Balázs Sax

Intrapericardial Angiotensin II Stimulates Endothelin-1 and Atrial Natriuretic Peptide Formation of the In Situ Dog Heart

Angiotensin (AT) II, endothelin (ET)-1, and atrial natriuretic peptide (ANP) play an important role in cardiovascular regulatory processes under physiologic and pathophysiologic conditions. All of these agents are present in the pericardial fluid, and alteration of their pericardial concentrations mirror changes in the myocardial interstitium. Moreover, the composition the pericardial fluid may also reflect the myocardial interaction of these agents. The local myocardial effects of AT II on cardiac ET-1 and ANP production, as well as on cardiovascular function, was studied by intrapericardial (ip) administration of AT II (0.125–1.0 μg/kg) to the in situ dog heart (n = 8). Big ET, ET-1, and ANP [1–28] fragment concentrations were measured by enzyme-linked immunosorbent assay in pericardial infusate samples and in peripheral blood before and after an AT II treatment of 15 mins. Systemic blood pressure (BP), heart rate (HR), and left ventricular contractility (dP/dt) were also recorded. In our studies, the pericardial big ET (but not ET-1) concentration was increased to a maximum value of 139 ± 28 versus 74 ± 12 pg/ml (control; P < 0.02) with ip AT II administration, with parallel elevations of the pericardial ANP levels (36.8 ± 7.2 vs. 24.4 ± 3.6 ng/ml; P < 0.05). The ip administration of AT II did not influence HR, and it elicited moderate changes in BP (BPmax, +14 ± 2 mm Hg, P < 0.001; dP/dtmax, +10 ± 3%, P < 0.02). The plasma levels of big ET, ET-1, and ANP did not change significantly. The results suggest that AT II promotes production of big ET and ANP in the heart. However, no detectable conversion of big ET-1 to ET-1 was observed within 15 mins. The myocardial formation of big ET-1 and ANP occurred, at least in part, independently of the changes in cardiovascular function.

Characterization of pericardial and plasma ghrelin levels in patients with ischemic and non-ischemic heart disease

Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologically active compartment of the heart that communicates with the myocardial interstitium. Thus, pericardial level of certain agents may reflect their concentration in the myocardium well. In our study we measured acylated (active) and total (acylated and non-acylated) pericardial and plasma ghrelin levels of patients with ischemic and non-ischemic heart disease. Pericardial fluid and plasma samples were obtained from patients with coronary artery disease (ISCH, n=54) or valvular heart disease (VHD, n=41) undergoing cardiac surgery. Acylated pericardial ghrelin concentrations were found to be significantly higher in patients with ischemic heart disease (ISCH vs. VHD, 32±3 vs. 16±2pg/ml, p<0.01), whereas plasma levels of the peptide showed no difference between patient groups. Pericardial-to-plasma ratio, an index abolishing systemic effects on local ghrelin level was also significantly higher in ISCH group for both acylated and total ghrelin. Plasma total ghrelin showed negative correlation to BMI, plasma insulin and insulin resistance index HOMA-A. Pericardial acylated and total ghrelin concentrations were negatively correlated with posterior wall thickness (R=-0.31, p<0.05 and R=-0.35, p<0.01, respectively). Plasma insulin concentration and HOMA-A showed significant negative correlation with pericardial ghrelin levels. In conclusion, increased pericardial active ghrelin content and higher pericardial-to-plasma ghrelin ratio were found in ischemic heart disease as compared to non-ischemic patients suggesting an increased ghrelin production of the chronically ischemic myocardium. According to our results, pericardial ghrelin content is negatively influenced by left ventricular hypertrophy and insulin resistance.

Coronary vasoconstrictor effect of ghrelin is not mediated by growth hormone secretagogue receptor 1a type in dogs

Ghrelin (GHR) is a recently discovered endocrine regulatory peptide of gastrointestinal origin with multiple functions including cardiovascular effects. However, contradictory data are available on the vascular actions of GHR in different organs and species. The aim of this study was to characterize the direct effect of the peptide on the canine coronary bed and to evaluate the role of the growth hormone secretagogue receptor (GHS-R) in the effect of GHR on coronary arterioles. The presence of GHS-R1a and 1b subtypes in canine coronary arterioles was investigated using Western blotting and immunohistochemistry. Responses of coronary arterioles with spontaneous and elevated vascular tone (the latter evoked by the thromboxane mimetic agent U46619, 10(-7)-10(-6)mol/l) to GHR (10(-9)-3×10(-7)nmol/l) were recorded by video-microscopy as changes of vessel diameter. Positive immunostaining for both GHS-R subtypes was found in the wall of intramural arterioles. The microarteriographic study results showed that GHR alone could not elicit any significant effect on vessel diameter of arterioles with spontaneous tone. However, when vascular smooth muscle was preconstricted by the thromboxane mimetic agent U46619, administration of GHR induced further constriction (+31±9% increase in contraction p<0.01). This was not abolished by the specific blockade of GHS-R1a by d-Lys(3)-GHRP-6 (5×10(-6)mol/l). The results suggest that GHR induces tone-dependent constriction of canine coronary arterioles which is mediated by a receptor other than GHS-R1a.

Dominance of free wall radial motion in global right ventricular function of heart transplant recipients

Assessment of right ventricular (RV) function using conventional echocardiography might be inadequate as the radial motion of the RV free wall is often neglected. Our aim was to quantify the longitudinal and the radial components of RV function using three‐dimensional (3D) echocardiography in heart transplant (HTX) recipients. Fifty‐one HTX patients in stable cardiovascular condition without history of relevant rejection episode or chronic allograft vasculopathy and 30 healthy volunteers were enrolled. RV end‐diastolic (EDV) volume and total ejection fraction (TEF) were measured by 3D echocardiography. Furthermore, we quantified longitudinal (LEF) and radial ejection fraction (REF) by decomposing the motion of the RV using the ReVISION method. RV EDV did not differ between groups (HTX vs control; 96 ± 27 vs 97 ± 2 mL). In HTX patients, TEF was lower, however, tricuspid annular plane systolic excursion (TAPSE) decreased to a greater extent (TEF: 47 ± 7 vs 54 ± 4% [−13%], TAPSE: 11 ± 5 vs 21 ± 4 mm [−48%], P < .0001). In HTX patients, REF/TEF ratio was significantly higher compared to LEF/TEF (REF/TEF vs LEF/TEF: 0.58 ± 0.10 vs 0.27 ± 0.08, P < .0001), while in controls the REF/TEF and LEF/TEF ratio was similar (0.45 ± 0.07 vs 0.47 ± 0.07). Current results confirm the superiority of radial motion in determining RV function in HTX patients. Parameters incorporating the radial motion are recommended to assess RV function in HTX recipients.

Comparison of Elimination and Cardiovascular Effects of Adenine Nucleosides Administered Intrapericardially or Intravenously in Anesthetized Dog

Intrapericardial (IP) administration of certain cardioactive agents allows investigation of local pharmacological actions on the heart and may carry potential benefit to influence myocardial function. The cardioprotective adenosine (ADO) and inosine (INO) may be the most representative candidates. Elimination and cardiovascular effects of IP and intravenously (IV) applied ADO and INO were compared on anesthetized dogs. Their pericardial and systemic concentrations were measured after consecutive administration of increasing ADO and INO doses. In the case of IP administration at the end of the incubation period, pericardial concentrations of adenine nucleosides significantly exceeded the control values. However, the IV applied ADO and INO were rapidly metabolized in the systemic plasma. As characteristic hemodynamic effects, small but sustained decrease in heart rate (IP ADO) and increase in myocardial contractility (IP INO) were observed. During IV administration, ADO and INO exerted remarkable effects on all hemodynamic variables, which then gradually disappeared in 15 minutes. In summary, the elimination of ADO and INO was significantly slower in the pericardial fluid than in the plasma. Considering the balanced cardiac actions and lack of strong systemic hemodynamic effects, IP administration of adenine nucleosides may suggest a promising approach in the local treatment of the diseased heart.

The impact of l-thyroxine treatment of donors and recipients on postoperative outcomes after heart transplantation

OBJECTIVE The effect of thyroid dysfunction on adverse outcomes has been studied in many different patient populations. The objective of this study was to investigate the effect of thyroid hormone supplementation of donors and recipients on postoperative outcomes after orthotopic heart transplantation. DESIGN Retrospective. SETTING Single center, university hospital. PARTICIPANTS Two-hundred and sixty-six consecutive patients undergoing heart transplantation. INTERVENTIONS No interventions. MEASUREMENTS AND MAIN RESULTS Demographic, hemodynamic, and clinical characteristics; donor and recipient United Network for Organ Sharing scores; and information on thyroid hormone support of donors and recipients were recorded. During the median follow-up of 4.59 years (interquartile range 4.26-4.92 y), 70 patients (26.3%) died. After adjustments were made for the United Network for Organ Sharing score, recipients who were treated preoperatively with l-thyroxine had a lower risk for all-cause mortality (adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.06-0.98; p = 0.047) compared with recipients who were not treated with l-thyroxine. In addition, l-thyroxine treatment of donors was associated with a better recipient survival (HR 0.31, 95% CI 0.11-0.87; p = 0.025). CONCLUSIONS Pretransplantation thyroid hormone supplementation of donors and recipients was associated with improved long-term survival after heart transplantation.

Higher Transaminase Levels in the Postoperative Period After Orthotopic Heart Transplantation Are Associated With Worse Survival

OBJECTIVE Preoperative liver function in heart failure patients is associated with extensive functional, structural, and hemodynamic abnormalities. The authors hypothesized that perioperative liver dysfunction is associated with worse 2-year survival after orthotopic heart transplantation. DESIGN Retrospective study. SETTING Single-center, university hospital. PARTICIPANTS The study comprised 209 consecutive patients undergoing heart transplantation. INTERVENTIONS No interventions. MEASUREMENTS AND MAIN RESULTS Hepatobiliary markers, hemodynamic parameters, echocardiographic parameters, the need for mechanical cardiac support, demographic parameters, and United Network for Organ Sharing and Model for End-Stage Liver Disease (MELD) scores were investigated. Fifty-five patients (26.3%) died, and the mean survival time was 3.61 years after transplantation. In multivariate Cox regression analysis, in addition to the preoperative modified MELD score, the 4th quartiles of the maximum aspartate transaminase (AST) and alanine transaminase levels on the 4th through 7th postoperative days were independently associated with mortality (odds ratio [OR] 2.46, 95% confidence interval [CI] 1.09-5.55; p = 0.031 and OR 2.41, 95% CI 1.13-5.18; p = 0.024, respectively). By expressing the transaminase values as the multiplier of the sex-specific top normal value, the maximum AST and alanine transaminase levels (OR 1.02, 95% CI 1.01-1.02; p < 0.001 and OR 1.02, 95% CI 1.01-1.03; p = 0.001, respectively) were linked to worse survival. Among the postdischarge parameters, the modified MELD score (OR 1.17, 95% CI 1.09-1.27; p < 0.001) and the AST level were associated with postdischarge mortality (OR 1.002, 95% CI 1.001-1.003; p < 0.001 as a continuous variable; OR 1.07, 95% CI 1.05-1.10; p < 0.001, expressed as the multiplier of the sex-specific normal value, respectively). CONCLUSIONS The severity of postoperative liver dysfunction negatively influences survival after heart transplantation, and liver function should be closely assessed in these patients.

Image Quality of Prospectively ECG-Triggered Coronary CT Angiography in Heart Transplant Recipients

OBJECTIVE Cardiac allograft vasculopathy (CAV) is among the top causes of death 1 year after heart transplantation (HTx). Coronary CT angiography (CTA) is a potential alternative to invasive imaging in the diagnosis of CAV. However, the higher heart rate (HR) of HTx recipients prompts the use of retrospective ECG-gating, which is associated with higher radiation dose, a major concern in this patient population. Therefore, we sought to evaluate the feasibility and image quality of low-radiation-dose prospectively ECG-triggered coronary CTA in HTx recipients. MATERIALS AND METHODS In total, 1270 coronary segments were evaluated in 50 HTx recipients and 50 matched control subjects who did not undergo HTx. The control subjects were selected from our clinical database and were matched for age, sex, body mass index, HR, and coronary dominance. Scans were performed using 256-MDCT with prospective ECG-triggering. The degree of motion artifacts was evaluated on a per-segment basis on a 4-point Likert-type scale. RESULTS The median HR was 74.0 beats/min (interquartile range [IQR], 67.8-79.3 beats/min) in the HTx group and 73.0 beats/min (IQR, 68.5-80.0 beats/min) in the matched control group (p = 0.58). In the HTx group, more segments had diagnostic image quality compared with the control group (624/662 [94.3%] vs 504/608 [82.9%]; p < 0.001). The mean effective radiation dose was low in both groups (3.7 mSv [IQR, 2.4-4.3 mSv] in the HTx group vs 4.3 mSv [IQR, 2.6-4.3 mSv] in the control group; p = 0.24). CONCLUSION Prospectively ECG-triggered coronary CTA examinations of HTx recipients yielded diagnostic image quality with low radiation dose. Coronary CTA is a promising noninvasive alternative to routine catheterization during follow-up of HTx recipients to diagnose CAV.

Szívtranszplantáció és műszívkezelés költséghatékonysági elemzési modellje

Absztrakt A szivtranszplantacio kiemelt projekt lett a Semmelweis Egyetemen belul. Ennek megfelelően a szivatultetes es a mechanikus keringestamogatas finanszirozasa is rendkivuli jelentőseget kapott. A szerzők a transzplantacios es műszives betegek koltsegeinek osszehasonlitasarol vegzett koltseghatekonysagi szamitasi modell felepiteseről szamolnak be. A modell megalkotasanal direkt allokacios koltsegszamitast, dontesifa-modellt, inkrementalis koltseghatekonysagi ratat es koltseghatekonysagi terkepmodszert hasznaltak. Modszerukkel ossze tudjak hasonlitani a műszivbeultetesen atesett es a szivtranszplantacios betegcsoportok kezdeti, perioperativ es utokezelesi koltsegeit. Modelljuk alkalmas lehet hosszu tavu utankovetes es kellő elemszamu beteg bevonasaval koltseghatekonysagi elemzesek elkeszitesere, gazdasagi dontestamogato kovetkeztetesek meghozatalara.

[Mechanical circulatory support saves lives -- three years' experience of the newly established assist device program at Semmelweis University, Budapest, Hungary].

INTRODUCTION Since the celebration of the 20th anniversary of the first heart transplantation in Hungary in 2012 the emerging need for modern heart failure management via mechanical circulatory support has evolved. In May 2012 the opening of a new heart failure and transplant unit with 9 beds together with the procurement of necessary devices at Semmelweis University accomplished this need. AIM The aim of the authors was to report their initial experience obtained in this new cardiac assist device program. METHOD Since May, 2012, mechanical circulatory support system was applied in 89 cases in 72 patients. Indication for support were end stage heart failure refractory to medical treatment and acute left or right heart failure. RESULTS Treatment was initiated for acute graft failure after heart transplantation in 27 cases, for end stage heart failure in 24 cases, for acute myocardial infarction in 21 cases, for acute postcardiotomy heart failure in 14 cases, for severe respiratory insufficiency in 2 cases and for drug intoxication in one case. Among the 30 survivor of the whole program 13 patients were successfully transplanted. CONCLUSIONS The available devices can cover all modalities of current bridge therapy from short term support through medium support to heart transplantation or long term support and destination therapy. These conditions made possible the successful start of a new cardiac assist device program.