Gabor Sütsch

Isolated Noncompaction of the Myocardium in Adults

OBJECTIVE To describe the entity of isolated ventricular noncompaction (IVNC) and present a series of cases of this rare disorder in an adult population. MATERIAL AND METHODS We review a 10-year experience with the diagnosis of IVNC and discuss the clinical, echocardiographic, and pathologic features of this condition. Echocardiographic diagnostic criteria included the absence of coexisting cardiac abnormalities, the presence of prominent and excessive trabeculations of one or more ventricular wall segments, and intertrabecular spaces perfused from the ventricular cavity. Pathologic examination focused on regions with exaggerated trabeculations and deep intertrabecular spaces. RESULTS IVNC is an unexplained arrest of myocardial morphogenesis previously encountered mainly in pediatric patients. Among 37,555 transthoracic echocardiographic studies performed at our hospital between January 1984 and October 1993, 17 cases of IVNC were identified in adult subjects (14 men and 3 women, 18 to 71 years of age). The mean time from onset of symptoms to correct diagnosis was 3.5 +/- 5.7 years, and the mean duration of follow-up was 30 +/- 28 months. Common clinical symptoms were heart failure, ventricular arrhythmias, and a history of embolic events. Two-dimensional echocardiography revealed 10 patients with left ventricular and 7 (41%) with biventricular IVNC. During a 6-year follow-up period, eight patients died and two underwent heart transplantation. CONCLUSION Although the diagnosis of IVNC in an adult population is often delayed because of similarities with more frequently diagnosed conditions, two-dimensional echocardiography will facilitate the diagnosis of IVNC in this subset of patients. Because of the high incidence of heart failure, ventricular arrhythmias, and embolization in adults with IVNC, early diagnosis is important.

Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure

Heart failure is commonly associated with high plasma concentrations of endothelin-1, a powerful vasoconstrictor produced by endothelium. The role of endogenously released endothelin-1 in the maintenance of vascular tone in chronic heart failure was assessed by acute administration of an endothelin receptor antagonist, bosentan. 24 patients with chronic heart failure received randomly and double blind two intravenous infusions of either placebo or bosentan (100 mg followed after 60 min by 200 mg). Systemic haemodynamics and plasma endothelin-1 and big-endothelin-1 concentrations were determined before and repeatedly during the 120 min observation period. Baseline endothelin-1 and big-endothelin-1 concentrations, which were above the normal range in all patients, correlated directly with the extent of pulmonary hypertension, with left and right heart filling pressures, and with pulmonary vascular resistance and inversely with cardiac index. Compared with placebo, bosentan reduced mean arterial pressure by 7.7% (95% CI 7.1-9.7), pulmonary artery pressure by 13.7% (10.5-16.9), right atrial pressure by 18.2% (12.0-24.4), and pulmonary artery wedged pressure by 8.6% (5.3-12.0); it increased cardiac index by 13.6% (9.1-18.2), decreased systemic vascular resistance by 16.5% (13.2-19.8), and decreased pulmonary vascular resistance by 33.2% (22.4-44.0). Heart rate did not change. Plasma endothelin-1 concentrations rose more than twofold from baseline in bosentan recipients while big-endothelin-1 concentrations were unchanged. These findings indicate that, in patients with chronic heart failure who have high circulatory endothelin-1 concentrations, this peptide contributes to maintenance of vascular tone. The acute haemodynamic effects of bosentan suggest that chronic endothelin antagonism could be beneficial in such patients.

Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure

BACKGROUND The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown. METHODS AND RESULTS Thirty-six men (mean age+/-SD, 55+/-8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4+/-4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15. 2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged. CONCLUSIONS Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.

Inflammatory Markers at the Site of Ruptured Plaque in Acute Myocardial Infarction Locally Increased Interleukin-6 and Serum Amyloid A but Decreased C-Reactive Protein

Background—Acute myocardial infarction (AMI) is associated with inflammation. However, it remains unclear whether it originates from the ruptured plaque or represents a systemic process. Methods and Results—In 42 patients with AMI, a balloon-based embolization protection device and aspiration catheter (PercuSurge) were used during acute coronary interventions. Samples from the site of the ruptured plaque were taken under distal balloon occlusion. Systemic samples were taken from the aorta. Sera, plaques, and thrombi were analyzed for inflammatory markers and lipoproteins. Systemic levels of C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) in the aorta amounted to 3.0 mg/L, 5.0 ng/L, and 22.1 mg/L, respectively (interquartile ranges [IQRs], 1.1 to 7.4 mg/L, 5.0 to 6.5 ng/L, and 13.9 to 27.0 mg/L, respectively). In blood surrounding ruptured plaques, local levels of IL-6 (8.9 ng/L; IQR, 5.0 to 16.9 ng/L) and SAA (24.3 mg/L; IQR, 16.3 to 44.0 mg/L) were significantly higher, whereas CRP levels (2.5 mg/L; IQR, 0.9 to 7.7 mg/L) were decreased compared with the aorta (all P<0.0001). The coronary levels of IL-6 determined in vivo showed biological activity in vitro. Harvested thrombus contained CD68-positive monocytes expressing IL-6 and showed extracellularly and intracellularly positive staining for SAA, whereas CRP was found exclusively in the cytoplasm of phagocyting white blood cells. Conclusions—Coronary levels of IL-6 and SAA at the site of plaque rupture were increased relative to the systemic circulation, indicating local production of biologically active inflammatory mediators. In contrast, CRP was locally decreased, at least in part by uptake by the phagocyting cells, suggesting a systemic origin of the protein.

Comparison of Costs and Safety of a Suture-Mediated Closure Device With Conventional Manual Compression After Coronary Artery Interventions

The aim of this study was to assess costs and safety of immediate femoral sheath removal and closure with a suture‐mediated closure device (Perclose, Menlo Park, CA) in patients undergoing elective (PCI). A total of 193 patients was prospectively randomized to immediate arterial sheath removal and access site closure with a suture‐mediated closure device (SMC; n = 96) or sheath removal 4 hr after PCI followed by manual compression (MC; n = 97). In the SMC group, patients were ambulated 4 hr after elective PCI if hemostasis was achieved. In the MC group, patients were ambulated the day after the procedure. In addition to safety, total direct costs including physician and nursing time, infrastructure, and the device were assessed in both groups. Total direct costs were significantly (all P < 0.001) lower in the SMC group. Successful hemostasis without major complication was achieved in all patients. The time to achieve hemostasis was significantly shorter in the SMC group (7.1 ± 3.4 vs. 22.9 ± 14.0 min; P < 0.01) and 85% of SMC patients were ambulated on the day of intervention. Suture‐mediated closure allows a reduction in hospitalization time, leading to significant cost savings due to decreased personnel and infrastructural demands. In addition, the use of SMC is safe and convenient to the patients. Cathet Cardiovasc Intervent 2002;57:297–302.

Left ventricular function in chronic mitral regurgitation: Preoperative and postoperative comparison

OBJECTIVES The present study was designed to evaluate the effects of surgical procedure on left ventricular systolic and diastolic function in patients with mitral regurgitation. BACKGROUND Left ventricular systolic function has been shown to decline after operation in patients with chronic mitral regurgitation. METHODS Using simultaneous cineangiography and left ventricular micromanometry, we evaluated left ventricular systolic and diastolic function in 14 patients with chronic mitral regurgitation both preoperatively and at an average of 22 months after operation. Eight patients underwent mitral valve reconstruction, and six had a valve replacement with interruption of the chordae tendineae. We compared these patients with 10 control subjects. RESULTS Preoperatively, patients with mitral regurgitation demonstrated normal global and regional left ventricular systolic function. Peak rate of diastolic filling was increased (p < 0.01), and passive chamber stiffness was decreased, compared with that in control subjects (p < 0.01), and there was normal myocardial stiffness. Postoperatively, systolic and diastolic function returned to normal in patients undergoing mitral valve reconstruction. In contrast, global systolic function was depressed in patients after valve replacement (p < 0.05), with regional dysfunction in the area of papillary muscle attachment (p < 0.01). Diastolic function was depressed in this group, with a prolonged time constant of pressure decay (p < 0.01) and a depressed rate of early diastolic filling and strain rate (p < 0.05). Passive elastic stiffness was within the normal range in all postoperative patients. CONCLUSIONS The type of operation performed to correct chronic mitral regurgitation has an important effect on postoperative left ventricular function. Systolic and diastolic function are preserved after mitral valve reconstruction. Mitral valve replacement with chordal interruption is associated with global and regional systolic dysfunction and early diastolic filling and relaxation abnormalities.

Acute and short-term effects of the nonpeptide endothelin-1 receptor antagonist bosentan in humans

SummaryIn recent years, evidence from various animal experiments has accumulated that emphasizes the role of endothelin-1 in the pathophysiology of several cardiovascular diseases, including congestive heart failure. The recent advent of potent antagonists of this system now allows the assessment of the involvement of endothelin-1 in the maintenance of vascular tone in animals and humans. We report hemodynamic data from two trails in patients with chronic severe congestive heart failure (i.e., reduced left ventricular ejection fraction of <30%, elevated resting pulmonary capillary wedged pressure >15 mmHg, and/or reduced cardiac index of 2.5 L/min/m2 or less) who were treated with the mixed endothelin-type A and type B-receptor antagonist bosentan. In the first study, the acute effect of bosentan (300 mg, intravenous) on hemodynamics and neurohormones was investigated. Bosentan was well tolerated and significantly improved impaired hemodynamics due to systemic and venous vasodilation. In the second trial, bosentan was given orally (0.5 g bid) for 14 days, in addition to conventional triple treatment for congestive heart failure, including digitalis, angiotensin-converting enzyme inhibitors, and diuretics. Cardiac hemodynamics were monitored during the first 24 hours of treatment, and measurements were repeated during the last day of bosentan therapy. Bosentan was well tolerated in these patients as well, and hemodynamic measures were compatible with an additional effect of bosentan after 2 weeks. However, there was a slight increase in heart rate as well. Our result underline the importance of endogenously generated endothelin-1 in congestive heart failure and suggest a potential benefit of endothelin antagonism in such patients. However, long-term studies are needed to establish whether chronic endothelin antagonism has beneficial clinical effects and is capable of improving survival and/or symptoms in severe heart failure patients who remain symptomatic despite standard triple therapy.

Effect of diltiazem on coronary flow reserve in patients with microvascular angina.

Microvascular angina is characterized by ischemia-like symptoms in patients with normal coronary arteries and reduced coronary flow reserve. Clinical observations suggested an improvement in clinical symptomatology and exercise tolerance after treatment with calcium antagonists. The effect of diltiazem on coronary flow reserve was evaluated in controls and in patients with microvascular angina. Coronary flow reserve was measured in 16 normotensive patients (7 females, 9 males, mean age 51 +/- 10 years) with angiographically normal coronary arteries. Coronary blood flow was determined at rest, after dipyridamole (0.5 mg/kg) and following intravenous administration of diltiazem (10 mg) using coronary sinus thermodilution technique. Coronary flow reserve was calculated as coronary blood flow after dipyridamole divided by coronary blood flow at rest. Patients with normal coronary flow reserve (coronary flow reserve > 2.0) received either dipyridamole alone (group 1, controls, n = 6) or dipyridamole and diltiazem (group 2, n = 5), whereas patients with reduced coronary flow reserve (coronary flow reserve < 2.0) obtained dipyridamole and diltiazem (group 3, n = 5). Resting coronary flow was identical in the three groups, but after maximal vasodilation with dipyridamole, coronary flow increased significantly more in groups 1 and 2 than in group 3 (P < 0.05, analysis of variance (ANOVA)). Coronary flow reserve was 2.5 in group 1 and 2.3 in group 2, but was significantly reduced in group 3 (1.3; P < 0.05, ANOVA). Intravenous diltiazem failed to increase coronary blood flow in groups 2 and 3. Therefore, diltiazem does not improve reduced coronary flow reserve in patients with microvascular angina, but leaves coronary flow reserve unaffected. The failure to ameliorate impaired coronary flow reserve with diltiazem is in contrast to the reported clinical improvement after calcium channel blockade in these patients. Thus, other factors such as structural abnormalities in the microcirculation or functional abnormality in smooth muscle relaxation not responsive to calcium channel blockade are probably responsible for the occurrence of myocardial ischemia in patients with microvascular angina.

Regulation of aldosterone secretion in patients with chronic congestive heart failure by endothelins.

We studied acute (day 1) and long-term (day 14) effects of endothelin (ET) receptor blockade with the mixed ET(A/B) antagonist bosentan (1 g twice daily; n = 18) or placebo (n = 12) on plasma angiotensin II and aldosterone in 30 patients with symptomatic chronic heart failure taking angiotensin-converting enzyme inhibitors, diuretics, and digoxin. Hormones were determined before and 3 hours after morning doses of diuretics and digoxin and the double-blind study drug, respectively, on days 1 and 14. On day 1, angiotensin II increased from 16.1+/-17.9 to 27.6+/-5.6 ng/L (p <0.05) with bosentan and similarly with placebo (15.5+/-9.3 and 36.0+/-49.1 ng/L, p = 0.06) after the morning dose of diuretics and digoxin. Aldosterone tended to increase from 322+/-239 to 362+/-254 pmol/L (bosentan) and from 271+/-70 to 297+/-136 pmol/L (placebo). On day 14, before drug intake, angiotensin II was unchanged compared with day 1 in both groups. However, aldosterone was lower than on day 1 with bosentan (213+/-124 vs. 322+/-239 pmol/L, p<0.05) and remained below baseline values 3 hours after drug intake, whereas it was unchanged with placebo. Thus, short-term ET(A/B) receptor antagonism decreases basal aldosterone secretion independently of angiotensin II, suggesting that ET participates in the regulation of aldosterone in patients already treated with angiotensin-converting enzyme inhibitors and diuretics.

Cyclosporine A and control of vascular tone in the human forearm: influence of post-transplant hypertension.

OBJECTIVE The use of cyclosporine A after organ transplantation is associated with a high incidence of hypertension, but the underlying mechanisms for this process are not clear. We investigated the effects of blockade of basal release of endothelial nitric oxide and the effects of endothelium-independent and -dependent vasodilators and vasoconstrictors in patients treated with cyclosporine A after heart transplantation. DESIGN We measured blood pressure and forearm blood flow responses to brachial artery infusions of NG-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine, norepinephrine and vasodilating and vasoconstricting doses of endothelin-1 in eight patients early (< 3 months) and in 11 patients late (> 18 months) after transplantation. RESULTS Diastolic blood pressure was higher late after transplantation, but calculated forearm vascular resistance was lower (P < 0.01). Thus, increased forearm vascular resistance does not contribute to the increase in blood pressure. The vasoconstrictor response to L-NMMA was similar in both groups but a reduced endothelium-dependent vasodilator response to acetylcholine was seen late after transplantation. However, impaired smooth muscle responsiveness to nitric oxide may have contributed to this finding, since the response to sodium nitroprusside tended to be reduced. Vasoconstrictor responses to norepinephrine and endothelin-1 were comparable but no vasodilation was seen with low doses of endothelin-1 late compared with early after transplantation (P < 0.05). CONCLUSIONS The findings in the forearm circulation question the concept of generalized increases in vasoconstrictor responses or a disturbance of tonic, basal release nitric oxide in the pathogenesis of cyclosporine-A-induced hypertension. Although the forearm vasodilator responses to the stimulation of endothelial nitric oxide production and release by acetylcholine, and to low doses of endothelin-1, were impaired, these findings could be explained by the increase in blood pressure rather than cyclosporine A itself.