; echocardiographic measurements were compared before implantation and after six months of CRT. RESULTS: Left ventricular end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively) were significantly reduced after six months (LVEDD from 71 +/- 10 to 68 +/- 11 mm, p = 0.027; LVESD from 63 +/- 11 to 58 +/- 11 mm, p = 0.007), as were LV end-diastolic and end-systolic volumes (LVEDV from 253 +/- 83 to 227 +/- 112 ml, p = 0.017; LVESV from 202 +/- 79 to 174 +/- 101 ml, p = 0.009). Ejection fraction was significantly increased (from 22 +/- 7% to 26 +/- 9%, p = 0.03). "Nonresponders," with regard to LV volume reduction, had significantly higher baseline LVEDV, compared with "responders" (351 +/- 52 vs. 234 +/- 74 ml, p = 0.018). Overall, there was only mild mitral regurgitation at baseline, with a minor reduction by semiquantitative analysis. The results of early hemodynamic testing did not predict the volume response. CONCLUSIONS: Cardiac resynchronization therapy may lead to a reduction in LV volumes in patients with advanced HF and conduction disturbances. Volume nonresponders have significantly higher baseline LVEDV.

Testing the reverse transcriptase model of somatic mutation.

Somatic hypermutation of the variable (V) regions of rearranged immunoglobulin genes leads to antibody affinity maturation. Although this process has been extensively studied, the mechanisms responsible for these multiple point mutations are still elusive. One mechanism that was proposed over 10 years ago by Steele and Pollard was that an intrinsic reverse transcriptase (RT) copies the nascent mRNA creating the large number of observed point mutations due to its high error rate. A cDNA copy of the mutated V region would then replace the endogenous DNA through a gene conversion-like event, thus integrating these point mutations into the genome. This model of hypermutation would account for the very high mutation rate, the presence of hotspots, strand bias, the requirement for transcription and localization of mutation within the immunoglobulin V region. Using AZT and ddC to inhibit endogenous RTs, we have assayed for somatic mutation using a murine in vivo model. Somatic mutation occurred at similar frequencies and with the same characteristics with or without treatment of RT inhibitors, suggesting that standard reverse transcription is not required for antibody V region hypermutation in the mouse.

[The Herz Handy--a new telemedical service concept for heart patients]. / Das Herz Handy--in neues telemedizinisches Servicekonzept für Herzpatienten.

Telemedicine is a new milestone for the health care system in the care of patients with heart disease. New technologies and the possibilities of fast data transmission have enabled this step forward. The Cardiophone offers a new telemonitoring Service Concept, which is available 24 hours a day. The patient is by the aid of the Cardiophone connected with the Medical Service Center at just the press of a button, can record and transmit an ECG and can be localized by the incorporated GPS. We report about our experiences with 363 patients over 3 years. Out of 5064 patient contacts associated with 7561 calls, 559 emergency contacts occurred. From the initial main complaints, working diagnoses were established. The final confirmed diagnoses were arrhythmias (27.8%), coronary heart disease (25.9%), psychovegetative syndrome (12.7%), backbone pain (6.2%), gastrointestinal syndrome (3.6%), others (1.8%), and exclusion diagnosis (19.9%). Ten myocardial infarctions were diagnosed, of whom 3 were confirmed; the other 7 were treated as stabile angina pectoris. Overall 823 ECG were transmitted, in average 1.6 ECGs per emergency contact. In 131 ECGs changes of the ST-segment or T-wave could be documented; 26 patients showed a pacemaker ECG. Atrial and ventricular arrhythmias as well as conduction disturbances were seen. The majority of emergency contacts (n=477, 85.3%) were successfully managed by the Service Center. In 38 emergency contacts (6.8%) admission to hospital was recommended; in 4 cases (0.7%) an ambulance was activated via the local dispatcher by the Service Center and in 29 cases (5.2%) the emergency ambulance.

Ischaemic preconditioning--time course of renewal in the pig.

OBJECTIVE: The aim was to examine whether ischaemic preconditioning can be renewed by a second cycle of brief coronary occlusions in pigs subjected to two different reperfusion intervals (1 h or 4 d). METHODS: Ischaemic preconditioning was induced by a cycle of two 10 min occlusions of the left anterior descending coronary artery separated by 30 min of reperfusion. Infarction was induced with a subsequent 1 h occlusion and a 2 h reperfusion period. There were four experimental groups: in group I (n = 5), a 30 min reperfusion was interposed after the preconditioning cycle prior to the sustained occlusion; in group II (n = 5), this time frame was extended to 1 h; in group III (n = 5), the preconditioning cycle was renewed 1 h after the first cycle; in group IV (n = 5), the second cycle was performed 4 d later. Control pigs (n = 5) were subjected to 1 h coronary occlusion and 2 h reperfusion without previous short occlusions. Infarct size was measured with p-nitro blue tetrazolium and was expressed as a percent of area at risk. RESULTS: The percent of the risk region infarcted was 69.9 (SEM 3.8)% for controls, 22.9 (3.5)% in group I (p < 0.001 v controls), 67.3 (5.2)% in group II, 66.3 (4.2)% in group III, and 17.9 (3.9)% in group IV (p < 0.001 v controls). Regional wall function measured with ultrasonic crystals deteriorated through the reperfusion intervals, indicating different underlying mechanisms for ischaemic preconditioning and myocardial stunning. CONCLUSIONS: Ischaemic preconditioning with two 10 min occlusions reduced infarct size resulting from a 60 min coronary occlusion when that was performed 30 min after the last short occlusion. This effect was lost after 1 h. Preconditioning could be renewed by a second cycle of brief coronary occlusion and reperfusion 4 d but not 1 h after the first cycle. These results suggest the release of a mediator from an exhaustible pool.

Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart.

OBJECTIVES: Coronary microembolisation in the pig heart induces angiogenesis in a model of sterile inflammation due to focal necrosis. We have recently shown in this model that insulin-like growth factor I (IGF-I) is involved in inflammation-linked angiogenic processes due to its enhanced transcription after 72 h of ischaemia by infiltrating monocytes in areas of microsphere-induced focal necrosis where capillary sprouting could be detected. To obtain further insights into this process we studied by means of Northern blot analysis and in situ hybridisation the gene expression of other members of the IGF family, i.e. the six IGF binding proteins (IGFBPs), the insulin receptor, and the type I IGF receptor. METHODS: Myocardial injury was induced by injection of 25 microns non-radioactive microspheres into the left circumflex artery (LCx) in pigs that were killed after 3-24, 72, or 168 h of microembolisation. Tissue was collected from a non-ischaemic control area and the LCx region of the same heart for further analysis. RESULTS: We found decreased IGFBP-5 (2.7-fold; P < 0.02) mRNA concentrations after 72 h of microembolisation in ischaemic tissue versus control tissue from the same heart, preceded by a 1.9-fold elevated level of IGFBP-3 mRNA at 3-24 h (P < 0.05). IGFBP-6 was increased in ischaemic tissue at all time points studied. In situ hybridisation identified myocytes as the main producers of IGFBP-3 and IGFBP-6 mRNA. The mRNA levels of IGFBP-2, IGFBP-4, the insulin receptor, and the type I IGF receptor were constitutively expressed but did not change after microembolisation. Neither in heart nor in other organs studied transcripts of IGFBP-1 could be detected. Furthermore, we demonstrated that mRNA of the other components of the IGF system was expressed in almost all porcine organs except liver. CONCLUSION: These results indicate a coordinate gene expression of the IGF system in microembolised porcine myocardium, compatible with a role of IGF-I, IGFBP-3, IGFBP-5, and IGFBP-6 in inflammation-linked angiogenesis and/or repair processes.

Insulin-like growth factor I is involved in inflammation linked angiogenic processes after microembolisation in porcine heart.

OBJECTIVE: Angiogenesis in the porcine heart can be induced by myocardial ischaemia following vascular occlusions. This process is characterised by increased numbers of monocytes/macrophages, known to be potent producers of various mitogens such as insulin-like growth factors (IGF) and interleukins (IL). The aim of the study was to examine gene expression of these factors by means of northern blot hybridisation, slot blot analysis, and in situ hybridisation in a porcine model of coronary angiogenesis. METHODS: Experimental ischaemia and subsequent focal necroses were induced by selective injection of 25 microns microspheres into the left circumflex artery. The hearts were excised after 3-168 h of microembolisation, and tissue was collected from a non-ischaemic control area and the circumflex region of the same heart for further analysis. RESULTS: IGF-I was constitutively transcribed in normal porcine myocardium mainly by myocytes. Following microembolisation, IGF-I mRNA expression was significantly increased in the experimental region (1.8-fold) after 72 h and to a lesser extent after 168 h. In the ischaemic region, characterised by capillary sprouting, numerous mononuclear cells contained IGF-I mRNA. In contrast, IGF-II mRNA levels, constitutively produced by porcine myocytes, were not altered by microembolisation. IL-1 alpha, IL-1 beta, and IL-4 mRNA expression was undetectable in our animal model, whereas IL-6 was constitutively transcribed in normal and ischaemic heart and remained insensitive to microembolisation and focal necrosis. CONCLUSION: After microembolisation, increased IGF-I mRNA expression occurred by infiltrating monocytes in areas of microsphere induced focal necrosis, where capillary sprouting can be detected, suggesting that IGF-I is involved in inflammation linked angiogenic processes.

Can right-sided atrioventricular sequential pacing provide benefit for selected patients with severe congestive heart failure?

This study reports on the methods and results of applying right-sided atrioventricular (AV) pacing in 26 patients with advanced cardiomyopathy. Ten of these patients had ischemic cardiomyopathy. Of the 16 patients with nonischemic cardiomyopathy, 10 were idiopathic and 6 were due to secondary causes. The patients had a mean age of 56 +/- 12 years and a left ventricular ejection fraction of 26 +/- 11%. Two transvenous stimulation electrodes were temporarily placed in the high right atrium and right ventricle, respectively. A Swan Ganz catheter was positioned into the pulmonary artery to determine cardiac output by the thermodilution method and to measure the pressure in the pulmonary artery and right atrium. In addition, aortic pressure was measured through a catheter sheath via the right femoral artery. Systemic and pulmonary vascular resistance were calculated. Stimulation was performed in VVI and DDD pacing modes using different AV intervals (40, 80, 125, 150, 175, 200, and 250 msec). No increase of cardiac output was observed for the overall study cohort (p = 0.51). At VVI pacing, stroke volume significantly decreased from 66 +/- 20 mL to 53 +/- 13 mL (p < 0.01). We distinguished between responders who developed an increase of cardiac output of > 1 L/min (n = 12, 46%) and nonresponders (n = 14, 54%). Etiology of either ischemic or nonischemic cardiomyopathy for responders, as well as conduction disturbances (first-degree AV block, LBBB, RBBB), were equally distributed among both groups. Using an AV delay of 150 and 175 msec, responders to DDD pacing derived a significant increase in cardiac output. An AV delay of 150 msec produced both a significant increase of stroke volume and decrease of systemic vascular resistance. In 46% of patients with dilated cardiomyopathy of either ischemic or nonischemic origin, right-sided AV-sequential pacing brought about an improvement of left ventricular function in terms of enhanced cardiac output. We suggest individual testing in all patients with severe left ventricular dysfunction to find responders.

The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study.

In conjunction with pharmacologic therapy, pacing has been proposed as a potential treatment to decrease symptoms in patients with moderate-to-severe congestive heart failure (CHF). Uncontrolled studies of pacing therapy for CHF dealing with different pacing sites, modes of pacing, and atrioventricular delays have reported mixed outcomes. The Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is a single-blind, randomized, crossover, controlled trial designed to evaluate the effects of pacing on acute hemodynamic function and to assess chronic clinical benefit in patients with moderate-to-severe CHF. The effect of pacing on oxygen consumption at peak exercise and at anaerobic threshold during cardiopulmonary exercise tests, and on 6-minute walk distance, have been selected as primary endpoints of the study. Secondary endpoints of the trial were changes in New York Heart Association (NYHA) functional class, quality-of-life as assessed by the Minnesota Living with Heart Failure questionnaire, and hospitalization frequency. Finally, changes in ejection fraction, cardiac output, and filling pattern were assessed by echocardiography. The trial was planned to include 53 patients from 7 centers in Europe over a period of 3 years. The study was divided into 2 parts: acute testing and chronic follow-up. The acute study, performed during the pacemaker implantation, involved extensive testing using a custom-designed computer (FLEXSTIM) and a unique burst pacing protocol (FLEXSTIM protocol) to determine the best ventricular pacing sites and the most appropriate atrioventricular delays. The chronic phase consisted of a crossover study designed to test in each patient the best univentricular pacing site and biventricular pacing as assessed by the acute hemodynamic study. The study started with the first implant in 1995 and has, to date, included 42 patients. The study is expected to be completed by the end of 1998. The results of a first interim analysis showed trends toward improvement in all primary and secondary endpoints during the pacing periods compared with no pacing.

Echocardiographic evidence of hemodynamic and clinical improvement in patients paced for heart failure.

Dilated cardiomyopathy is frequently associated with electrical conduction disturbances. Development of left bundle-branch block with discoordinated ventricular contraction pattern further contributes to impaired hemodynamic performance. Biventricular pacing has evolved as a new treatment option for patients with dilated cardiomyopathy and conduction disturbances. The "electrical" approach aims to normalize the disturbed contraction pattern, thereby improving hemodynamic function by simultaneous stimulation at different ventricular sites. Acute hemodynamic improvement with biventricular pacing has been demonstrated in patients with depressed left ventricular function and delayed intraventricular conduction. Due to the variations in optimal pacing site and atrioventricular delay, individual optimization to achieve optimal hemodynamic benefit is necessary. Echocardiography has the potential to provide hemodynamic data by Doppler techniques and combine these with geometric information about ventricular volumes, ejection fraction, and contraction patterns. This article focuses on the use of echocardiographic techniques for noninvasive optimization in cardiac pacing and presents preliminary experience from the initial trials on multisite pacing in heart failure.