Pharmacokinetics of pentoxifylline and its main metabolites in patients with different degrees of heart failure following a single dose of a modified-release formulation.

Pentoxifylline (PTX) is extensively metabolized in the body, and all its 3 plasma metabolites (M1, M4, M5) are pharmacologically active. The authors evaluated the pharmacokinetics of PTX and its metabolites in 20 patients with chronic heart failure (CHF). Eleven had moderate and 9 severe CHF. The time courses of PTX, M1, M4, and M5 plasma levels were determined after oral administration of a sustained-release 600-mg tablet of PTX, and for each compound, AUC, maximal plasma concentration (C(max)), and time to C(max) (T(peak)) were calculated. Compared with patients with moderate CHF, those with severe CHF showed a significant delay in T(peak) of PTX (3.9 vs 1.6 hours) and M5 (5.6 vs 3.6 hours), a 59% significant increase in M5 AUC, and a 56% nonsignificant increase in PTX AUC. In the whole population, the AUCs of PTX, M4, and M5 were inversely correlated with markers of liver function, whereas the AUCs of M4 and M5 were inversely correlated with the creatinine clearance. In view of the kinetic features of slow-release formulations (flip-flop phenomenon), the delay in T(peak) of PTX in patients with severe CHF compared with moderate CHF should be ascribed to a reduced elimination rate.

In-hospital management of heart failure: in 10 years we have improved, but not enough.

It is well recognized that the majority of patients with heart failure (HF) are admitted to General Medicine Departments (GMDs), and that the recommendations of the international guidelines for the treatment of HF are often incorrectly applied in hospital practice. We evaluated the treatment of patients with HF discharged from a single hospital over a period of 10 years. The study population comprised two series of patients who were discharged from six GMDs of a single hospital with the diagnosis of HF in the first 2 months of 1998 and 2008. The patients were also divided in two groups on the basis of the type of HF, systolic or diastolic. In 10 years, the number of patients who were discharged with the diagnosis of HF increased, the median age rose from 79 to 82 years and diastolic has become the more common type of HF. The prevalence of comorbidities rose significantly. There was an increased use of ACE-inhibitors and betablockers, and a reduction of digoxin and nitrates. The mortality decreased from 16.7% in 1998 to 9.6% in 2008 (p < 0.02) and hospitalizations became shorter (p < 0.05) considering patients with systolic HF (EF ≤ 45%) the median age rose from 74 to 79 years old (p < 0.01). We recorded an increasing use of betablockers, a reduction in the prescription of digoxin. The percentage of Diastolic HF rose from 55.7% in 1998 to 65.0% in 2008 (p < 0.001). The median age of these patients changed from 79 to 82 years old (p < 0.05). In 10 years, the clinical characteristics and management of HF patients who are hospitalized have changed. Pharmacological treatment has improved, but it still remains far from being adequately compliant with guideline recommendations.

HPLC determination of plasma dimethylarginines: method validation and preliminary clinical application.

BACKGROUND: Asymmetric dimethylarginine (ADMA) has been suggested as a possible marker of endothelial dysfunction, and interest in its use in clinical practice is increasing. However, the potential role of symmetric dimethylarginine (SDMA) as an endogenous marker of renal function, has been less widely investigated. The aims of the present study were therefore to determine reference values for dimethylarginines in plasma after method validation, and to ascertain ADMA plasma concentrations in patients with disorders characterized by endothelial dysfunction; a further end-point was to investigate the relationship between SDMA plasma concentrations and estimated GFR (eGFR) as well as plasmatic creatinine in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: HPLC with fluorescence detection was used for the determination of plasma dimethylarginines. To verify the clinical usefulness of ADMA and SDMA, values from 4 groups of patients at a high risk of cardiovascular complications as well renal dysfunction (chronic heart failure n=126; type II diabetes n=43; pulmonary arterial hypertension n=17; chronic kidney disease n=42) were evaluated, and compared with the reference values, obtained from 225 blood donors. RESULTS: The intra- and inter-assay CVs (<5.2%), the absolute and relative recoveries (96-106%) were highly satisfactory. ADMA levels were significantly elevated in all groups of patients compared with controls (p<0.001) with the exception of samples from patients with type II diabetes. SDMA levels were significantly elevated both in the patients with chronic kidney disease and in the patients with type II diabetes complicated by renal insufficiency, the values being closely correlated with both eGFR (R=0.740) and plasmatic creatinine (R=0.700). CONCLUSIONS: The findings made in the present study shows that ADMA levels are significantly increased in patients with diseases associated with endothelial dysfunction This molecule might, therefore, be used as a biochemical marker for the evaluation of endothelial function. Furthermore, the preliminary results reported suggest that SDMA might be a reliable marker of renal function, especially in peadiatric populations, for which the use of eGFR is not recommended.

Pharmacological treatment of chronic systolic heart failure: are we scraping the bottom of the barrel?

Heart failure is a major health problem and its prevalence is growing, primarily as a consequence of the aging of the population. Recently, we have witnessed significant progress in reducing the mortality associated with chronic heart failure due to the introduction of renin-angiotensin-aldosterone system inhibitors, beta-blocking agents and the use of electrical devices. However, the prognosis of heart failure is still so disappointing that it remains the leading cause of death in developed countries. This grim record impels the search for new therapeutic strategies. The objective of this paper is to briefly review the results of some recent trials that have been put in place to test the effects of drugs that are deemed to be potentially capable of improving the prognosis of chronic systolic heart failure patients. Despite compelling theoretical premises, the results to date appear to be weak or even disappointing.

Interleukin-6 and tumor necrosis factor-alpha as biochemical markers of heart failure: a head-to-head clinical comparison with B-type natriuretic peptide.

BACKGROUND: The reliability of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) as biochemical markers of heart failure in comparison to B-type natriuretic peptide (BNP) has not been investigated in depth. AIM: To compare the correlations between IL-6, TNF, BNP plasma concentrations and some clinical and instrumental variables and their prognostic value in heart failure patients. METHODS: In 79 patients with heart failure, the correlations between IL-6, TNF and BNP plasma concentrations and a series of 18 variables were studied. Outcome events were death from any cause and combined death and heart transplantation. RESULTS: At univariate analysis, BNP and IL-6 plasma concentrations correlated with each other (r = 0.4828; P < 0.0001), with New York Heart Association class, fluid retention, left ventricular ejection fraction, mean right atrial pressure, mean pulmonary pressure and cardiac index. All these correlations were stronger with BNP. TNF plasma concentration correlated only with New York Heart Association class and left ventricular ejection fraction.During follow-up, 1-32 months, 14 patients died and nine underwent heart transplantation. At univariate analysis, both BNP and IL-6 plasma concentrations were predictors of death and heart transplantation, but only BNP was a predictor of death; however, only creatinine plasma level was an independent predictor of prognosis. CONCLUSION: IL-6 and TNF are less reliable biochemical markers than BNP in heart failure patients.

Renal dysfunction is a confounder for plasma natriuretic peptides in detecting heart dysfunction in uremic and idiopathic dilated cardiomyopathies.

BACKGROUND: The diagnostic value of natriuretic peptides in uremic cardiomyopathy has not been defined, nor has the effect of a hemodialysis (HD) session on peptides. METHODS: We performed an observational study of 100 white adult outpatients in New York Heart Association class I-II, with neither diabetes nor ischemic heart disease, 50 of whom had idiopathic dilated cardiomyopathy (DCM) and 50 of whom had uremic cardiomyopathy and were undergoing HD. We measured plasma N-terminal proB-type natriuretic peptide (NT-proBNP), BNP, and atrial natriuretic peptide (ANP) both before and after a dialysis session. Doppler echocardiograms were evaluated. We performed multiple regression analysis on the logarithm of peptide concentrations using clinical, laboratory, and echocardio-Doppler data as explanatory variables. RESULTS: Mean peptide concentrations were higher in the HD group, with an HD:DCM ratio of 25 for NT-proBNP and 5 for BNP and ANP. Peptides were correlated with each other (r > 0.85). After HD, NT-proBNP significantly increased by 14%, BNP decreased by 17%, and ANP decreased by 56%. Predialysis concentrations correlated with postdialysis values (r > 0.85). A multiple regression equation significantly fitted the observed peptide concentrations, both pre- and postdialysis, using the same set of 4 variables: disease group (DCM or HD), diastolic pattern, left atrial volume, and body mass index. CONCLUSIONS: Renal dysfunction was a confounder for natriuretic peptides, which were present in higher concentrations in the uremic patients with milder cardiac dysfunction than in those with idiopathic DCM without renal dysfunction. Left diastolic function pattern and atrial volume were cardiac determinants of peptide concentrations in DCM and HD.

Contrast-enhanced cardiovascular magnetic resonance in primary and ischemic dilated cardiomyopathy.

OBJECTIVES: Differentiation between primary dilated cardiomyopathy and ischemic cardiomyopathy has an important clinical significance. Contrast-enhanced cardiovascular magnetic resonance can play a role in this task, identifying myocardial scarring or fibrosis as presence of delayed enhancement. The aim of the present study was to evaluate the diagnostic potential of contrast-enhanced cardiovascular magnetic resonance in differentiating dilated cardiomyopathy from ischemic cardiomyopathy. METHODS: Contrast-enhanced cardiovascular magnetic resonance was performed in 100 patients with left ventricular dilatation and reduced systolic function: 24 had normal coronary arteries (dilated cardiomyopathy group) and 76 had significant coronary artery disease (ischemic cardiomyopathy group), with or without previous myocardial infarction. RESULTS: In the dilated cardiomyopathy group, only seven (29%) patients showed delayed enhancement and its pattern was characterized by mid-wall, patchy or diffuse location. All patients with ischemic cardiomyopathy and prior myocardial infarction (54 subjects) showed delayed enhancement with subendocardial (n = 4) or transmural (n = 50) extension. Among the 22 patients with ischemic cardiomyopathy but without previous myocardial infarction, 13 (59%) showed either subendocardial (n = 4) or transmural (n = 9) delayed enhancement. CONCLUSIONS: Patterns of delayed enhancement are different in dilated cardiomyopathy and ischemic cardiomyopathy, reflecting the presence of scarring or various degrees of fibrosis in left ventricular myocardium. The presence of subendocardial or transmural delayed enhancement at contrast-enhanced cardiovascular magnetic resonance allowed distinction between dilated cardiomyopathy and ischemic cardiomyopathy with high sensitivity (88%) and specificity (100%). Integration of cardiovascular magnetic resonance results with angiographic information can be useful in the identification of pathogenic mechanisms underlying left ventricular dysfunction.

Cystatin C in heart failure is nothing more than a bystander of glomerular filtration.

BACKGROUND: Cystatin is an ubiquitous protease inhibitor involved in degradation of cellular proteins and has recently been associated with increased risk of cardiovascular disease and heart failure independent of renal function. We tested whether cystatin in heart failure is only associated with renal function or also with echocardio-Doppler parameters and factors of myocardial remodeling (C-reactive protein, endothelin, and natriuretic peptides). METHODS: This was an observational study conducted in 100 adult Caucasian outpatients with NYHA class I-II heart function without diabetes and ischemic heart, 50 with idiopathic dilated cardiomyopathy (DCM) and 50 with uremic cardiomyopathy undergoing hemodialysis (HD). Multiple linear regression analysis was performed on cystatin concentration using clinical, laboratory (creatinine, high sensitivity C-reactive protein, endothelin, B-type natriuretic peptide [BNP]) and echocardio-Doppler data as explanatory variables. RESULTS: The heart was more severely involved in DCM patients (worse ejection fraction, diastolic volume index, index of myocardial performance, left ventricular mass index). Mean values of cystatin, creatinine, BNP and C-reactive protein in HD compared with DCM patients were 6, 9, 5 and 3 times higher, respectively. Mean values of endothelin were comparable in both groups. Cystatin significantly correlated with creatinine in both groups (r=0.50 in DCM and r=0.37 in HD, and r=0.95 in pooled groups). In the multiple regression analysis, only disease group and creatinine within groups were significant independent factors that accounted for 94% of the variability of cystatin. CONCLUSION: Renal function was the determinant of cystatin in a concentration range of 6 times regardless of severity of heart involvement.

Evidence for decreased circulating apelin beyond heart involvement in uremic cardiomyopathy.

BACKGROUND: Plasma apelin concentration in heart failure has been described in small studies reporting conflicting results. In hemodialysis (HD) patients, apelin decreased more in those with more severe heart involvement. It is unclear if uremia is connected to this reduction irrespective of heart failure. We compared apelin in two cardiomyopathies with different renal function. METHODS: Observational study conducted in 30 adult Caucasian outpatients in class I NYHA not affected by diabetes or ischemic heart, 15 with idiopathic dilated cardiomyopathy (DCM) and 15 with uremic dilated cardiomyopathy undergoing HD. Plasma apelin, creatinine, high-sensitivity C-reactive protein, endothelin, NT proB-type natriuretic peptide (NT-proBNP), and Doppler echocardiogram were evaluated. RESULTS: Heart involvement was more severe in the DCM patients (lower ejection fraction, greater diastolic volume index, and worse index of myocardial performance). Median value of apelin in HD patients (19.1 pg/ml) was one third of that in DCM patients (58.2 pg/ml) whereas creatinine, NT-proBNP, and C-reactive protein were 11, 80, and 9 times higher respectively in HD than in DCM patients. Median values of endothelin were comparable in both groups. Apelin was not significantly correlated with any variable. CONCLUSION: Uremic status was the determinant for decreased plasma apelin in HD patients regardless of the severity of heart involvement.

Correlations between clinical presentation, brain natriuretic peptide, big endothelin-1, tumor necrosis factor-alpha and cardiac troponins in heart failure patients.

BACKGROUND: The term "biochemical marker" of heart failure is used to define a biochemical substance whose plasma levels correlate with the clinical and hemodynamic status and predict the prognosis of patients with heart failure. The aim of this study was to prospectively evaluate, in a single population of patients with heart failure, the correlations between the plasma levels of brain natriuretic peptide (BNP), big endothelin-1 (BET-1), tumor necrosis factor-alpha (TNF-alpha), cardiac troponin I (cTnI) and T (cTnT), the clinical presentation, and the left ventricular function. METHODS: The study population included a series of 120 patients (97 males, 81%, mean age 56+/-12 years) in NYHA functional class I (49%), II (20%), III (26%), IV (5%) who were admitted to our institution or followed up as outpatients. All patients underwent cardiologic evaluation, standard electrocardiography, two-dimensional echocardiography, and venous blood sampling on the same day. RESULTS: At univariate analysis the following correlations were found to be significant: all the laboratory parameters correlated with the NYHA class (BNP r = 0.63, BET-1 r = 0.56, cTnI r = 0.25, cTnT r = 0.24, TNF-alpha r = 0.23); BNP (r = -0.39) and BET-1 (r = -0.27) with left ventricular ejection fraction; BNP (r = 0.37) and BET-1 (r = 0.21) with the degree of mitral insufficiency; BNP (r = -0.39), BET-1 (r = 0.25) and TNF-alpha (r = -0.19) with systolic blood pressure; cTnT (r = 0.34), cTnI (r = 0.33), BNP (r = 0.22) and BET-1 (r = 0.19) with heart rate; BNP with age (r = 0.33) and body mass index (r = -0.28). The plasma levels of BNP, BET-1, cTnT and cTnI were significantly higher in case of systemic or pulmonary congestion. At multiple regression analysis the following correlations were still present: BNP with the NYHA functional class (p < 0.005) and with pulmonary venous congestion (p < 0.05); BET-1 with the presence of pulmonary venous congestion (p < 0.005); TNF-alpha with the NYHA class (p < 0.05) and systolic blood pressure (p < 0.001); cardiac troponins with heart rate (p < 0.05). CONCLUSIONS: The plasma concentrations of BNP and BET-1 showed the best and comparable correlations with parameters describing the clinical status of patients with heart failure, in particular with the presence of pulmonary venous congestion. The value of the plasma concentration of TNF-alpha and those of cardiac troponins were found to be limited in patients with relatively stable heart failure.

Effects of carvedilol on ventriculo-arterial coupling in patients with heart failure.

BACKGROUND: Ventriculo-arterial coupling, defined as the ratio of the effective afterload (Ea) to contractility (Ees), reflects the mechano-energetic performance of the heart and is increased in chronic heart failure (CHF); the aim of treatment is to reduce its value. We studied the effect of carvedilol on the Ea/Ees ratio in patients with CHF treated with ACE-inhibitors, diuretics, and digoxin. METHODS: Between November 1999 and October 2001, 36 consecutive ambulatory patients (aged 31 to 76 years) with stable CHF and idiopathic or hypertensive cardiomyopathy, in sinus rhythm and with a left ventricular ejection fraction < or = 40%, were started on carvedilol and the dose was increased to the maximum tolerated. Ees was calculated as the left ventricular systolic pressure--taken as the systolic arterial pressure measured using the cuff manometer simultaneously with two-dimensional echocardiographic recordings--divided by the left ventricular end-systolic volume. Ea was measured as the ratio of the left ventricular systolic pressure to the stroke volume. All patients were investigated prospectively after 6 and 12 months of treatment. RESULTS: Out of 36 patients, 4 did not tolerate the drug and were dropped out. At 6.35 +/- 1 months, the daily dosage of carvedilol was 49.7 +/- 21 mg. The NYHA functional class improved from 1.52 +/- 0.67 to 1.29 +/- 0.53 (p = 0.017), the heart rate markedly diminished from 73.6 +/- 13.3 to 60.8 +/- 10.8 b/min (p < 0.001) and so did Ea (3.35 +/- 0.91 to 2.84 +/- 0.93, p = 0.001). Peripheral resistances and Ees did not change. Therefore, the decrease in the Ea/Ees ratio (2.61 +/- 0.78 vs 2.19 +/- 0.89, p = 0.004) and the related increase in left ventricular ejection fraction (28.8 +/- 5.68 vs 33.3 +/- 7.5%, p < 0.001) were due to the decrease in Ea, while Ees did not vary significantly. Moreover, the Ea reduction was related linearly to the decrease in heart rate (r = 0.46, p = 0.001). There was no change in diuretic or ACE-inhibitor dosing during carvedilol titration. At 14.7 +/- 2 months of follow-up, no further variation occurred, short of a trend toward a slight increase in Ees (1.38 +/- 0.49 to 1.58 +/- 0.65, p = 0.07). CONCLUSIONS: Carvedilol, added to the conventional therapy of CHF, improves left ventricular performance and reduces the Ea/Ees ratio by decreasing Ea, mainly through a reduction in heart rate. This effect is already evident at 6 months and persists later on, while only after 12 months does Ees tend to increase slightly.

Overexpression of tumor necrosis factor (TNF)alpha and TNFalpha receptor I in human viral myocarditis: clinicopathologic correlations.

Proinflammatory cytokines, including tumor necrosis factor (TNF)alpha, have been recognized as important physiopathogenetic factors in the initiation and continuation of inflammatory cardiomyopathies. Experimental and preliminary human studies have demonstrated that TNFalpha plays a crucial role in enteroviral-induced myocarditis. In this study, we investigated the expression of TNFalpha and both its receptors (TNFRI and TNFRII) in both viral and nonviral myocarditis. Myocardial expression of TNFalpha was then correlated with different clinical and pathologic findings. TNFalpha expression was investigated in endomyocardial biopsies obtained from 38 patients with myocarditis and from eight control subjects by using reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry. Viral etiology was diagnosed by PCR in 20 cases: enterovirus in seven, Epstein-Barr virus in four, hepatitis C virus in three, adenovirus in two, influenza virus in two, cytomegalovirus in one, and double infection adenovirus and enterovirus in one. Immunohistochemistry was also used to analyze both TNFalpha receptors (RI and RII). A semiquantitative analysis was employed (score 0-3) for necrosis, inflammation, fibrosis and immunohistochemical findings. TNFalpha mRNA and TNFalpha protein were significantly more present in viral myocarditis than in nonviral myocarditis (16/20 vs 3/18, P=0.001). Remarkable immunostaining was observed for both receptors, particularly TNFRI. Histological analysis revealed that myocardial necrosis (mean score 1.89 vs 1.15, P=0.01) and cellular infiltration (mean score 2.26 vs 1.78, P=0.05) were more prominent in TNFalpha-positive cases. Among TNFalpha-positive cases, the greater TNFalpha mRNAs, the more impaired was cardiac function. Our findings suggest that the expression of TNFalpha may play an important role in the pathogenesis of viral myocarditis of any etiology and may influence the severity of cardiac dysfunction. Cytokine effects are more strictly linked to overexpression of TNFRI.

Plasma levels of tumor necrosis factor-alpha correlate with the six-minute walk test results in patients with mild to moderate heart failure.

BACKGROUND: The plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins have been reported to correlate with the severity of heart failure. METHODS: In a single population of 80 outpatients with mild to moderate chronic heart failure the correlation between the patient's functional capacity, as evaluated at a 6-min walk test, the clinical parameters and plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins was evaluated. RESULTS: A significant inverse correlation was found with the patient's age (p < 0.0001), NYHA functional class (p < 0.0001), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.0005), heart rate (p < 0.05), plasma levels of brain natriuretic peptide (p < 0.05) and of tumor necrosis factor-alpha (p < 0.0005). At multiple regression analysis a correlation was found between the 6-min walk test results and the patient's age (p < 0.05), NYHA functional class (p < 0.01), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.05) and tumor necrosis factor-alpha plasma levels (p < 0.05). CONCLUSIONS: In our patients with mild to moderate heart failure, a significant correlation was found between the results of the 6-min walk test and only the plasma concentrations of tumor necrosis factor-alpha among the laboratory parameters analyzed in this study.

Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications.

Myocarditis is the most common cause of heart failure in children. We investigated viral etiology of myocarditis/dilated cardiomyopathy (DCM) in children and correlated molecular findings with pathologic and clinical data. Polymerase chain reaction (PCR) or reverse transcription (RT)-PCR were used to analyze 59 endomyocardial biopsies from 48 consecutive young (<18 yrs) patients (pts) with clinical and histologic diagnosis of myocarditis and DCM, employing primers designed to amplify specific sequences of various DNA and RNA viruses. Nucleic acids were successfully extracted in 41 pts and viral genomes were found in 20 (49%): 12 out of 26 pts (46%) with myocarditis, 6 out of 13 (46%) pts with DCM, and both patients with endocardial fibroelastosis. Enteroviruses were more common in DCM (72%), whereas adenoviruses and enteroviruses shared the same rate (36%) in myocarditis. The mumps virus genome was detected in the two pts with endocardial fibroelastosis. More diffuse inflammatory infiltrates and myocyte damage as well as more impaired left ventricular end diastolic volume and shortening fraction were noted in viral positive cases. PCR positive pts had a worse outcome, resulting in transplantation or death. Three out of 8 pts with viral myocarditis who underwent cardiac transplantation had recurrent PCR-proven graft viral infection. Viral myocarditis/DCM appeared to be a more severe disease than nonviral forms. Enteroviruses were more common in DCM, whereas adenoviruses were as frequent as enteroviruses in myocarditis. Persistence of viral infection was associated with disease deterioration. Viral myocarditis relapsed after transplantation.