Angiotensin receptor blocker therapy for heart failure patients: is combination treatment a feasible prospect?

BACKGROUND: The addition of the angiotensin II type 1 receptor blocker (ARB) candesartan to a angiotensin-converting enzyme inhibitor (ACEI) has been associated with improved clinical outcomes in patients with heart failure. However many do not tolerate combination therapy and concerns have been raised regarding excessive neurohormonal inhibition. HYPOTHESIS: The majority of patients with chronic heart failure are not eligible or do not tolerate combination therapy with an ACEEI and ARB. METHODS: We prospectively evaluated 115 consecutive patients with heart failure (median age 74 y; 74% males; mean left ventricular ejection fraction 30%) within a district general hospital for eligibility and tolerance to combination therapy using candesartan in addition to recommended doses of an ACEI. RESULTS: Overall, 109 (95%) were ineligible to initiate candesartan. The most frequent reasons were that, despite best efforts at optimization, 77% of patients were unable to achieve recommended doses of an ACEI, 29% were relatively asymptomatic, 20% had symptomatic hypotension, and 35% were already taking an ARB due to previous ACEI "intolerance." Overall, 6 (5%) of patients satisfied the eligibility criteria of whom 3 (3% of total) were already taking "optimal" doses of an ARB in addition to an ACEI. The remaining 3 patients commenced the titration schedule with candesartan. All 3 patients failed the first titration phase (4 mg once daily) within 2 weeks of initiation, due to the development of hyperkalemia. CONCLUSIONS: The use of combination therapy with an ARB in addition to recommended doses of ACEI does not appear feasible in patients with heart failure in the general population, as the vast majority are not eligible.

Massive cardiac invasion by amelanotic melanoma with obstructive clinical features.

Reports of malignant melanoma involving the heart usually describe metastatic spread of pigmented (melanotic) forms of this tumour. We describe, and illustrate, a patient presenting with features related to cardiac tamponade and intracardiac obstruction. Transthoracic echocardiography initially showed a large mass within the right ventricular outflow tract. The full extent of infiltration of this tumour was demonstrated by computed tomography scanning and the specific tumour type by immunohistochemical staining procedures. The case is unusual in relation to the extreme size of this amelanotic melanoma at presentation and the fact that it appears to be a solitary metastasis.

Heart failure in a district general hospital: are target doses of beta-blockers realistic?

BACKGROUND: Carvedilol therapy reduces mortality in patients with chronic heart failure. Multi-centre studies suggest a low first dose failure rate and high levels of tolerability to carvedilol. Little is known, however, concerning the eligibility and tolerance to treatment with carvedilol within a district general hospital setting. AIM: To evaluate the eligibility and tolerance of patients with heart failure to carvedilol within a district general hospital. DESIGN: Prospective clinical audit analysis. METHODS: We assessed 100 heart failure patients eligibility to commence carvedilol therapy. In those who satisfied clinical criteria, we evaluated first dose failure rate, target dose achievement, reasons for intolerance, heart rate and blood pressure reduction and resource requirements over a six-month period. RESULTS: Of 100 patients, 16% had contra-indications to commence carvedilol and 22% were receiving a beta-blocker as part of their existing heart failure therapy. Although 62% satisfied eligibility criteria, 1% refused therapy, thus 61% were initiated on carvedilol. The first dose failure rate was 11.5% and 6.6% of patients achieved 'target dose'. Mean heart rate and systolic blood pressure reductions were 15 (SE 1.2)bpm and 17 (SE 1.7) mmHg, respectively. Resource requirements included 155 hours of work-time for a trained heart failure specialist nurse and doctor. CONCLUSIONS: In the general setting, eligible patients appear to display a high first dose failure rate, poor tolerance to higher doses and achievement of a 'target dose' of carvedilol. Responses to adrenergic blockade were similar to previously published data, irrespective of the final tolerated dose, suggesting that the concept of achieving a 'target dose' may not be clinically useful. Guidelines and treatment protocols for heart failure should reflect not only what is considered gold standard, but also what is practical in general hospitals.

Feasibility and reproducibility of off-line tissue Doppler measurement of regional myocardial function during dobutamine stress echocardiography.

AIMS: Off-line post-processing of colour tissue Doppler from digital loops may allow objective quantification of dobutamine stress echocardiography. We assessed the reproducibility of off-line measurements of regional myocardial velocities. METHODS AND RESULTS: Nine observers analysed 10 studies, each making 2400 observations. Coefficients of variation in basal segments from apical windows, at rest and maximal stress, were 9-14% and 11-18% for peak systolic velocity, 16-18% and 17-19% for time-to-peak systolic velocity, 9-17% and 18-24% for systolic velocity time integral, and 18-23% and 21-27% for systolic acceleration. Coefficients of variation for diastolic velocities in basal segments at rest were 11-40%. Coefficients of variation for peak systolic velocity were 10-24% at rest and 14-28% at peak in mid segments, and 19-53% and 29-69% in apical segments. From parasternal windows coefficients of variation for peak systolic velocity were 14-16% in basal posterior, and 19-29% in mid-anterior segments. High variability makes measurement unreliable in apical and basal anterior septal segments. The feasibility of obtaining traces was tested in 92 subjects, and >90% in all basal and mid segments apart from the anterior septum. CONCLUSION: Quantification of myocardial functional reserve by off-line analysis of colour tissue Doppler acquired during dobutamine stress is feasible and reproducible in 11 segments of the left ventricle. The most reliable measurements are systolic velocities of longitudinal motion in basal segments.

Effects of nitric oxide synthase inhibition on Basal function and the force-frequency relationship in the normal and failing human heart in vivo.

BACKGROUND: Nitric oxide (NO) exerts autocrine/paracrine effects on cardiac function, including alterations of the inotropic state. In vitro studies suggest that NO modulates the myocardial force-frequency relationship. Basal left ventricular (LV) contractility is depressed and the force-frequency relationship is blunted in human heart failure, and it is speculated that an increase in NO production is involved. METHODS AND RESULTS: We compared the effects of intracoronary NO synthase inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 25 micromol/min) on basal LV function and the response to incremental atrial pacing in patients with dilated cardiomyopathy (n=11; mean age, 51 years) and in control subjects with atypical chest pain and normal cardiac function (n=7; mean age, 54 years). In controls, L-NMMA significantly reduced basal LV dP/dt(max) (from 1826 to 1578 mm Hg/s; P<0.002), but had no effect on heart rate, mean aortic pressure, or right atrial pressure. Pacing-induced increases in LV dP/dt(max) were unaltered by L-NMMA. In patients with dilated cardiomyopathy, L-NMMA had no effect on baseline LV dP/dt(max) (from 1313 to 1337 mm Hg/s; P=NS). The blunted pacing-induced rise in LV dP/dt(max) in these patients was unaltered by L-NMMA. CONCLUSION: Endogenous NO has a small baseline positive inotropic effect in the normal human heart, which is lost in heart failure patients. NO does not significantly influence the force-frequency relationship in either the normal or failing human heart in vivo. Because this study was performed in patients with moderate heart failure, whether the findings apply to subjects with more severe heart failure requires further investigation.

Long-term results after aortic valve replacement in patients with congestive heart failure. Homografts vs prosthetic valves.

OBJECTIVES: The aim of this study was to assess the influence of valve substitute (homograft vs prosthetic valve) on the long-term survival and late valve-related complication rates following aortic valve replacement in patients with aortic valve disease and congestive heart failure. BACKGROUND: The effect of choice of valve substitute on outcome after aortic valve replacement in patients with pre-operative heart failure is unknown. The superior haemodynamic profile of homografts may be of particular benefit. METHODS: We retrospectively analysed pre-operative, operative and follow-up data on 518 adults in functional classes III and IV, who, over the 25 years 1969-1993, had their initial aortic valve replacement at Harefield hospital. Follow-up conducted during 1996 to April 1997 and totalling 4439 patient-years was 96.1% complete. Using multivariate analysis, independent risk factors for different complications and mortality were defined. RESULTS: Overall 5-, 10- and 20-year survival was 80+/-2%, 62+/-2% and 30+/-3%, respectively, with no significant difference between valve types. However, homografts (n=381) independently reduced the rate of serious complications and cardiac death, whereas mechanical valves were an independent adverse risk factor for late mortality. The rates of anticoagulant-related bleeding and thromboembolism were increased by mechanical valves, whereas primary tissue failure was the main complication of homografts. CONCLUSIONS: Long-term outcome of homograft aortic valve replacement in patients with congestive heart failure is acceptable, with a reduced rate of serious complications and cardiac death. Further improvements would be expected if the rate of primary tissue failure could be reduced.

Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist.

BACKGROUND: Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its physiological effects on intrinsic myocardial contractile function in humans in vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the failing human heart are also unknown. METHODS AND RESULTS: A specific ET(A) receptor antagonist, BQ123, was infused (40 nmol/min, 16 minutes) into the left coronary artery in 8 patients with atypical chest pain (normal left ventricular ¿LV function and coronary arteries) and 8 patients with nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic catheterization. In normal subjects, BQ123 rapidly induced a significant reduction in LV dP/dt(max) (-270+/-71 mm Hg/s after 16 minutes; P<0.05) and in LV dP/dt at a developed pressure of 40 mm Hg (LV dP/dt(40)) (-179+/-54 mm Hg/s; P<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dt(max) (62+/-49 mm Hg/s after 16 minutes) or LV dP/dt(40) (83+/-51 mm Hg/s;P<0.05 compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation, LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either patient group. CONCLUSIONS: Endogenous ET-1 has a tonic positive inotropic effect in normal subjects, independent of effects on the peripheral vasculature and unmasked by inhibition of ET(A) receptors. However, the effect of short-term ET(A) blockade in DCM patients was opposite to that in normal subjects, which suggests that ET-1 may cause negative inotropic effects in the failing heart.

Primary aortic valve replacement with allografts over twenty-five years: valve-related and procedure-related determinants of outcome.

OBJECTIVES: Allografts offer many advantages over prosthetic valves, but allograft durability varies considerably. METHODS: From 1969 through 1993, 618 patients aged 15 to 84 years underwent their first aortic valve replacement with an aortic allograft. Concomitant surgery included aortic root tailoring (n = 58), replacement or tailoring of the ascending aorta (n = 56), and coronary artery bypass grafting (n = 87). Allograft implantation was done by means of a "freehand" subcoronary technique (n = 551) or total root replacement (n = 67). The allografts were antibiotic sterilized (n = 479), cryopreserved (n = 12), or viable (unprocessed, harvested from brain-dead multiorgan donors or heart transplant recipients, n = 127). Maximum follow-up was 27.1 years. RESULTS: Thirty-day mortality was 5.0%, and crude survival was 67% and 35% at 10 and 20 years. Ten- and 20-year rates of freedom from complications were as follows: endocarditis, 93% and 89%; primary tissue failure, 62% and 18%; and redo aortic valve replacement, 81% and 35%. Multivariable Cox analyses identified several valve- and procedure-related determinants: rising allograft donor age and antibiotic-sterilized allograft for mortality; donor more than 10 years older than patient for endocarditis; rising donor age minus patient age, rising implantation time (from harvest to aortic valve replacement), and donor age more than 65 years for tissue failure; and rising donor age minus patient age, young patient age, rising implantation time, and subcoronary implantation preceded by aortic root tailoring for redo aortic valve replacement. Estimated 10- and 20-year rates of freedom from tissue failure for a 70-year-old patient with a viable valve from a 30-year-old donor and no other risk factors were 91% and 64%; the figures were 71% and 20% if the donor age was 65 years. The rates of freedom from tissue failure for a 30-year-old patient with a 30-year-old donor were 82% and 39%; the figures were 49% and 3% with a 65-year-old donor. Beneficial influences of a viable valve were largely covered by short harvest time (no delay for allografts from brain dead organ donors or heart transplant recipients) and short implantation time. CONCLUSIONS: Primary allograft aortic valve replacement can give acceptable results for up to 25 years. The late results can be improved by the use of a viable allograft, by matching patient and donor age, and by more liberal use of free root replacement with re-implantation of the coronary arteries rather than tailoring the root to accommodate a subcoronary implantation.

Effects of sulphydryl- and non-sulphydryl-containing ACE inhibitors on left ventricular relaxation in the isolated guinea pig heart.

ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (e.g remodelling, diastolic dysfunction). We have previously reported that the ACE inhibitor captopril induces selective left ventricular (LV) relaxant effects in the isolated ejecting guinea pig heart. The aim of the present study was to further investigate the mechanism of the captopril-induced changes in early LV relaxation by comparing the effects of two sulphydryl and two non-sulphydryl containing ACE inhibitors in the same experimental preparation. Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter transducer inserted in the LV cavity. The sulphydryl-containing ACE inhibitors captopril and zofenaprilat enhanced early LV relaxation, whereas the non-sulphydryl-containing ACE inhibitors lisinopril and quinaprilat did not. The effects of captopril and zofenaprilat were attenuated both by the nitric oxide-scavenger haemoglobin and the bradykinin B2-kinin receptor antagonist HOE 140. Neither the oxygen free-radical scavenger superoxide dismutase nor the sulphydryl-containing compound N-acetyl cysteine administered together with lisinopril had any effect on LV relaxation. These data demonstrate that inhibition of intra-cardiac ACE activity may acutely modulate LV relaxation through increased activity of the bradykinin-nitric oxide pathway. The presence of a sulphydryl group on the relevant ACE inhibitor appears to be essential for this LV relaxant effect.

The cardiac endothelium: cardioactive mediators.

Endothelial cells within the heart release a number of substances that modulate myocardial contractile function. These agents include nitric oxide, endothelin, prostanoids, adenylpurines, and other substances that have so far been characterized only in bioassay studies. A notable feature of many of these agents is that they influence contractile behavior predominantly by modifying cardiac myofilament properties rather than altering cytosolic Ca2+ transients. A consequence of this subcellular action is often a disproportionate effect on myocardial relaxation and diastolic tone. The paracrine modulation of cardiac myocyte function by endothelial cell factors is likely to be an important mechanism contributing to the overall regulation of cardiac contractile function, both physiologically and in pathological states.

Enhancement of left ventricular relaxation in the isolated heart by an angiotensin-converting enzyme inhibitor.

BACKGROUND: ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (eg, remodeling, diastolic dysfunction) in experimental studies and in patients. They inhibit the formation of angiotensin II as well as the degradation of endogenous bradykinin. We recently reported that bradykinin induces selective left ventricular (LV) relaxant effects in isolated hearts via the release of nitric oxide. The present study examined the direct effects of interaction between the ACE inhibitor captopril and endogenous bradykinin on cardiac contractile function. METHODS AND RESULTS: Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter. Captopril (1 mumol/L, n = 9) caused a progressive acceleration of LV relaxation without significantly affecting early systolic parameters (eg, LV dP/dtmax) or coronary flow. These effects were inhibited by the nitric oxide scavenger hemoglobin (1 mumol/L, n = 5) or by the B2-kinin receptor antagonist HOE140 (10 nmol/L, n = 5). In the presence of captopril, bradykinin (0.1 nmol/L, n = 6) markedly accelerated LV relaxation (significantly more than captopril alone), whereas bradykinin alone (0.1 nmol/L, n = 6) had no effect. CONCLUSIONS: These data indicate that the ACE inhibitor captopril causes an acute and selective enhancement of LV relaxation independent of changes in coronary flow, probably via an endogenous bradykinin/nitric oxide pathway.