Roger Luccioni

Hyperhomocysteinemia-Induced Vascular Damage in the Minipig Captopril-Hydrochlorothiazide Combination Prevents Elastic Alterations

BACKGROUND Previous attempts in animals failed to reproduce the metabolic, pathological, and clinical situations encountered in homocystinuric patients. Minipigs on a methionine-rich caseinate-based diet, however, have a special long-lasting postprandial plasma accumulation of methionine, the metabolic precursor of homocysteine. We hypothesized that these minipigs develop hyperhomocysteinemia in the long term. Angiotensin-converting enzyme (ACE) inhibition prevents atherogenic alteration of viscoelastic functions of arterial pulsatility and compliance and reduces fragmentation of vascular elastic laminae in the minipigs. We consequently analyzed the therapeutic effects of the captopril-hydrochlorothiazide combination against the typical hyperhomocysteinemia-induced alterations of vascular elastic features. METHODS AND RESULTS Thirty-two Götingen minipigs were randomized as control diet-fed (C), captopril (25 mg/d)/hydrochlorothiazide (12.5 mg/d)-treated C (C+Cp), caseinate-based diet-fed (M), and M+Cp minipigs. After 4 months, M and M+Cp animals had hyperhomocysteinemia (9.64 +/- 4.10 mumol/L, n = 16) compared with C and C+Cp minipigs (5.67 +/- 1.14 mumol/L, n = 16) (P < .05). In the M group, one minipig died from thromboembolic syndrome, and one had pulmonary infarction. M minipigs presented with systolic-diastolic hypertension and extended reactive hyperemia, as well as a mega-artery syndrome in hyperpulsatile arteries due to expanded volumetric compliance, curtailed stiffness, strengthened vascular tension, and prevalence of the viscous wall component. In their arterial tree, hypertrophic endothelial cells covered a thickened subendothelial space. Major elastic lamina dislocations were observed, as well as hypertrophy and reorientation of smooth muscle cells, resulting in the settlement of spreading pathways for medial cells between muscular laminae. In C+Cp and M+Cp animals, serum and lung ACE activity were inhibited by 74% and 40%, respectively. Although the treatment with captopril-hydrochlorothiazide did not modify the hyperhomocysteinemia per se, the therapeutic effects of the drug combination are made evident by the absence of death and ischemic diseases in the M+Cp group. Specifically, the drug combination prevented diastolic hypertension and improved aortic blood flow by normalizing peripheral resistances, abolished the vascular hyperpulsatile characters, and restrained the fragmentation and the splitting of elastic fibers in capacitance arteries. In contrast, the drugs slightly prevented systolic and mean hypertension. In addition, the aortic stiffness and stress response remained altered and vascular smooth muscle cell hypertrophy was still observed in the M+Cp group. CONCLUSIONS In minipigs, the present methionine-rich caseinate-based diet induced hyperhomocysteinemia, which reproduces the metabolic and histopathological situation found in homocysteic patients. Our results show that hyperhomocysteinemia-induced vascular alterations favor the viscous component of the wall rheology to the detriment of the elastic component. Furthermore, they extend to hyperhomocysteinemia the therapeutic effects characteristically shared by ACE inhibitors in association with hydrochlorothiazide against the atherogenic activation of elastinolytic processes.

Current clinical applications of spectral tissue Doppler echocardiography (E/E' ratio) as a noninvasive surrogate for left ventricular diastolic pressures in the diagnosis of heart failure with preserved left ventricular systolic function

Congestive heart failure with preserved left ventricular systolic function has emerged as a growing epidemic medical syndrome in developed countries, which is characterized by high morbidity and mortality rates. Rapid and accurate diagnosis of this condition is essential for optimizing the therapeutic management. The diagnosis of congestive heart failure is challenging in patients presenting without obvious left ventricular systolic dysfunction and additional diagnostic information is most commonly required in this setting. Comprehensive Doppler echocardiography is the single most useful diagnostic test recommended by the ESC and ACC/AHA guidelines for assessing left ventricular ejection fraction and cardiac abnormalities in patients with suspected congestive heart failure, and non-invasively determined basal or exercise-induced pulmonary capillary hypertension is likely to become a hallmark of congestive heart failure in symptomatic patients with preserved left ventricular systolic function. The present review will focus on the current clinical applications of spectral tissue Doppler echocardiography used as a reliable noninvasive surrogate for left ventricular diastolic pressures at rest as well as during exercise in the diagnosis of heart failure with preserved left ventricular systolic function. Chronic congestive heart failure, a disease of exercise, and acute heart failure syndromes are characterized by specific pathophysiologic and diagnostic issues, and these two clinical presentations will be discussed separately.

Comparison of clinical and echocardiographic characteristics of Streptococcus bovis endocarditis with that caused by other pathogens

The aim of our study was to compare the clinical, echographic, and prognostic features of Streptococcus bovis (S. bovis) endocarditis with those caused by other streptococci and pathogens in a large sample of patients with definite endocarditis by Duke criteria, using transesophageal echocardiography. Two hundred six patients (149 men, mean age 57 +/- 15 years) with a diagnosis of infective endocarditis formed the study population. All patients underwent multiplane transesophageal echocardiography and blood cultures. Cerebral, thoracoabdominal computed tomographic scan was performed in almost all patients (95%). All patients with S. bovis endocarditis underwent colonoscopy. Incidence of S. bovis endocarditis in our sample was 19%. Patients with S. bovis endocarditis were older than other groups. Multiple valve involvement, native valves, and large vegetations (>10 mm) were more frequent in patients with S. bovis. There was a significantly higher occurrence of embolism in the S. bovis group. Splenic embolism and multiple embolisms were significantly more frequent in patients with S. bovis. Gastrointestinal lesions, anemia, and spondylitis were observed more frequently with S. bovis endocarditis. In addition to the requirement for gastrointestinal examination for S. bovis endocarditis, our study underlines the need for systematic screening for vertebral and splenic localizations, and suggests the use of early surgery to prevent the high risk of embolism in these patients.

Hypoalbuminemia in elderly patients with acute diastolic heart failure

OBJECTIVES This study evaluated the relative contribution of serum colloid osmotic pressure (COP) lowering and pulmonary artery wedge pressure (PAWP) elevation in the pathogenesis of pulmonary edema in patients with systolic or isolated diastolic heart failure (DHF). BACKGROUND The role of hypoalbuminemia and the resulting low COP have been shown in some patients with acute systolic heart failure (SHF). Colloid osmotic pressure and PAWP were determined in 100 patients with acute heart failure (HF) (56 with DHF and 44 with SHF; mean age, 78 +/- 12 years), in 35 patients with acute dyspnea from pulmonary origin, and in 15 normal controls. Pulmonary artery wedge pressure was estimated using transthoracic Doppler echocardiography. RESULTS Colloid osmotic pressure was significantly lower in the DHF group (20.5 +/- 5 mm Hg) than in the SHF group (24.2 +/- 3.7 mm Hg, p < 0.001), pulmonary disease group (25.1 +/- 4.2 mm Hg, p < 0.001), or normal control group (24.7 +/- 3 mm Hg). Low COP resulted from hypoalbuminemia due to age, malnutrition, and sepsis. Pulmonary artery wedge pressure was significantly higher in patients with SHF (26 +/- 6.3 mm Hg) than in the patients with DHF (20.3 +/- 7 mm Hg, p < 0.001) and was significantly higher in the patients with DHF than in the patients with pulmonary disease (13 +/- 4.2 mm Hg, p < 0.001). The COP-PAWP gradient was similar in patients with SHF (-1.6 +/- 7.1 mm Hg) and patients with DHF (0.7 +/- 6 mm Hg). CONCLUSIONS Frequent hypoalbuminemia resulting in low COP facilitates the onset of pulmonary edema in patients with DHF who usually have lower PAWP than patients with SHF.

Association of mild hyperhomocysteinemia with cardiac graft vascular disease

In non-transplant patients mild hyperhomocysteinemia is an independent risk factor for vascular disease. The aim of this study was to determine whether hyperhomocysteinemia is associated with graft vascular disease. Fasting total plasma homocysteine was assessed in 18 patients with graft vasculopathy and 18 transplanted patients without graft vasculopathy matched for age, sex and the time since transplant. All were on cyclosporin. Graft vasculopathy was defined at coronary angiography as stenoses > or = 25%, or aneurysms. We found that hyperhomocysteinemia ( > or = 15 micromol/l) is common among transplanted heart recipients and significantly more frequent in the patients with graft vasculopathy (17/18 versus 11/18). Accordingly, the mean homocysteinemia was significantly higher in the group with graft vasculopathy (23.6+/-7.8 versus 16.9+/-7.1 micromol/l, P=0.01). The elevation of homocysteine plasma levels in the heart transplant recipients has probably multiple causes. The main cause seems to be renal failure. Additional causes could be azathioprine treatment or genetic polymorphisms. These results suggest that besides the immunological factors, homocysteine can play an additional role in the pathogenesis of graft vascular disease.

Effects of angiotensin-converting enzyme inhibition with perindopril on hemodynamics, arterial structure, and wall rheology in the hindquarters of atherosclerotic mini-pigs

The effects of ACE inhibition with perindopril on the atherosclerosis-induced impairment of arterial flow were investigated via histopathologic studies, hemodynamics, and vascular rheology of hindlimb arteries in 7 adult Pitman-Moore mini-pigs (7 months of age) fed for 4 months with an atherogenic diet and perindopril (at the daily oral dose of 4 mg, which induced a continuous 70% inhibition of serum ACE activity), versus 7 atherogenic and 7 control animals. Major fibroproliferative fatty lesions with medial intimalization were observed in the abdominal aorta. Atherosclerosis impaired the function of both capacitance and resistance hindlimb arteries. In atherogenic mini-pigs, blood pressure (BP) increased significantly due to increased hindlimb peripheral resistance (HPR) and aortic input impedance, although aortic blood flow was not affected. Altered aortic wall rheology revealed that the stiffness of the aorta was markedly increased due to increased wall tension and reduced viscoelasticity, the viscous component being reduced in the arterial wall. Perindopril significantly opposed these alterations by reducing BP, HPR and input impedance and by returning parietal stiffness to control values by increasing aortic compliance. Angiotensin converting enzyme (ACE) inhibition significantly prevented the development of atherosclerosis in the abdominal aorta by decreasing the cross-sectional area of lesions and the presence of lipid-laden cells, as well as by preventing alteration and fragmentation of elastic laminae. In conclusion, ACE inhibition with perindopril showed a significant preventive action on atherosclerosis-induced deleterious effects on vascular wall function and structure in mini-pig arteries.

Effects of folate supplementation in hyperhomocysteinemic pigs.

OBJECTIVES The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia. BACKGROUND We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions. METHODS Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state, 19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four months). CONCLUSIONS In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.

Standard Orthotopic Heart Transplantation Versus Total Orthotopic Heart Transplantation A Transesophageal Echocardiography Study of the Incidence of Left Atrial Thrombosis

BACKGROUND After standard orthotopic heart transplantation (Sd HT), the enlarged resultant atria may promote atrial thrombosis. The purpose of this study was to compare the incidence of spontaneous echo contrast and left atrial thrombosis after Sd HT and total orthotopic (Tot HT) heart transplantation. METHODS AND RESULTS Transesophageal echocardiography (TEE) was performed in 75 patients with Sd HT and in 20 patients with Tot HT. Despite the use of antiplatelet therapy, an acute arterial embolism occurred in 11 (15%) of the 75 patients with Sd HT but in none of the 20 Tot HT patients. All patients were in sinus rhythm. Left ventricular ejection fraction was similar in Sd HT and Tot HT patients. Left atrial diameter was smaller in Tot HT patients than in Sd HT patients (41 +/- 4 versus 58 +/- 6 mm, P < .001). In Sd HT patients, spontaneous echo contrast was present in 43 patients (57%) and was associated with left atrial thrombus in 20 patients (on the left atrial appendage in 12 patients, on the posterior wall in 6, and on the suture in 2). No thrombus was detected by transthoracic echocardiography; all thrombi were detected by TEE. On the other hand, no left atrial thrombus was observed in Tot HT patients, and only 1 patient had spontaneous echo contrast. Of the 11 Sd HT patients who experienced an arterial embolism, 5 had both spontaneous echo contrast and left atrial thrombus and 5 had only spontaneous echo contrast. CONCLUSIONS This study demonstrates a high rate of left atrial thrombus after Sd HT and emphasizes the role of TEE in the follow-up of these patients. The therapeutic implications are the need for a preventive anticoagulant therapy in the high-risk population receiving Sd HT diagnosed with TEE and the consideration of Tot HT as a better surgical approach as far as thrombotic complications are concerned.

Accuracy of tissue Doppler echocardiography in the emergency diagnosis of decompensated heart failure with preserved left ventricular systolic function: comparison with B-type natriuretic peptide measurement.

Background: Tissue Doppler echocardiography provides a reliable noninvasive estimation of left ventricular (LV) filling pressures irrespective of LV ejection fraction. However, the diagnostic accuracy of E/Ea ratio has not been adequately determined in patients with suspected heart failure (HF) with preserved LV systolic function in the acute care setting. Objective: To investigate the accuracy of E/Ea ratio in the emergency diagnosis of decompensated HF with preserved LV systolic function. Methods: Seventy patients with a LV ejection fraction ≥45%, 32 with decompensated HF (77 ± 12 years of age), and 38 with noncardiac cause of acute dyspnea (74 ± 12) were enrolled. B‐type natriuretic peptide (BNP) was measured on admission; lateral, septal and average E/Ea ratios were calculated within 24 hours. Results: Using receiver‐operating characteristic curves to evaluate diagnostic performance, BNP (AUC of 0.875, P < 0.0001) and E/Ea ratios (AUC of 0.90–0.92, P < 0.0001) provided similar accuracy for predicting decompensated HF. Optimal cutoffs were 146 pg/ml for BNP (sensitivity and specificity of 90.6% and 76.3%), 9.8 for lateral E/Ea (83.3% and 88.9%), 12.7 for septal E/Ea (76.7% and 91.4%), and 11.5 for average E/Ea ratio (80% and 94.3%). On multivariate logistic regression analysis, average E/Ea ratio yielded independent additional information to a model based on the clinical judgment and BNP level according to the standard cutoff of 100 pg/ml. Conclusions: Tissue Doppler echocardiography is accurate for predicting decompensated HF with preserved LV systolic function and may be used as a diagnostic complement to inconclusive BNP level in this setting.

Accuracy of Tissue Doppler Echocardiography in the Diagnosis of New-Onset Congestive Heart Failure in Patients with Levels of B-Type Natriuretic Peptide in the Midrange and Normal Left Ventricular Ejection Fraction

Background: Based on the hypothesis that it reflects left ventricular (LV) diastolic pressures, B‐type natriuretic peptide (BNP) is largely utilized as first‐line diagnostic complement in the emergency diagnosis of congestive heart failure (HF). The incremental diagnostic value of tissue Doppler echocardiography, a reliable noninvasive estimate of LV filling pressures, has been reported in patients with preserved LV ejection fraction and discrepancy between BNP levels and the clinical judgment, however, its clinical validity in such patients in the presence of BNP concentrations in the midrange, which may reflect intermediate, nondiagnostic levels of LV filling pressures, is unknown. Methods: 34 patients without history of HF, presenting with acute dyspnea at rest, BNP levels of 100–400 pg/ml and normal LV ejection fraction were prospectively enrolled (17 with congestive HF and 17 with noncardiac cause). Tissue Doppler echocardiography was performed within 3 hours after admission. Results: unlike BNP (P = 0.78), Boston criteria (P = 0.0129), radiographic pulmonary edema (P = 0.0036) and average E/Ea ratio (P = 0.0032) were predictive of congestive HF by logistic regression analysis. In this clinical setting, radiographic pulmonary edema had a positive predictive value of 80% in the diagnosis of congestive HF. In patients without evidence of radiographic pulmonary edema, average E/Ea > 10 was a powerful predictor of congestive HF (area under the ROC curve of 0.886, P < 0.001, sensitivity 100% and specificity 78.6%). Conclusion: by better reflecting LV filling pressures, bedside tissue Doppler echocardiography accurately differentiates congestive HF from noncardiac cause in dyspneic patients with intermediate, nondiagnostic BNP levels and normal LV ejection fraction.