Schulte Hd

Guidelines for Management of Left-Sided Prosthetic Valve Thrombosis: A Role for Thrombolytic Therapy

OBJECTIVES We sought to form a consensus recommendation for management of prosthetic valve thrombosis (PVT) from previous case and uncontrolled reports from a consensus of international specialists. BACKGROUND PVT and thromboembolism relate to inadequate anticoagulation and valve type and location. PVT is suspected by history (dyspnea) and auscultation (muffled valve sounds or new murmurs) and confirmed by Doppler echocardiography showing a marked valve gradient. METHODS A consensus conference was held to recommend management of left-sided PVT. RESULTS Transesophageal Doppler echocardiography is used to visualize abnormal leaflet motion and the size, location and mobility of thrombus. Thrombolysis is used for high risk surgical candidates with left-sided PVT (New York Heart Association functional class III or IV) because cerebral thromboembolism may occur in 12% of patients. Duration of thrombolysis depends on resolution of pressure gradients and valve areas to near normal by Doppler echocardiography performed every few hours. Lysis is stopped after 72 or 24 h if there is no hemodynamic improvement (operation indicated). Heparin infusion with frequent measurement of activated partial thromboplastin time (aPTT) begins when aPTT is more than twice control levels and can be converted to warfarin (international normalized ratio [INR] 2.5 to 3.5) plus aspirin (81 to 100 mg/day). Patients in functional class I or II have lower surgical mortality, and those with large immobile thrombi on the prosthetic valve or left atrium have responded to endogenous lysis with combined subcutaneous heparin every 12 h (aPTT 55 to 80 s) plus warfarin (INR 2.5 to 3.5) for 1 to 6 months. Operation is advised for nonresponders or patients with mobile thrombi. CONCLUSIONS Thrombolysis, followed by heparin, warfarin and aspirin, is advised for high risk surgical candidates with left-sided PVT.

Lower intensity anticoagulation therapy results in lower complication rates with the St. Jude Medical prosthesis

Six hundred consecutive patients were operated on between September 1978 and October 1982 for isolated aortic (n = 298), mitral (n = 215), or multiple valve replacement (n = 87) with the St. Jude Medical bileaflet prosthesis. Mean age of the 303 female and 297 male patients was 50.7 +/- 9.6 (range 12 to 83) years. All patients were followed up prospectively; follow-up was complete and averaged 122.2 +/- 1.1 months for operative survivors. Total follow-up for aortic patients was 2904.1 patient-years, for mitral replacement 1859.5 patient-years, and for multiple valve replacement 736 patient-years. When the prothrombin times measured with different thromboplastins were converted into an international normalized ratio, four patient groups could be separated; that is, the groups comprised patients whose anticoagulation was maintained during the follow-up within an international normalized ratio corridor of 4.0 to 6.0, 3.0 to 4.5, 2.5 to 3.5, or 1.75 to 2.75. Less intensive anticoagulation in terms of the international normalized ratio values caused only a mild increase in the incidence of thromboembolic complications but a highly significant decrease in the rate of bleeding. Severe bleeding complications in the aortic valve group were highest with an international normalized ratio of 4.0 to 6.0 (1.15 per patient-year) and lowest with an international normalized ratio of 1.75 to 2.75 (0.24 per patient-year). The same held true for patients with single St. Jude Medical mitral valve replacement (2.09 per patient-year versus 0.72 per patient-year) and multiple valve replacements (4.45 per patient-year versus 1.20 per patient-year). These results suggest that the generally recommended international normalized ratio of 3.0 to 4.5 may be too high for patients with St. Jude Medical aortic valve replacement and also for patients with St. Jude Medical prostheses in the mitral position if, with respect to the thromboembolic hazard, there is not a predominating patient-related comorbidity. A large multicenter prospective randomized study is therefore proposed to establish the safe international normalized ratio levels accompanied by the lowest complication rates for both bleeding and thromboembolic events after St. Jude Medical prosthesis implantation (German experience with low intensity anticoagulation study).

Calcineurin in Human Heart Hypertrophy

Background—In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. Methods and Results—We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. Conclusions—Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) can be caused by mutations in genes encoding for the ventricular myosin essential and regulatory light chains. In contrast to other HCM disease genes, only a few studies describing disease-associated mutations in the myosin light chain genes have been published. Therefore, we aimed to conduct a systematic screening for mutations in the ventricular myosin light chain genes in a group of clinically well-characterised HCM patients. Further, we assessed whether the detected mutations are associated with malignant or benign phenotype in the respective families. We analysed 186 unrelated individuals with HCM for the human ventricular myosin regulatory (MYL2) and essential light chain genes (MYL3) using polymerase chain reaction, single strand conformation polymorphism analysis and automated sequencing. We found eight single nucleotide polymorphisms in exonic and adjacent intronic regions of MYL2 and MYL3. Two MYL2 missense mutations were identified in two Caucasian families while no mutation was found in MYL3. The mutation Glu22Lys was associated with moderate septal hypertrophy, a late onset of clinical manifestation, and benign disease course and prognosis. The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death. In conclusion, myosin light chain mutations are a very rare cause of HCM responsible for about 1% of cases. Mutations in MYL2 could be associated with both benign and malignant HCM phenotype.

Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors

The basic helix‐loop‐helix transcription factors eHAND and dHAND are involved in developmental cardiac growth and differentiation. We investigated HAND gene expression in the normal and in the hypertrophied right and left ventricle of patients with tetralogy of Fallot (ToF) and hypertrophic obstructive cardiomyopathy (HOCM). HAND mRNA was constitutively expressed in the hypertrophied heart and increased in the hypertrophic tissue of both patient groups. HAND genes had a complementary left‐right cardiac asymmetry of expression with dHAND predominantly in the right and eHAND in the left ventricle. The two cardiac bHLH factors have the ability to form heterodimers with the ubiquitous bHLH protein E12, subsequently recognizing E‐boxes in the promoter region of target genes like ALC‐1. We found a highly significant positive correlation between HAND and ALC‐1 mRNA. The total ALC‐1 protein level in ToF was smaller than in HOCM, although ALC‐1 mRNA as well as HAND mRNA levels were significantly higher. ToF patients expressed around four times more ALC‐1 mRNA for similar amounts of ALC‐1 than HOCM patients. Suggesting disturbed ALC‐1 translation in ToF, we found ALC‐1 antisense mRNA expression in the hypertrophied, but not in the normal, ventricles. The higher the antisense/sense ALC‐1 mRNA ratio, the lower ALC‐1 protein was expressed. J. Cell. Biochem. 74:551–561, 1999.

Expression of calcium channel subunits in the normal and diseased human myocardium

We investigated the expression of α1 and β subunits of the L-type Ca2+ channel on the protein level in cardiac preparations from normal human heart ventricles and from the hypertrophied septum of patients with hypertrophic obstructive cardiomyopathy (HOCM). 1,4-Dihydropyridine (DHP) binding and immunorecognition by polyclonal antibodies directed against the C-terminal amino acid sequences of the β2 and β3 subunits were used for detection and quantification of α1, β2, and β3 subunits. Bmax of high-affinity DHP binding was 35±2 fmol/mg protein in HOCM and 20±2 fmol/mg protein in normal human hearts (P<0.05). In rabbit hearts the anti-β2 subunit antibody immunoprecipitated 80% of the total amount of DHP-labeled Ca2+ channels present in the assay. Under identical experimental conditions 25% of labeled Ca2+ channels were recovered in the immunoprecipitates of both normal and HOCM ventricles. A similar partial immunoprecipitation was observed in pig hearts. Immunoblot analysis demonstrated that the β2 subunit was associated with the DHP receptor/Ca2+ channel in cardiac muscle of rabbit, pig, and human heart. In neither of these purified cardiac Ca2+ channels was the β3 subunit isoform detected. Our results suggest that both α1 and β2 subunit expression is upregulated in HOCM in a coordinate manner.

Expression of atrial myosin light chains but not α-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy

Abstract. The adult rodent heart adapts to increased work load by reexpression of its fetal genes, for example, β-myosin heavy chain (MHC), in order to improve contractile function. However, the human ventricle regulates contractility by expression of atrial essential myosin light chain (ALC-1) rather than β-MHC. We evaluated the impact of both mechanisms in patients with hypertrophic cardiomyopathy. MHC isoform expression was quantified at the mRNA and protein levels by reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Although α-MHC mRNA was detected in control and hypertrophied human ventricular tissue, α-MHC protein was not observed. Similarly, we investigated the expression of ALC-1 by two-dimensional polyacrylamide gel electrophoresis and the clinical and hemodynamic parameters of the patients with hypertrophic cardiomyopathy. We found a significant positive correlation between ALC-1 protein expression and dP/dtmax in the hypertrophied human ventricle in vivo. Correlations between dP/dtmax and expression of protein for the ryanodine receptor and L-type Ca2+ channel were excluded. Our data suggest that reexpression of ALC-1 improves the contractile state of the adult human heart. We propose that two evolutionarily divergent compensatory mechanisms for increased work demand exist in the mammalian heart: MHC regulation in rodents and essential MLC regulation, of cardiac contractility, in humans.

Techniques and complications of transaortic subvalvular myectomy in patients with hypertrophic obstructive cardiomyopathy (HOCM)

The natural history of hypertrophic obstructive cardiomyopathy (HOCM) is usually characterized by development of mitral insufficiency, congestive heart failure (CHF) and sudden death. In patients (pts) belonging to at least clinical class III (NYHA) after failed medical therapy (beta-blocking agents and calcium-antagonists) surgery should be considered (by means of transaortic subvalvular myectomy). The history and development of different surgical techniques and procedures has been described in detail since 1958, when Cleland performed the first transaortic subvalvular myotomy. Our surgical series (1963-May 31, 1986) consists of 212 pts (mean age 40 years, range 6-73 years) with typical and atypical HOCM. The total hospital mortality rate was 6.6% (n = 14), which was reduced to 3.8% (n = 6), if only transaortic subvalvular myectomy (TSM) was performed (n = 160). In the group of 52 pts with additional surgical procedures the mortality rate was 15.4% (n = 8). The main problems occurred in pts with additional mitral valve replacement (MVR) (n = 15, three deaths). The rate of HOCM-related complications (secondary VSD, total AV-block, cerebral embolism, intraoperative re-myectomy) and those related to surgery (bleeding, pulmonary embolism, wound dehiscence, septicemia) was low. Therefore TSM for HOCM is a low-risk surgical procedure with a good long-term prognosis. However, in pts with a need for additional surgical procedures, the risk is considerably increased. Subjective impression of the pts and hemodynamic data indicate a clear clinical improvement postoperatively. Concerning long-term survival and reduction of the sudden death rate, our data do not allow a final judgement at the moment.

DRINGLICHER HERZKLAPPENERSATZ NACH AKUTER HIRNEMBOLIE WAHREND FLORIDER ENDOKARDITIS

Zusammenfassung□ HintergrundWegen der hohen Rezidivgefahr verlangt das Auftreten embolischer Komplikationen während florider Endokarditiden, die Indikation zu einer operativen Klappenintervention zu prüfen. Bei zerebraler Embolisation ist deren prognostischer Nutzen umstritten, da im Gefolge der Operation sekundäre zerebrale Blutungskomplikationen gefürchtet werden. Wir analysierten die Häufigkeit thromboembolischer Komplikationen, mögliche Prädispositions-faktoren und den prognostischen Einfluß der jeweils gewählten Therapiestrategie (medikamentös-konservativ versus dringlich-operativ) bei Patienten mit gesicherter Endokarditis. Insbesondere wurde geprüft, wie hoch das sekundäre zerebrale Blutungsrisiko nach dringlich durchgeführter klappenchirurgischr Intervention unter Einsatz der Herz-Lungen-Maschine zu veranschlagen ist.⌖ Patienten und MethodikZwischen 1978 und 1993 wurde bei 288 konsekutiven, prospektiv beobachteten Patienten (131 Frauen, 157 Männer; mittleres Alter 53,6±8,7 [9 bis 81] Jahre) eine mikrobiell verursachte Nativklappenendokarditis gesichert. Um den prognostischen Nutzen einer früh nach zerebraler Embolisation durchgeführten klappenchrirurgischen Intervention abzuschätzen, wurden die kumulativen Überlebensraten von Patienten mit und ohne Operation unter Berücksichtigung des Operationszeitpunktes und inkrementaler Risikofaktoren verglichen.□ ErgebnisseDer Krankheitsverlauf war bei 50 Patienten (17,4%) durch eine und bei 58 Patienten (20,2%) durch rezidivierende Emboline kompliziert. 80% der Erstembolien traten innerhalb von 33 Tagen nach Geginn der initialen Endodarditissymptomatik, 80% der Rezidive innerhalb von 32 Tagen nach dem initialen embolischen Ereignis auf. 71% der diagnostizierten Embolien waren Hirnembolien. Bei Patienten mit computertomographisch bestätigten zerebralen Embolien war der klinische Verlauf in 12,5%, bei Patienten ohne zerebrale Embolien in 1,5% durch Hirnblutungen kompliziert. Von 49 Patienten mit rezidivierenden, mindestens einmal das Zerebrum betreffenden Embolien war bei 11 im Abstand von vier bis 366 Stunden nach der Erstembolie notfallmäßig ein Herzklappenersatz erforderlich. Die kumulativen Überlebensraten der während der ersten 72 Stunden nach Auftreten der Hirnembolie operierten Patienten erwiesen sich als erheblich günstiger (p<0,000) als für nicht oder später als acht Tage nach der Embolie operierte Patienten.□ SchlußfolgerungenEine Embolie während florider Endokarditis prädisponiert mit einer Wahrscheinlichkeit von über 50% zu Rezidiven. Bei Patienten mit kurzer Erkrankungsdauer und postembolisch echokardiographisch weiterhin nachweisbaren Vegetationen beträgt das Risiko mehr als 80%, so daß zumindest bei diesem Teilkollektiv eine dringliche Operation zur Beseitigung von Infektions- und Emboliequelle sinnvoll ist. Nach zerebraler Embolisation sollte die Operation möglichst rasch durchgeführt werden, da dann ein signifikant niedrigeres (p≤0,000) zerebrales Blutungsrisiko besteht als bei Operationen, die mit einer Latenz von 72 Stunden oder mehr durchgeführt werden. Zum Ausschluß einer insgesamt seltenen, frühen Reperfusionsblutung im Gefolge spontaner Thrombusfragmentation ist zeitnah vor der Herzoperation eine zerebrale computertomographische Kontrolle erforderlich.Abstract□ BackgroundThe indication for urgent cardiac surgical interventions in patients with active infective endocarditis has to be considered carefully following thromboembolic events, because of the high recurrence rate of such complications. In the case of brain embolisms the prognostic benefit of urgent surgery has been discussed controversially as effective anticoagulation during open heart surgery may result in secondary cerebral hemorrhages.□ Patients and MethodsBetween 1978 and 1993 infective endocarditis (IE) was proven in 288 consecutive and prospectively followed patients (131 females, 157 males; mean age 53.6±8.7 [9 to 81] years). To analyze potential benefits and risks of an urgent surgical intervention early after embolic cerebral infarction, cumulated survival rates were calculated for patients with and without surgical intervention with special reference to incremental risk factors and the timing of surgery.□ ResultsIn 50 patients (17.4%) the clinical course was complicated by one, and in 58 patients (20.2%) by recurrent embolic events. In 80% the first embolism occurred within 33 days following the first manifestation of typical signs and symptoms of IE. 80% of recurrent events were observed within 32 days following the initial embolism. 71% of all embolic events were cerebral. In patients with cerebral embolism corroborated by computed tomography (CCT), the clinical course was complicated by intracranial hemorrhage in 12.5% while it was only 1.5% for patients without cerebral embolism. Because of a lack of therapeutic alternatives, 22 of 49 patients with recurrent embolic events, of which at least one was cerebral, underwent urgent cardiac surgery within 4 to 366 hours after the first cerebral manifestation. The cumulated survival rate of patients operated within 72 hours after the initial cerebral embolism was significantly more favorable (p<0.000) than for unoperated patients or those who were operated after more than 8 days.□ ConclusionAn embolic event during IE carries a more than 50% risk of recurrence. In patients with short duration of signs and symptoms of IE and postembolic echocardiographic demonstration of persistent vegetations the probability is >80%. At least for those patients urgent surgical intervention to remove the source of infection and embolic hazard seems to be beneficial. Surgical intervention using the heart-lung-machine should be performed within 72 hours. Such early timing results in a significant lower rate of secondary cerebral hemorrhages (p<0.000) than a postponed operation. To exclude early reperfusion hemorrhage due to spontaneous thrombus fragmentation, CCT should be repeated directly preoperatively.BACKGROUND The indication for urgent cardiac surgical interventions in patients with active infective endocarditis has to be considered carefully following thromboembolic events, because of the high recurrence rate of such complications. In the case of brain embolisms the prognostic benefit of urgent surgery has been discussed controversially as effective anticoagulation during open heart surgery may result in secondary cerebral hemorrhages. PATIENTS AND METHODS Between 1978 and 1993 infective endocarditis (IE) was proven in 288 consecutive and prospectively followed patients (131 females, 157 males; mean age 53.6 +/- 8.7 [9 to 81] years). To analyze potential benefits and risks of an urgent surgical intervention early after embolic cerebral infarction, cumulated survival rates were calculated for patients with and without surgical intervention with special reference to incremental risk factors and the timing of surgery. RESULTS In 50 patients (17.4%) the clinical course was complicated by one, and in 58 patients (20.2%) by recurrent embolic events. In 80% the first embolism occurred within 33 days following the first manifestation of typical signs and symptoms of IE. 80% of recurrent events were observed within 32 days following the initial embolism. 71% of all embolic events were cerebral. In patients with cerebral embolism corroborated by computed tomography (CCT), the clinical course was complicated by intracranial hemorrhage in 12.5% while it was only 1.5% for patients without cerebral embolism. Because of a lack of therapeutic alternatives, 22 of 49 patients with recurrent embolic events, of which at least one was cerebral, underwent urgent cardiac surgery within 4 to 366 hours after the first cerebral manifestation. The cumulated survival rate of patients operated within 72 hours after the initial cerebral embolism was significantly more favorable (p < or = 0.000) than for unoperated patients or those who were operated after more than 8 days. CONCLUSION An embolic event during IE carries a more than 50% risk of recurrence. In patients with short duration of signs and symptoms of IE and postembolic echocardiographic demonstration of persistent vegetations the probability is > 80%. At least for those patients urgent surgical intervention to remove the source of infection and embolic hazard seems to be beneficial. Surgical intervention using the heart-lung-machine should be performed within 72 hours. Such early timing results in a significant lower rate of secondary cerebral hemorrhages (p < or = 0.00) than a postponed operation. To exclude early reperfusion hemorrhage due to spontaneous thrombus fragmentation, CCT should be repeated directly preoperatively.

Hypertrophic cardiomyopathy: A desensitized cardiac \-adrenergic system in the presence of normal plasma catecholamine concentrations

Only few data are available concerning the biochemical and functional state of the \-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial \-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM).Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of \-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the \-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC50-values were about 10 fold higher than the respective EC50-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the \-adrenoceptors, \-adrenoceptor density and \1:\2-adrenoceptor subtype distribution were determined in the same myocardium using 125I-Iodocyanopindolol saturation binding.Myocardial \-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 ± 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of \1-adrenoceptors (24.9 ± 3.7 fmol/mg protein vs NF: 46.4 ± 6.8 fmol/mg protein, P < 0.05), whereas \2-adrenoceptor density was unchanged (19.0 ± 1.9 fmol/mg protein vs NF: 18.4 ± 3.3 fmol/mg protein, n.s.). In MR both \-adrenoceptor subtypes were reduced (\1: 26.9 ± 1.4 fmol/mg protein, \2: 9.6 ± 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM.In summary, myocardial \-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the \-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the \-adrenergic desensitization previously described to occur in congestive heart failure.