David M. Shavelle

Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial

BACKGROUND Results of previous studies support the hypothesis that implantable haemodynamic monitoring systems might reduce rates of hospitalisation in patients with heart failure. We undertook a single-blind trial to assess this approach. METHODS Patients with New York Heart Association (NYHA) class III heart failure, irrespective of the left ventricular ejection fraction, and a previous hospital admission for heart failure were enrolled in 64 centres in the USA. They were randomly assigned by use of a centralised electronic system to management with a wireless implantable haemodynamic monitoring (W-IHM) system (treatment group) or to a control group for at least 6 months. Only patients were masked to their assignment group. In the treatment group, clinicians used daily measurement of pulmonary artery pressures in addition to standard of care versus standard of care alone in the control group. The primary efficacy endpoint was the rate of heart-failure-related hospitalisations at 6 months. The safety endpoints assessed at 6 months were freedom from device-related or system-related complications (DSRC) and freedom from pressure-sensor failures. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00531661. FINDINGS In 6 months, 83 heart-failure-related hospitalisations were reported in the treatment group (n=270) compared with 120 in the control group (n=280; rate 0·31 vs 0·44, hazard ratio [HR] 0·70, 95% CI 0·60-0·84, p<0·0001). During the entire follow-up (mean 15 months [SD 7]), the treatment group had a 39% reduction in heart-failure-related hospitalisation compared with the control group (153 vs 253, HR 0·64, 95% CI 0·55-0·75; p<0·0001). Eight patients had DSRC and overall freedom from DSRC was 98·6% (97·3-99·4) compared with a prespecified performance criterion of 80% (p<0·0001); and overall freedom from pressure-sensor failures was 100% (99·3-100·0). INTERPRETATION Our results are consistent with, and extend, previous findings by definitively showing a significant and large reduction in hospitalisation for patients with NYHA class III heart failure who were managed with a wireless implantable haemodynamic monitoring system. The addition of information about pulmonary artery pressure to clinical signs and symptoms allows for improved heart failure management. FUNDING CardioMEMS.

HMG CoA reductase inhibitor (statin) and aortic valve calcium

There is no known pharmacological therapy for calcific aortic valvular sclerosis or stenosis. Because leaflet calcification occurs in areas of lipoprotein deposition, we hypothesised that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG COA) reductase inhibitors (statins) might slow aortic valve calcium (AVC) accumulation. We retrospectively identified 65 patients who had undergone two electron-beam computed tomography scans at a mean (SD) interval of 2.5 (1.6) years. 28 (43%) patients were receiving statins. Patients who were treated with statins had a 62-63% lower median rate of AVC accumulation (p=0.006) and 44-49% fewer statin patients had definite AVC progression (p=0.043). These findings suggest that statins may decrease AVC accumulation.

Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma.

Background—Recent studies have demonstrated that lesions of aortic sclerosis and stenosis share several similarities with lesions of atherosclerosis. In atherosclerosis, angiotensin-converting enzyme (ACE) is expressed by a subset of macrophages. This study was undertaken to determine whether ACE might be present in aortic sclerosis or stenosis lesions. Methods and Results—Immunohistochemistry was performed on 26 paraffin-embedded human aortic valves. Monospecific antibodies were used to identify ACE, macrophages, angiotensin II type 1 receptor (AT-1 receptor), angiotensin II, and apolipoprotein B. Human low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were isolated from plasma of normal volunteers by sequential density-gradient ultracentrifugation. ACE was not present in normal valves but was present in all valves with aortic sclerosis or stenosis lesions. ACE was detected on a subset of lesion macrophages but was present primarily in an extracellular distribution, where it colocalized with apolipoprotein B. ACE was detected by Western blotting on plasma LDL but not on HDL isolated from normal volunteers. Angiotensin II, the enzymatic product of ACE, was colocalized with ACE in valve lesions. ACE also was colocalized with apolipoprotein B in an adjacent coronary atherosclerotic plaque. Conclusions—ACE is present in aortic sclerosis and stenosis lesions, where it may participate in lesion development, as is evidenced by the presence of its enzymatic product, angiotensin II. The observation of an association of ACE with LDL in both lesions and plasma suggests that LDL may deliver ACE to lesions and has implications for the role of ACE-containing LDL in other diseases, such as atherosclerosis.

Features of the Metabolic Syndrome and Diabetes Mellitus as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis

Background— Calcific aortic valve disease is common in the elderly, is correlated with common cardiovascular risk factors, and is associated with increased cardiovascular event risk; however, whether metabolic syndrome is associated with an increased prevalence of aortic valve calcium (AVC) is not known. Methods and Results— The prevalence of AVC, as assessed by computed tomography, was compared in 6780 Multi-Ethnic Study of Atherosclerosis (MESA) participants with metabolic syndrome (n=1550; National Cholesterol Education Program’s Adult Treatment Panel III [ATP III] criteria), diabetes mellitus (n=1016), or neither condition (n=4024). The prevalence of AVC for those with neither condition, metabolic syndrome, or diabetes mellitus was, respectively, 8%, 12%, and 17% in women (P<0.001) and 14%, 22%, and 24% in men (P<0.001). Compared with those with neither condition, the adjusted relative risks for the presence of AVC were 1.45 (95% CI 1.11 to 1.90) for metabolic syndrome and 2.12 (95% CI 1.54 to 2.92) for diabetes mellitus in women and 1.70 (95% CI 1.32 to 2.19) for metabolic syndrome and 1.73 (95% CI 1.33 to 2.25) for diabetes mellitus in men. There was a graded, linear relationship between AVC prevalence and the number of metabolic syndrome components in both women and men (both P<0.001). Similar results were obtained when the International Diabetes Federation metabolic syndrome definition was used. Conclusions— In the MESA cohort, the metabolic syndrome and diabetes mellitus are associated with increased risk of AVC, and AVC prevalence is increased with increasing number of metabolic syndrome components.

Usefulness of electron beam computed tomography scanning for distinguishing ischemic from nonischemic cardiomyopathy

OBJECTIVES This study was undertaken to evaluate the ability of electron beam computed tomography (EBCT) to distinguish ischemic from nonischemic causes of cardiomyopathy by evaluating heart failure patients for coronary calcification (CC). BACKGROUND The etiology of heart failure, whether coronary-induced or nonischemic, may be difficult to discern clinically. Differentiation of ischemic from nonischemic etiology is clinically important for both therapeutic and prognostic implications. With its ability to noninvasively discern and quantitate coronary artery calcification, EBCT correlates well with angiographic stenosis and thus may be useful in distinguishing ischemic and nonischemic cardiomyopathies. METHODS One hundred and twenty-five patients with cardiomyopathy (ejection fraction <0.40) and known coronary anatomy underwent EBCT coronary scanning to evaluate for CCs within 3 months of coronary angiography. RESULTS Of the 72 patients who were found to have ischemic cardiomyopathy, 71 patients had CC by EBCT (sensitivity 99%, p < 0.001), mean score 798+/-899. In comparison, among the 53 patients without significant coronary artery disease (CAD) (nonischemic cardiomyopathy), the mean score was significantly lower (17+/-51; p < 0.0001), and 44 patients had a CC score of 0 (no CC present). The specificity of EBCT to exclude CAD in patients with cardiomyopathy was 83%, using a threshold CC score of 0, and 92% for scores <80 (p < 0.001). Overall accuracy for determining the etiology of cardiomyopathy (differentiating ischemic from nonischemic) was 92% for this technique. CONCLUSIONS This prospective, blinded study indicates that EBCT detected CC accurately and can noninvasively distinguish between cardiomyopathy because of CAD and nonischemic causes of left ventricular dysfunction.

Hemodynamic effects of the angiotensin-converting enzyme inhibitor, ramipril, in patients with mild to moderate aortic stenosis and preserved left ventricular function

Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in patients with aortic stenosis (AS). We determined the hemodynamic effects of ACE inhibitors in patients with mild to moderate aortic stenosis (AS) and preserved left ventricular function. Methods Thirteen elderly patients (mean [SD] age = 65 [17] years), with mild to moderate AS (aortic jet velocity 2.5-4.0 m/s), normal left ventricular and renal function, and no clinical coronary artery disease, were enrolled in a single-center, open-label trial comparing the hemodynamic effects at baseline and following titration of ramipril to a maximum dose of 7.5 mg twice daily. Patients were identified from echocardiography laboratory logs. Despite a presumed contraindication to ACE inhibitor use in AS patients, 30% (71 of 235) of patients otherwise meeting inclusion or exclusion criteria were excluded owing to current ACE inhibitor use. Patients were monitored with weekly clinic visits, biweekly laboratory tests, and monthly echocardiograms. Results There were no significant changes from baseline to week 8 in echocardiographic parameters, including mean (SD) aortic jet velocity [2.9 (0.4) vs 2.9 (0.4) m/s], calculated aortic transvalvular gradient [18 (6) vs 18 (6) mm Hg], or cardiac output [5.5 (1.2) vs 6.0 (2.1) L/min], or significant changes in blood pressure or heart rate. Early discontinuations were for asymptomatic low blood pressure (one patient) or a reversible creatinine increase of 0.3 mg/dL (one patient). Conclusions Short-term treatment with up to 7.5 mg twice daily of ramipril was well tolerated in patients with mild to moderate AS and preserved left ventricular function. A surprisingly high proportion of patients with documented AS were already receiving ACE inhibitors.

Valvular and thoracic aortic calcium as a marker of the extent and severity of angiographic coronary artery disease

BACKGROUND The presence of calcified extracoronary structures as a useful indicator of underlying coronary artery disease (CAD) has not yet been established. The purpose of this study was to evaluate whether valvular and thoracic aortic calcification is associated with obstructive CAD. METHODS We evaluated 99 patients who underwent both coronary angiography and electron beam tomography (EBT) coronary scanning. We identified the presence, absence, and amount of calcification in the aortic valve (AVC), mitral annulus (MAC), descending aorta (DAC), and ascending aorta (AAC). The extent of CAD was graded according to the number of vessels diseased (VD). RESULTS Patients with multivessel disease (MVD) had a higher proportion of DAC. The presence of DAC significantly increased the specificity of EBT to detect CAD (58% with a calcium score >0 to 88% for calcium score>0 and DAC >0, P <.001). Both AAC and DAC were associated with a significantly higher rate of MVD in women (DAC, 63% in MVD vs 19% without, P <.01.; AAC, 65% vs 22%, P <.05). MAC had no relationship to either stenosis severity or the presence of obstructive CAD. AVC was the strongest predictor of the severity of CAD and predicted the presence of 3-vessel disease. CONCLUSION AVC and thoracic aortic calcification as detected with EBT are associated with the angiographic extent and severity of CAD and add incremental diagnostic value to the coronary artery calcium score. MAC does not add incremental value.

Exercise testing and Electron beam computed tomography in the evaluation of coronary artery disease

OBJECTIVES This study compared coronary artery calcium (CC) as detected by electron beam computed tomography (EBCT) with conventional stress testing in the evaluation of patients with symptoms suggestive of coronary artery disease (CAD). BACKGROUND Exercise electrocardiogram treadmill stress testing (treadmill-ECG) is limited by its requirement of a normal resting ECG and the ability of the patient to exercise adequately. The addition of myocardial imaging agents such as technetium improves the sensitivity and specificity but substantially increases the cost and prolongs the testing time. The use of EBCT provides a noninvasive and rapid method for identifying the presence and amount of CC, which has been shown to be related to atherosclerosis, and may provide additional information in combination with more traditional noninvasive testing methods. METHODS A total of 97 patients underwent technetium stress testing (technetium-stress), treadmill-ECG, and EBCT coronary scanning within three months of coronary angiography for the evaluation of chest pain. RESULTS The relative risk (RR) of obstructive angiographic CAD for an abnormal test was higher for EBCT (4.53) than either treadmill-ECG (1.72) or technetium-stress (1.96). The low specificity of EBCT (47%) was improved by the addition of treadmill-ECG (83%, p < 0.05). CONCLUSIONS Electron beam computed tomography has a higher diagnostic ability than either treadmill-ECG or technetium-stress for the detection of obstructive angiographic CAD. Electron beam computed tomography is an accurate and noninvasive alternative to traditional stress testing for the detection of obstructive CAD in symptomatic patients.

Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography.

It was previously reported that event-free survival rates of symptomatic patients with coronary artery disease (CAD) diagnosed by computed tomographic angiography decreased incrementally from normal coronary arteries to obstructive CAD. The aim of this study was to investigate the clinical outcomes of symptomatic patients with nonobstructive CAD with luminal stenoses of 1% to 49% on the basis of coronary plaque morphology in an outpatient setting. Among 3,499 consecutive symptomatic subjects who underwent computed tomographic angiography, 1,102 subjects with nonobstructive CAD (mean age 59 ± 14 years, 69.9% men) were prospectively followed for a mean of 78 ± 12 months. Coronary plaques were defined as noncalcified, mixed, and calcified per patient. Multivariate Cox proportional-hazards models were developed to predict all-cause mortality. The death rate of patients with nonobstructive CAD was 3.1% (34 deaths). The death rate increased incrementally from calcified plaque (1.4%) to mixed plaque (3.3%) to noncalcified plaque (9.6%), as well as from single- to triple-vessel disease (p <0.001). In subjects with mixed or calcified plaques, the death rate increased with the severity of coronary artery calcium from 1 to 9 to ≥ 400. The risk-adjusted hazard ratios of all-cause mortality in patients with nonobstructive CAD were 3.2 (95% confidence interval 1.3 to 8.0, p = 0.001) for mixed plaques and 7.4 (95% confidence interval 2.7 to 20.1, p = 0.0001) for noncalcified plaques compared with calcified plaques. The areas under the receiver-operating characteristic curve to predict all-cause mortality were 0.75 for mixed and 0.86 for noncalcified coronary lesions. In conclusion, this study demonstrates that the presence of noncalcified and mixed coronary plaques provided incremental value in predicting all-cause mortality in symptomatic subjects with nonobstructive CAD independent of age, gender, and conventional risk factors.

Relationship of Metabolic Syndrome With Incident Aortic Valve Calcium and Aortic Valve Calcium Progression: The Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE Metabolic syndrome (MetS) has been associated with increased prevalence of aortic valve calcium (AVC) and with increased progression of aortic stenosis. The purpose of this study was to determine whether MetS is associated with increased risks for the development of new (“incident”) AVC or for progression of established AVC as assessed by CT. RESEARCH DESIGN AND METHODS The relationships of MetS or its components as well as of diabetes to risks for incident AVC or AVC progression were studied among participants with CT scans performed at baseline and at either year 2 or year 3 examinations in the Multi-Ethnic Study of Atherosclerosis (MESA). RESULTS Of 5,723 MESA participants meeting criteria for inclusion, 1,674 had MetS by Adult Treatment Panel III criteria, whereas 761 had diabetes. Among the 5,123 participants without baseline AVC, risks for incident AVC, adjusted for time between scans, age, sex, race/ethnicity, LDL cholesterol, lipid-lowering medications, and smoking, were increased significantly for MetS (odds ratio [OR] 1.67 [95% CI 1.21–2.31]) or diabetes (2.06 [1.39–3.06]). In addition, there was an increase in incident AVC risk with increasing number of MetS components. Similar results were found using the International Diabetes Federation MetS criteria. Among the 600 participants (10.5%) with baseline AVC, neither MetS nor diabetes was associated with AVC progression. CONCLUSIONS In the MESA cohort, MetS was associated with a significant increase in incident (“new”) AVC, raising the possibility that MetS may be a potential therapeutic target to prevent AVC development.