Effect of immunosuppressive therapy in inflammatory cardiomyopathy: data from The Czech Inflammatory Cardiomyopathy Immunosuppressive Trial.

INTRODUCTION: The indications for specific treatment in the cases of inflammatory cardiomyopathy are based on limited data from several small clinical trials. AIM: A comparison of the effect of two dose regimens of combined immunosuppressive therapy by adding them to conventional heart failure therapy and comparing them with conventional heart failure therapy alone in patients with inflammatory cardiomyopathy. METHODS AND STUDY POPULATION: We enrolled 20 patients; mean age 46.10±7.33 years, duration of symptoms <6 months, LVEF ≤40 %, NYHA class II-IV, with biopsy­proven myocarditis. Patients were randomly separated into groups treated with immunosuppressive therapy in addition to conventional heart failure therapy or to a group treated with conventional heart failure therapy alone. Clinical and echocardiographic parameters were evaluated. RESULTS: The baseline values of LVEF in the group of immunosuppressive therapy (LVEF 22.3±4.7 %) were similar to those in the group treated with conventional heart failure therapy (LVEF 21.7±4.7 %; p=0.757). After twelve months there was no statistically significant difference in LVEF between the two studied groups (LVEF 33.7±9.5 % for the immunosuppressive therapy group and 41.3±13.0 % for the conventional therapy group; p=0.175). CONCLUSION: In our study population, we proved no positive effect of combined immunosuppressive therapy on the left ventricular function over 12 months. The main limitation of the study is the small number of enrolled patients (Tab. 4, Fig. 1, Ref. 35).

Conservative versus invasive treatment in hypertrophic obstructive cardiomyopathy: an echocardiography study.

AIM AND METHODS: The aim of our study was to compare the development of echocardiographic parameters and functional status of patients with hypertrophic obstructive cardiomyopathy (HOCM) treated conservatively (n = 41) or by alcohol septal ablation (ASA; n = 39). RESULTS: Left ventricular outflow tract gradient (LVOTG) decreased in the first year by 53.7±36.4 mmHg in ASA group versus 5.5±47.1 mmHg in conservatively treated group (p<0.001), in the third year by 53.1±41.4 mmHg versus 23.9±42.7 mmHg (p = NS) and in the fifth year, the reduction of LVOTG was 52.1±44.5 mmHg in ASA group and 3.0±63.2 mmHg in conservatively treated group (p<0.05).Change in NYHA class in the first year was -1.1±0.4 versus 0.1±0.5, in the third year -1.0±0.6 versus 0.1±0.4 and in the fifth year -0.8±0.5 versus 0.1±0.4 (all p<0.001). CONCLUSION: Our results showed for the first time that decline of LVOTG after ASA creates a favorable left ventricle remodeling and leads to significant improvement of functional status of HOCM patients in comparison with conservative treatment (Tab. 3, Fig. 2, Ref. 42).

[Contemporary view on liver impairment in heart failure]. / Soucasný pohled na onemocnení jater u srdecního selhání

Cardiac failure has a negative impact on the function of all parenchymatous organs, based both on the low organ perfusion in the left-sided forward failure and on the venous congestion in the right-sided backward failure. Current studies dealing with the cardiac hepatopathy focus not only on the liver enzyme changes, but also analyse its clinical and prognostic relevance. The aim of the article is to provide the comprehensive and contemporary view on liver dysfunction in heart failure patients.

[Cardiorenal syndrome by heart failure]. / Kardiorenální syndrom u srdecního selhání

Cardiorenal (CR) syndrome is defined for the purposes of the following text mainly as primary cardiac dysfunction with a consequent failure of renal haemodynamics. Heart failure leads to a decrease in cardiac output and to the activation of vasoconstrictors; this gradually precipitates a decrease in the level of renal perfusion, the vasoconstriction of renal vessels and a decrease in glomerular filtration with a gradual development of renal failure. The following paper analyses the pathophysiological mechanisms, the characteristics of the patients, the role of medication during CR syndrome, the relationship between proteinuria and anaemia during CR syndrome and the application of bio-markers and pulmonary hypertension in the prognosis of patients with CR syndrome.

[Renal denervation 2013]. / Renální denervace 2013.

Arterial hypertension is a worldwide serious clinical problem. It affects 30- 40% of the adult population. Resistant hypertension is defined as systolic blood pressure that remains 140mmHg while in the doctors surgery and/ or as average systolic blood pressure during a 24- hour monitoring of an outpatient 130mmHg after a combination of three antihypertensive agents (including a diuretic) has been administered in the maximum tolerated dose amounts. Renal denervation is an invasive method of catheter radio frequency ablation of sympathetic nerves located in the walls of renal arteries. The results of the Symplicity HTN 1 and HTN 2 trials proved that renal denervation can safely decrease blood pressure in patients with resistant hypertension. Further research is necessary in order to verify these data, to clarify the questions which remained unanswered and to evaluate future applications of renal denervation. Current experience and recommendations are included, as well as an overview of existing denervation devices and devices which are in development.

[Diuretics in monotherapy and in combination with other diuretics and nondiuretics in the treatment of hypertension]. / Diuretika v monoterapii a v kombinaci s diuretiky a nediuretiky v lécbe hypertenze.

Diuretics belong to the basic group of medicines for the treatment of hypertension and heart failure. In the case of hypertension treatment, their main indication is higher age and isolated systolic hypertension. In the case of heart failure they are used for the treatment of swellings and shortness of breath. The most frequently prescribed group of diuretics is thiazides and similar products. In patients with renal insufficiency, loop diuretics are administered. In the case of hypertension, diuretics are mainly used in the combination treatment. The most frequently used diuretic in combination is again hydrochlorothiazide, which is combined with reninangiotensin system blockers. It is mainly the combination of an ACE inhibitor + indapamide that seems to be modern and promising, and it is, on the basis of large clinical trials, recommended also for diabetics (ADVANCE) or for secondary prevention following a cerebrovascular accident (PROGRESS) or for the elderly (HYVET). Also a combination of two diuretics is popular -  mainly hydrochlorothiazide + amiloride. A combination of a betablocker and diuretic is less suitable.

[Heart transplantation and the subsequent treatment of AL amyloidosis]. / Transplantace srdce a následná lécba AL-amyloidózy.

UNLABELLED: Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. CASE DESCRIPTIONS: Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the λ free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 µg/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High-dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. CONCLUSION: It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments.

[Fixed combinations in the treatment of hypertension]. / Fixní kombinace v lécbe hypertenze.

We present an overview of current opinions on combination therapy and the role of fixed combinations in the treatment of hypertension as per the ESH/ESC and CSH guidelines of 2007 and the revised European guidelines of 2009. A renin-angiotensin system blocker (ACE-I or sartan) combined with a calcium channel blocker is the most frequently recommended combination, followed by renin-angiotensin system blocker and a diuretic and a calcium channel blocker and a diuretic. A fixed combination of a calcium channel blocker and a beta-blocker has now been also recommended. Higher patient compliance and thus better control of hypertension is the main advantage of fixed combinations. We present an overview of fixed combinations registered in the Czech Republic until May 2012.

[Farmacotherapy of hypertension after heart transplantation]. / Farmakoterapie hypertenze po transplantaci srdce.

Heart transplantation is now used for the treatment of severe heart failure. In a long-term patient follow-up, hypertension has been identified as a complication. Incidence of hypertension in patients treated with cyclosporine and prednisone is between 70-90%. Besides the traditional mechanisms (renin-angiotensin system, fluid volume and peripheral resistance), aetiology of hypertension includes negative effect of cardiac denervation, cyclosporine immunosuppression, administration of corticosteroids and nephropathy. There is no night drop in the blood pressure and heart rate. Treatment aims to maintain cyclosporine level as low as possible and, if feasible, to discontinue steroids during the first year. Hypertension is usually treated with a combination therapy. Our own observations suggest that the majority of post-transplantation patients have a dual therapy. Calcium channel blockers should be the treatment of choice as they also have an effect on graft vasculopathy. Angiotenzin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), beta-blockers and diuretics are also recommended. Long-acting products should be preferred.

[Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and health related quality of life: results from the SHIFT substudies]. / Snízení srdecní frekvence u srdecního selhání: zmeny funkce levé komory a kvalita zivota v podstudiích SHIFT.

The SHIFT study showed a positive effect of ivabradine in patients with chronic heart failure, sinus rhythm and heart rate at rest above 70 beats per minute. The aim of the first sub-study was to ascertain the effect of ivabradine on changes to the left ventricle function using echocardiography; ivabradine significantly increased ejection fraction of the left ventricle and reduced terminal left ventricular end-systolic and end-diastolic volumes. The second sub-study explored changes to the quality of life in patients treated with ivabradine or placebo. This study also showed statistically significantly improved quality of life after treatment with ivabradine. Both sub-studies confirmed the positive effect of ivabradine on patients with optimal treatment of heart failure, including maximum tolerated dose of beta-blockers and sinus heart rate above 70/min.

[Pharmacotherapy of chronic heart failure after the first decade of 21st century]. / Farmakoterapie chronického srdecního selhání po prvních 10 letech 21. století.

We provide an overview of the main principles of pharmacological treatment of chronic heart failure. Chronic heart failure is considered to be an epidemic of the 21th century; in the Czech Republic, around 200,000 persons suffer from this condition. Over the last decade, pharmacological and non-pharmacological treatment of heart failure has undergone significant progress and new knowledge arises every year. Generally accepted pharmacological treatment steps include administration of ACE inhibitors, All antagonists (ARB) or beta-blockers, discussions exists on an indication for digoxin, diuretics and lipid-lowering drugs as well as on the importance of ACE-I and ARB. The role of antiarrhythmics is unclear and 2009-2011 have brought about some completely new drug groups-If, channel blockers, factor Xa blockers, thrombin blockers and other agents.

[Pharmacotherapy following myocardial infarction]. / Farmakoterapie po srdecním infarktu.

Early reperfusion is the treatment of choice for acute coronary syndrome. In the Czech Republic, reperfusion therapy is well accessible thanks to the network of 22 catheterization centres. Every year, 28,000 patients are treated using this technique. Successful reperfusion should be followed by life style changes--smoking cessation, maintenance of appropriate body weight etc. These steps than has to be accompanied by effective pharmacotherapy to prevent remodelling of the left ventricle, re-stenosis of the coronary artery, re-thrombosis and arrhythmias. Four drug groups provide the desired effects--renin-angiotensin-aldosterone system blockers, beta-blockers, antiplatelet agents and statins.

[FARIM - FARmakoterapie po Infarktu Myokardu (Post-Myocardial Infarction Pharmacotherapy Study)]. / FARIM - FARmakoterapie po Infarktu Myokardu.

A total of 2,500 patients with an anamnesis of myocardial infarction at least 1 month prior to inclusion in the study who visited a general practitioner or an internal medicine or cardiology specialist were examined. Through an internet-based portal, physicians entered patient data, their complaints, treatment, blood pressure, heart rate and main biochemical parameters. There were more men (1 787 vs. 713) and patients under 70 years of age (1 491 vs. 1 009) in the cohort. Eighteen percent of patients had more than one MI. Mean age at the first infarction was 59.2 years in men and 64.9 in women (p < 0.001). NYHA breathlessness category higher than II was reported by 13.0% of patients only, 57.2% of patients reported they never had chest pain following an MI. Hypertension was the most frequent co-morbidity (84%). The mean blood pressure was 132/79 mmHg with no difference between men and women, the mean heart rate was 68/min, the mean cholesterol level was 4.55 mmol/l. 66% of patients had been prescribed all recommended pharmacotherapeutic groups according to guidelines (RAAS blockers, beta-blockers, statins, antiaggregation agents) and each group individually was used in > 90% of patients. There were no differences between men and women and older and younger patients. ACE inhibitors and statins were not always prescribed in recommended (high) doses. Ramipril and perindopril were the most frequently prescribed ACE inhibitors and atorvastatin the most frequently prescribed statin. There was a high level of compliance when it came to achieving the target blood pressure and heart rate values as well as to prescribing of the recommended drug groups. However, renin-angiotensin system-blocking agents and statins are not being prescribed in sufficiently high doses and this should be improved.

Difference in angiotensinogen haplotype frequencies between chronic heart failure and advanced atherosclerosis patients - new prognostic factor?

Numerous association studies have been involved in studying the angiotensinogen (AGT) variants, AGT plasma levels and relations to cardiovascular diseases, such as hypertension, myocardial infarction, coronary heart disease. To investigate a role of AGT G(-6)A and M235T genetic variants for chronic heart failure (CHF) and advanced atherosclerosis (AA), a total of 240 patients with CHF and 200 patients with AA of the Czech origin were evaluated for the study. The study shows the role of polymorphism AGT G(-6)A in genetic background among advanced atherosclerosis patients and chronic heart failure patients (Pg=0.001). This difference was also observed in comparison of AA patients with subgroup of CHF with dilated cardiomyopathy (Pg=0.02; Pa=0.009), and ischemic heart disease (Pg=0.007). The greatest difference between triple-vessel disease and chronic heart failure groups was observed in frequency of GT haplotype (P<0.001) and GGMT associated genotype (P<0.001). Retrospectively, we found the same trend when the subgroups of CHF were compared to AA group (AA vs. IHD with CHF P<0.001; AA vs. DCM P<0.001). These results suggest AGT genetic variants as a risk factor for chronic heart failure compared to advanced atherosclerosis disease without heart failure, with a strong difference between IHD patients and chronic heart failure patients with ischemic heart disease, especially in haplotypes and associated genotypes.

[Heart transplantations--the past, the present and outlook into the future]. / Transplantace srdce--minulost, soucasnost a výhled do budoucna.

We provide an overview of the history, current status and future perspectives of heart transplantations. We describe indication criteria and possible post-transplantation complications. Finally, we list the options that could, as an alternative, complement transplantations in the future. This is mainly the use of mechanical heart support devices.

[Is there circadian variation of big endothelin and NT-proBNP in patients with severe congestive heart failure?]. / Existuje diurnální variabilita big endotelinu a NT-proBNP u nemorných s tezkým chronickým srdecním selháním?

INTRODUCTION: Circadian rhytmus have long been recognized to occur in many biologic phenomena, including secretion of hormones as well as autonomic nervous system. There is increasing evidence that circadian rhythms have been also found in cardiovascular events, for example, myocardial infarction, sudden cardiac death as well as stroke have shown a circadian pattern of the distribution. The pathophysiology and the mechanism underlying these variations are the focus of much investigation, while i tis not full understood up to date. Heart rate, blood pressure, neurohumoral vasoactive factors, such as plasma norepinephrine levels and renin activity, and probably also contractility are increased in the morning hours. THE AIM OF OUR STUDY: To evaluate the circadian variability of plasma big endothelin and NT-proBNP level in patients with severe heart failure. PATIENTS: 13 patients with severe heart failure, stable for at least one month, male/female--8/5, NYHA III/IV--11/2, mean left ventricle ejection fraction 23 +/- 5%, mean cardiothoracic ratio 59 +/- 7%, all treated with RAAS blocade (11 x ACE-I, 2x ARB), all treated with diuretics, 12 patients treated with beta-blockers, 7 with digoxin. The cause of heart failure was ischemic heart disease (9) or dilated cardiomyopathy (4). METHODS: Blood samples for big endothelin and NT-proBNP were taken every two hours during a standartised daily regime. RESULTS: Mean plasma level of big endothelin (ranging from 1.25 to 1.71 pmol/l) had significant diurnal variability (upper limit of normal values 0.7 pmol/l). Mean plasma level of NT-proBNP (ranging from 782 to 934 pmol/l) had no diurnal variability (upper limit of normal values of 350 pmo/l). SUMMARY: Plasma level of NT-proBNP is stable during 24 hours and shows no circadian variability. Plasma big endothelin showed a morning peak after a systematic increase during bed rest. NT-proBNP could be evaluated any time during the day, big endothelin sample should be taken during standartised condition.

[Heart transplantation]. / Transplantace srdce.

The first heart transplantation (SHT) was performed by Professor Ch. Barnard in 1967 but it was not until 1980s that this method became an established approach to treatment of patients with end-stage heart failure. Considering the limited number of donor organs and the number of potential post-transplantation complications, the decision to perform heart transplantation at the right time in an indicated patient is difficult and complex. Subsequent pharmacological management with immunosuppressive agents and other medication becomes everyday life reality. Knowledge of drug interactions and collaboration with cardiologists are necessary in order to maintain long-term treatment success. Despite the current developments in surgical methods, examination methods and immunosuppressant therapy, a range of complications has to be dealt with. The future of care for patients with transplants will rely on the development of new immunosuppressive drugs with a minimum of adverse effects and discovery of a non-invasive technique for graft rejection diagnosis.

[Cholesterol levels according to age]. / Hladiny cholesterolu v závislosti na veku.

Cholesterol levels were measured at public places (mostly department stores) from 2005 to 2008. Sampling was conducted at random, from volunteers, without any prior dietary restrictions. In total, 14,539 persons were assessed. We did not find any significant differences between sexes in cholesterol levels (overall median was 5 mmol/l; 4.9 mmol/l in men and 5.1 mmol/l in women). Smaller proportion of women than men had cholesterol levels lower than 5.0 mmol/l (53.0% of men and 45.2% of women). Cholesterol levels raise with age in both sexes, stagnate at a certain point and subsequently decline; we identified a significant difference in this between men and women--the levels start to stagnate at the age of 50 in men and beyond the age of 65-70 years in women. The levels fall with increasing age in both sexes after the age 65 years. Cholesterol levels rise with age in both sexes before the age of 50 years; this trend is the same in both sexes (i.e. there is no significant difference between sexes, p = 0.687). Nevertheless, cholesterol levels are statistically significantly higher in women than in men in the over 55 years age group (the difference in the cholesterol level values median is up to 0.8-0.9 mmol/l). This difference is retained to advanced age of > 75 years.

Genetics of humoral and cytokine activation in heart failure and its importance for risk stratification of patients.

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.