Outcome of cryoballoon ablation for atrial fibrillation. Medium-term follow-up from a single center.

OBJECTIVE: We analyzed the medium-term follow-up of cryoballoon ablation (CBA) for atrial fibrillation (AF) and the clinical risk factors predicting outcome. METHODS: AF patients treated for the first time with CBA in a 4.5-year period were studied retrospectively. Pulmonary vein isolation (PVI) was achieved via a single cryoballoon with diameter of 28 mm. Left atrial diameter (LAD) was measured by transthoracic echocardiography. Failure of cryoablation treatment was defined as detection of an episode of AF, atrial flutter, or atrial tachycardia lasting more than 30 s during the 3-month follow-up. RESULTS: A total of 212 patients were enrolled and in 87.7 % patients PVI was achieved by CBA. The complication rate was 2.83 %. The mean follow-up was 28 ± 15 months; in 166 patients follow-up was complete. The rate of successful treatment for primary CBA was 45.8 %. The percentage of patients who experienced atrial arrhythmia recurrence in the first 12 months was 84.44 %. Patients in whom treatment failed had a larger LAD (47 ± 6 mm vs. 43 ± 5 mm, p < 0.0001). The Kaplan-Meier curve showed that the patients with LAD < 45 mm had a higher success rate than patients with LAD ≥ 45 mm [57.9 % (44/76) vs. 35.6 % (32/90), log rank = 5.492, p = 0.019]. The LAD [odds ratio, OR = - 0.1053(0.303, 12.2040), p = 0.0005] was shown in logistic regression analysis to be independently predictive of CBA treatment failure. CONCLUSION: The CBA procedure for AF patients is safe and effective. Most atrial arrhythmia recurrences occurred during the first 12 months after CBA. The LAD can independently predict failure of CBA treatment.

Comparison of acquisition time and dose for late gadolinium enhancement imaging at 3.0 T in patients with chronic myocardial infarction using Gd-BOPTA.

OBJECTIVES: To compare contrast doses and acquisition times for late gadolinium enhancement (LGE) imaging at 3.0 T using gadobenate dimeglumine (Gd-BOPTA) in patients with chronic myocardial infarction. METHODS: Thirty-four patients with chronic myocardial infarction were randomised to 0.10, 0.15 and 0.20 mmol/kg of Gd-BOPTA. T1-weighted inversion recovery gradient echo sequences were performed at 5, 10, 15 and 20 min post-administration of contrast in a 3.0-T scanner. Scar-to-myocardium contrast-to-noise ratio (CNR), scar-to-blood CNR, scar size and image quality were assessed. RESULTS: Imaging at 5 min was associated with a lower scar-to-blood CNR in comparison to 10, 15 and 20 min at 0.10 mmol/kg, and in comparison to 15 and 20 min at 0.20 mmol/kg. At 0.10-mmol/kg, imaging at 5 min yielded smaller infarct sizes in comparison to 15 and 20 min. Finally, at 0.20-mmol/kg, imaging at 5 min was associated with poorer image quality in comparison to later times. CONCLUSIONS: In LGE imaging at 3.0 T, low doses of Gd-BOPTA perform equally well as higher doses. Early acquisition (5 min) is associated with lower infarct sizes and image quality. Studies with sufficient diagnostic quality can be obtained after 10 min using 0.10 mmol/kg Gd-BOPTA. KEY POINTS: Good performance of low Gd-BOPTA doses for LGE imaging at 3.0 T. Imaging at 5 min yields lower contrast, infarct sizes and image quality. Diagnostic quality can be obtained after 10 min using 0.10-mmol/kg Gd-BOPTA.

[PCSK9 as new target in hyperlipidemia treatment]. / PCSK9 als neues Target in der Therapie der Hypercholesterinämie.

Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a key regulator of cholesterol homeostasis acting via degradation of the low density lipoprotein (LDL) receptor. Loss of function PCSK 9 mutations result in very low LDL cholesterol serum levels and protection from cardiovascular disease whereas gain of function mutations increase serum LDL cholesterol. Based on in vitro and in vivo data antibodies targeting PCSK 9 have now emerged as a novel treatment option in patients with cardiovascular disease. This review briefly summarizes the biochemistry and function of PCSK9 and the results from recent phase II trials.

Dobutamine stress cardiovascular magnetic resonance at 3 Tesla.

PURPOSE: The assessment of inducible wall motion abnormalities during high-dose dobutamine-stress cardiovascular magnetic resonance (DCMR) is well established for the identification of myocardial ischemia at 1.5 Tesla. Its feasibility at higher field strengths has not been reported. The present study was performed to prospectively determine the feasibility and diagnostic accuracy of DCMR at 3 Tesla for depicting hemodynamically significant coronary artery stenosis (> or = 50% diameter stenosis) in patients with suspected or known coronary artery disease (CAD). MATERIALS AND METHODS: Thirty consecutive patients (6 women) (66 +/- 9.3 years) were scheduled for DCMR between January and May 2007 for detection of coronary artery disease. Patients were examined with a Philips Achieva 3 Tesla system (Philips Healthcare, Best, The Netherlands), using a spoiled gradient echo cine sequence. Technical parameters were: spatial resolution 2 x 2 x 8 mm3, 30 heart phases, spoiled gradient echo TR/TE: 4.5/2.6 msec, flip angle 15 degrees . Images were acquired at rest and stress in accordance with a standardized high-dose dobutamine-atropine protocol during short breath-holds in three short and three long-axis views. Dobutamine was administered using a standard protocol (10 microg increments every 3 minutes up to 40 microg dobutamine/kg body weight/minute plus atropine if required to reach target heart rate). The study protocol included administration of 0.1 mmol/kg/body weight Gd-DTPA before the cine images at rest were acquired to improve the image quality. The examination was terminated if new or worsening wall-motion abnormalities or chest pain occurred or when > 85% of age-predicted maximum heart rate was reached. Myocardial ischemia was defined as new onset of wall-motion abnormality in at least one segment. In addition, late gadolinium enhancement (LGE) was performed. Images were evaluated by two blinded readers. Diagnostic accuracy was determined with coronary angiography as the reference standard. Image quality and wall-motion at rest and maximum stress level were evaluated using a four-point scale. RESULTS: In 27 patients DCMR was performed successfully, no patient had to be excluded due to insufficient image quality. Twenty-two patients were examined by coronary angiography, which depicted significant stenosis in 68.2% of the patients. Patient-based sensitivity and specificity were 80.0% and 85.7% respectively and accuracy was 81.8%. Interobserver variability for assessment of wall motion abnormalities was 88% (kappa = 0.760; p < 0.0001). Negative and positive predictive values were 66.7% and 92.3%, respectively. No significant differences in average image quality at rest versus stress for short or long-axis cine images were found. CONCLUSION: High-dose DCMR at 3T is feasible and an accurate method to depict significant coronary artery stenosis in patients with suspected or known CAD.

WITHDRAWN: Non-invasive Estimation of Left Ventricular End-diastolic Pressure by Pulmonary Venous Flow Deceleration Time.

The publisher regrets that this was an accidental duplication of an article that has already been published in Eur. J. Echocardiogr., 4 (2003) 162-168, . The duplicate article has therefore been withdrawn.

Correlates of online health information-seeking behaviors in a low-income Hispanic community.

OBJECTIVE: The purpose of this study was to explore the correlates of online health information-seeking behaviors among Hispanic residents of a low-income urban neighborhood. METHODS: Data were collected with a community survey from 1045 unique participants at ambulatory care clinics in a largely Hispanic immigrant community in northern Manhattan, New York. A descriptive correlational analysis was conducted using logistic regression. RESULTS: A majority of the participants were born outside the United States (85.7%), and half (50.3%) had completed high school. A logistic regression revealed that five independent variables were significantly correlated with online health information-seeking behaviors: age, education, marital status, primary language, and health literacy. Age and Spanish as preferred language were negatively associated with online health information-seeking (OR = 0.93 and 0.50), whereas education and health literacy were positively associated with online health information-seeking (OR = 4.28 and 1.28). CONCLUSIONS: The findings have implications for designing online health information resources and interventions appropriate for the populations they are likely to reach. Furthermore, the findings highlight the need for special efforts to ensure access to reliable health information for immigrant populations and those with low health literacy.

Differences in the prognostic relevance of myocardial ischaemia and scar by cardiac magnetic resonance in patients with and without diabetes mellitus.

AIMS: To evaluate the prognostic significance of myocardial ischaemia and scar in patients with and without diabetes mellitus (DM) who undergo dobutamine stress cardiac magnetic resonance (DCMR) and late gadolinium enhancement (LGE) imaging for known and suspected coronary artery diseases (CADs). METHODS AND RESULTS: A total of 1969 consecutive patients [age 63 ± 12 years, 29% female, left ventricular ejection fraction = 59 ± 12%] referred for a cardiac magnetic resonance (CMR) examination including DCMR and LGE with the suspicion of CAD or progression of CAD in three tertiary cardiac centres were analysed. Cardiac death and nonfatal myocardial infarction (MI) were registered as hard cardiac events. Patients with a revascularization procedure within the first 3 months after CMR were censored at the time of 'early' revascularization. Patients were followed for 3.2 ± 1.5 years (median 2.9, interquartile range 2-4.3 years). In total, 90 (4.6%) cardiac deaths and MI were registered. Among them, 328 patients (16.6%) had diabetes. The proportion of dobutamine-induced wall motion abnormalities (DWMA) and LGE was higher in patients with DM when compared with those without DM (27 vs. 19% and 53.6 vs. 41.2%, respectively, P < 0.001 for both for proportions). Both DWMA and LGE were independent predictors of cardiac death and MI in patients without DM (HR for DWMA 8, CI 4.5-14.3, HR for LGE 2.1, CI 1.1-4.1) and with DM (HR for DWMA 8.6, CI 3.5-21, HR for LGE 4.5, CI 1.5-13.1). Tests for interaction showed that LGE more strongly influences prognosis in patients with than in those without DM (P = 0.03 for interaction), whereas the presence of DWMA is related to similarly poor outcomes in patients with and without DM (P = NS). CONCLUSION: Myocardial scar by LGE is a hallmark of markedly poorer outcome in patients with DM, while the presence of inducible myocardial ischaemia seems to be predictive both in patients with and without DM. Both markers surpass the predictive value of conventional atherogenic risk factors both in patients with and without DM.

Investigation of coronary venous anatomy by retrograde venography in patients with malignant ventricular tachycardia.

BACKGROUND: The coronary venous system is increasingly used for left ventricular or biventricular pacing in patients with severe heart failure. The present study investigated the structure of the coronary veins in patients presenting with structural heart disease and malignant ventricular tachyarrhythmias. The availability of veins for possible lead placement was assessed. METHODS AND RESULTS: The number, relative size, and location of coronary veins were evaluated by retrograde venography in 129 patients undergoing cardioverter-defibrillator implantation. Detailed x-ray image analysis was performed in 86 patients, for whom optimal coronary sinus occlusion and vein visualization was achieved. The anterior interventricular vein and the middle cardiac vein were visible in 85 (99%) of 86 patients and in 86 (100%) of 86 patients, respectively. Between these 2 veins, at least 1 additional prominent vein was visible in 85 (99%) of 86 patients. Just 1 vein was present in 44 (51%) of 86 patients. Two veins were observed in 40 (46%) of 86 patients, and >2 veins were visualized in 2 (2%) of 86 patients. Venous anatomy allowed positioning of a 0.014-in guidewire in a coronary vein in 115 (93%) of 124 patients. CONCLUSIONS: The presence, diameter, angulation, and tortuosity of veins as visualized by retrograde venography determine their acceptability for the placement of a lead in a predetermined location. Despite the considerable variability of the coronary venous system among patients, a lateral vessel for lead introduction was available in 82%, and a posterior or lateral vessel was available in 99% of individuals within a patient population that could potentially benefit from a lead on the left ventricle.

Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves systolic function in heart failure patients with ventricular conduction delay by stimulating the left ventricle (LV) or both ventricles (biventricular, BV). Optimal LV site selection is of major clinical interest for CRT device implantation; however, the dependence of hemodynamics on LV stimulation site has not been established. Thus, the objective of this study was to compare the hemodynamic response to CRT for 2 LV coronary vein sites: the free wall and anterior wall. Methods and Results- A total of 30 patients (mean NYHA class, 2.7; mean QRS interval, 152 ms; mean PR interval, 194 ms) enrolled in the PATH-CHF-II trial were studied. CRT was administered with LV and BV stimulation in VDD mode at 4 AV delays. LV stimulation was at the lateral free wall or anterior wall, whereas right ventricular stimulation was fixed near the apex. LV+dP/dt(max) and aortic pulse pressure changes from baseline during CRT were compared for LV sites. Free wall sites with LV and BV stimulation yielded significantly larger LV+dP/dt(max) (14% versus 6%, P<0.001 for LV; 12% versus 5%, P<0.001 for BV) and pulse pressure (8% versus 4%, P<0.001 for LV; 9% versus 5%, P<0.001 for BV) compared with anterior sites. In one third of patients, CRT at free wall sites increased LV+dP/dt(max), whereas it decreased at anterior sites over most AV delays. CONCLUSION: CRT with LV free wall stimulation produced significantly better LV systolic performance compared with anterior stimulation. Further studies are warranted to prove the clinical superiority of the LV free wall as a site for long-term CRT.

Transvenous biventricular defibrillation halves energy requirements in patients.

BACKGROUND: Defibrillation thresholds (DFT) with standard implantable cardioverter-defibrillator leads in the right ventricle (RV) may be determined by weak shock field intensity in the myocardium of the left ventricle (LV). Adding a shocking electrode in a coronary vein on the middle of the LV free wall, thereby establishing biventricular defibrillation, substantially reduced defibrillation requirements in animals. We investigated the feasibility of this approach in 24 patients receiving an implantable cardioverter-defibrillator using a prototype over-the-wire temporary LV defibrillation lead. METHODS AND RESULTS: The LV lead was inserted through the coronary sinus, using a guide catheter and guidewire, into a posterior or lateral coronary vein whose location was determined by retrograde venography. Paired DFT testing compared a standard system (RV to superior vena cava plus can emulator [SVC+Can], 60% tilt biphasic shock) to a system including the LV lead. The biventricular system was tested with a dual-shock waveform (20% tilt monophasic shock from LV-->SVC+Can, then 60% tilt biphasic shock from RV-->SVC+Can). Twenty patients completed DFT testing. Venography and LV lead insertion time was 46+/-40 minutes. The biventricular system reduced mean DFT by 45% (8.9+/-1.1 J versus 4.9+/-0.5 J, P<0.001). Twelve patients (60%) had a standard system DFT >/=8 J, and the biventricular system gave a lower DFT in all patients. There were no adverse events related to the use of the LV lead, which was removed after testing. CONCLUSIONS: Internal defibrillation using a transvenously inserted LV lead is feasible, produces significantly lower DFTs, and seems safe under the conditions tested. Biventricular defibrillation may be a useful option for reducing DFTs or could be added to an LV pacing lead for heart failure.

Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion.

BACKGROUND: Dobutamine stress MR (DSMR) is highly accurate for the detection of inducible wall motion abnormalities (IWMAs). Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion. We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography. METHODS AND RESULTS: Seventy-nine consecutive patients (suspected or known coronary disease, no history of prior myocardial infarction) scheduled for cardiac catheterization underwent cardiac MR (1.5 T). After 4 minutes of adenosine infusion (140 microg x kg(-1) x min(-1) for 6 minutes), wall motion was assessed (steady-state free precession), and subsequently perfusion scans (3-slice turbo field echo-echo planar imaging; 0.05 mmol/kg Gd-BOPTA) were performed. After a 15-minute break, rest perfusion was imaged, followed by standard DSMR/atropine stress MR. Wall motion was classified as pathological if > or =1 segment showed IWMAs. The transmural extent of inducible perfusion deficits (<25%, 25% to 50%, 51% to 75%, and >75%) was used to grade segmental perfusion. Quantitative coronary angiography was performed with significant stenosis defined as >50% diameter stenosis. Fifty-three patients (67%) had coronary artery stenoses >50%; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89% and 80%, 40% and 96%, and 91% and 62%, respectively. Adenosine IWMAs were seen only in segments with >75% transmural perfusion deficit. CONCLUSIONS: DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease. Visual assessment of adenosine stress perfusion is sensitive with a low specificity, whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high-grade perfusion deficits. Thus, DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infarction.

Changes in surface expression of platelet membrane glycoproteins and progression of heart transplant vasculopathy.

BACKGROUND: Transplant vasculopathy is the main limiting factor of the long-term success of heart transplantation. We sought to establish the role of platelets in the development and progression of transplant vasculopathy. METHODS AND RESULTS: Platelet analysis and intracoronary ultrasound examination were performed in 78 heart transplant recipients. Quantitative intracoronary ultrasound was used to define the severity of disease at baseline (48.8+/-4.5 months after transplantation) and at 1-year follow-up. Platelet activation was assessed with the use of immunological surface markers of activation (ligand-induced binding site 1 [LIBS-1], P-selectin, GPIIb-IIIa) and flow cytometry. We found that LIBS-1 immunoreactivity was significantly increased in patients with diffuse disease when compared with focal transplant disease (median [quartile], 27[14, 64] versus 18[7.9, 47], P=0.04). In a logistic regression model, we found that LIBS-1 was an independent predictor for the presence and progression of diffuse transplant vasculopathy (P=0.04). Patients with enhanced LIBS-1 levels (>75% quartile) had a 3.3-fold increased relative risk (95% CI 1.8 and 18.9, P=0.002) for the presence of diffuse transplant vasculopathy. When a cutoff value of 16.5 for the level of LIBS-1 was used, patients had a 4.8-fold increased relative risk (95% CI 1.9 and 12.5, P<0.01) for the progression of transplant vasculopathy. CONCLUSIONS: Enhanced platelet activation is strongly associated with the development and progression of transplant vasculopathy. Understanding the underlying pathophysiological mechanisms might contribute to the development of treatment strategies to prevent transplant vasculopathy.

Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance.

BACKGROUND: Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated. METHODS AND RESULTS: In 15 patients with single-vessel coronary artery disease and 5 patients without significant coronary artery disease, the signal intensity-time curves of the first pass of a gadolinium-DTPA bolus injected through a central vein catheter were evaluated before and after dipyridamole infusion to validate the technique. A linear fit was used to determine the upslope, and a cutoff value for the differentiation between the myocardium supplied by stenotic and nonstenotic coronary arteries was defined. The diagnostic accuracy was then examined prospectively in 34 patients with coronary artery disease and was compared with coronary angiography. A significant difference in myocardial perfusion reserve between ischemic and normal myocardial segments (1.08+/-0.23 and 2.33+/-0.41; P<0.001) was found that resulted in a cutoff value of 1.5 (mean minus 2 SD of normal segments). In the prospective analysis, sensitivity, specificity, and diagnostic accuracy for the detection of coronary artery stenosis (> or =75%) were 90%, 83%, and 87%, respectively. Interobserver and intraobserver variabilities for the linear fit were low (r=0.96 and 0.99). CONCLUSIONS: MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity-time curves.

Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans.

OBJECTIVES: Our study goal was to analyze whether gene variants of angiotensin II type 2-receptor (AT2-R) modulate the effects of angiotensin II on the left ventricle (LV). BACKGROUND: Experimental data suggest that angiotensin II modifies ventricular growth responses via angiotensin II type 1-receptors (AT1-R) and AT2-R. METHODS: In 120 white, young male subjects with normal or mildly elevated blood pressure, we assessed plasma angiotensin II and aldosterone concentrations (RIA), 24-h urinary sodium excretion, 24-h ambulatory blood pressure and LV structure (two-dimensional guided M-mode echocardiography). The intronic +1675 G/A polymorphism of the X-chromosomal located AT2-R gene was investigated by single-strand conformational polymorphism analysis and DNA-sequencing. RESULTS: Hypertensive subjects with the A-allele had a greater LV posterior (11.0 +/- 1.3 vs. 9.9 +/- 1.3 mm, p < 0.001), septal (11.8 +/- 1.4 vs. 10.1 +/- 1.2 mm, p < 0.001) and relative wall thickness (0.44 +/- 0.06 vs. 0.39 +/- 0.06, p < 0.01) as well as LV mass index (138 +/- 23 vs. 120 +/- 13 g/m2, p < 0.001) than those with the G-allele. Confounding factors (i.e., body mass index and surface area, plasma angiotensin II, sodium excretion, systolic and diastolic ambulatory blood pressure) were similar between the two genotypes. In normotensive subjects, relative wall thickness (0.36 +/- 0.05 vs. 0.35 +/- 0.05) and LV mass index (115 +/- 21 vs. 112 +/- 17 g/m2) were nearly identical across the two genotypes, with similar confounding variables. CONCLUSIONS: Our data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.

Improvement of myocardial perfusion reserve early after coronary intervention: assessment with cardiac magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to determine the potential value of magnetic resonance myocardial perfusion in the follow-up of patients after coronary intervention. BACKGROUND: In some patients a residual impairment of myocardial perfusion reserve (MPR) early after successful coronary intervention has been observed. In this study we evaluated an MPR index before and after intervention with magnetic resonance. METHODS: Thirty-five patients with single- and multivessel coronary artery disease were studied before and 24 h after intervention. The signal intensity time curves of the first pass of a gadolinium-diethylene triamine pentacetic acid bolus injected via a central vein catheter were evaluated before and after dipyridamole infusion. The upslope was determined using a linear fit. Myocardial perfusion reserve index was estimated from the alterations of the upslope. RESULTS: The MPR index in segments perfused by the stenotic artery was significantly lower than in the control segments (1.07 +/- 0.24 vs. 2.18 +/- 0.35, p < 0.001) and improved significantly after intervention (1.89 +/- 0.39, p < 0.001) but did not normalize completely (p < 0.01). After intervention the MPR index remained significantly lower in the balloon percutaneous transluminal coronary angioplasty group (1.72 +/- 0.38; n = 13) in comparison with the stent group (1.99 +/- 0.36, n = 18, p < 0.05). In the stent group a complete normalization of the MPR index was found 24 h after stenting. CONCLUSIONS: Magnetic resonance perfusion measurements allow a reliable assessment of MPR index. An improvement of MPR index can be observed after coronary intervention, which is more pronounced after stenting. Magnetic resonance perfusion measurements allow the assessment and may be useful for the follow-up of patients with coronary artery disease after coronary intervention.

Aldosterone synthase (CYP11B2) -344 C/T polymorphism is associated with left ventricular structure in human arterial hypertension.

OBJECTIVES: This study examined the association between the -344 C/T polymorphism of the human aldosterone synthase promoter and left ventricular structure in arterial hypertension. BACKGROUND: Because of conflicting results from different studies, the mechanism of such an association, if any, has not been determined. METHODS: We examined the aldosterone synthase promoter genotype in 120 young (age: 26 +/- 3 years) male, white subjects with normal or mildly elevated blood pressure. Left ventricular structural parameters and urinary sodium excretion over 24 h before and after additional oral sodium load (6 g/day over 1 week) were determined. RESULTS: Hypertensive subjects with the CC genotype had a greater left ventricular end-diastolic diameter but smaller relative wall thickness than those with the TT genotype (54 +/- 2 vs. 50 +/- 4 mm, and 0.37 +/- 0.07 vs. 0.44 +/- 0.06 mm, respectively; p < 0.05). Hypertensive subjects with the TT genotype (n = 15) had a greater increase in urinary sodium excretion after oral sodium load than those with the CC genotype (n = 11) (135 +/- 95 vs. 24 +/- 133 mmol/liter/day; p < 0.05). Serum aldosterone levels were found to be decreased after oral sodium load in hypertensive subjects with the TT and CT genotypes only (-37 +/- 45 and -38 +/- 51 pg/ml, respectively; all p < 0.01) but not in those with the CC genotype (-12 +/- 30 pg/ml, n.s.). Such differences were not found in normotensive subjects. CONCLUSIONS: Hypertensive subjects with the -344 CC genotype of the aldosterone synthase promoter are characterized by a pattern of early eccentric left ventricular hypertrophy. Differences in renal sodium handling across the genotypes might contribute to this finding.

Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.

OBJECTIVES: We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components. BACKGROUND: In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available. METHODS: In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay. RESULTS: Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF). CONCLUSIONS: In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.

OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. BACKGROUND: Mutations in the MYBPC3 gene represent the cause of HCM in approximately 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. METHODS: The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. RESULTS: We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/- 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). CONCLUSIONS: Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.

Acute complications of excimer laser coronary angioplasty: a detailed analysis of multicenter results. Coinvestigators of the U.S. and European Percutaneous Excimer Laser Coronary Angioplasty (PELCA) Registries.

OBJECTIVES: The aim of this study was to document and analyze the incidence and consequences of complications of excimer laser coronary angioplasty. BACKGROUND: Excimer laser coronary angioplasty has been reported to be a safe and feasible alternative or adjunct to conventional balloon angioplasty, but serious and unique complications have been observed. METHODS: Data on 1,595 interventions of excimer laser coronary angioplasty in 1,521 patients were analyzed, using a merged data base from the U.S. and European Percutaneous Excimer Laser Coronary Angioplasty (PELCA) registries. RESULTS: Procedural success was achieved in 89.3% of interventions. Stand-alone laser angioplasty was performed in 17.8% of interventions. Complications included dissection (22.0%), vasospasm (6.1%), filling defects (4.8%), abrupt reclosure (6.1%), embolization (2.3%), perforation (2.4%), arrhythmia (0.7%) and aneurysm formation (0.3%). Major complications were non-Q wave myocardial infarction (2.3%), Q wave myocardial infarction (1.0%), coronary artery bypass grafting (3.1%) and death (0.7%). Logistic regression analysis revealed correlation between dissections and the use of larger catheter size (p = 0.0005), high energy per pulse levels (p = 0.0001 for native vessels), lesion length > 10 mm (p = 0.001) and presence of a side branch (p = 0.01). The incidence of perforations was higher in women (p = 0.004), in treatment of total occlusions (p = 0.02) and in the presence of a side branch (p = 0.03). Fatal complications were correlated with patients with multivessel disease (p < 0.0001), patients with acute myocardial infarction (p = 0.0009) and older patients (> 70 years old, p = 0.004). The incidence of major complications decreased after performance of 50 laser angioplasty procedures at one institution (p = 0.02). CONCLUSIONS: This analysis defines both the learning curve and the profile of complications for excimer laser angioplasty and provides insight into the selection of appropriate patients and proper performance of the procedure.

Selective downregulation of rat cardiac beta 1-adrenoceptors by cyclosporine A: prevention by diltiazem or angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study attempted to determine whether long-term treatment with cyclosporine A in rats affects cardiac beta 1-adrenoceptors and whether this can be prevented by angiotensin-converting enzyme inhibitors or calcium-entry blocking agents. BACKGROUND: In the transplanted human heart the density of beta 1-adrenoceptors decreases with time after transplantation, whereas that of beta 2-adrenoceptors does not. Because heart transplant recipients are treated with cyclosporine A, we studied whether administration of cyclosporine A in rats might cause this beta 1-adrenoceptor downregulation. METHODS: We performed two studies. First, we treated groups of 10 male normotensive Wistar rats orally with 30 mg/kg body weight per day of cyclosporine A, 10 mg/kg per day of enalapril and 60 mg/kg per day of diltiazem, alone or in combination, for 6 weeks each. Second, we treated groups of 15 male normotensive Wistar rats orally with 15 mg/kg per day of cyclosporine A and 10 mg/kg per day of lisinopril, alone or in combination, for 6 weeks each. At the end of each treatment regimen, cardiac beta-adrenoceptor density and subtype distribution were assessed by (-)-[125I]iodocyanopindolol binding. RESULTS: Both doses of cyclosporine A caused a significant decrease in cardiac beta 1-adrenoceptor density without affecting beta 2-adrenoceptor density. Although diltiazem and the angiotensin-converting enzyme inhibitors alone did not affect cardiac beta-adrenoceptors, they prevented the cyclosporine A-induced downregulation of beta 1-adrenoceptors. CONCLUSIONS: In normotensive Wistar rats, cyclosporine A causes a significant decrease in cardiac beta 1-adrenoceptors without affecting beta 2-adrenoceptors. This can be prevented by diltiazem or angiotensin-converting enzyme inhibitors. In heart transplant recipients, who undergo long-term treatment with cyclosporine A, there is a very similar beta 1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine A may cause these beta-adrenoceptor subtype alterations.