Anders M. Greve

Clinical Implications of Electrocardiographic Left Ventricular Strain and Hypertrophy in Asymptomatic Patients with Aortic Stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis Study

Background— The prognostic impact of ECG left ventricular strain and left ventricular hypertrophy (LVH) in asymptomatic aortic stenosis is not well described. Methods and Results— Data were obtained in asymptomatic patients randomized to simvastatin/ezetimibe combination versus placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Primary end point was the first of myocardial infarction, nonhemorrhagic stroke, heart failure, aortic valve replacement, or cardiovascular death. The predictive value of ECG left ventricular strain (defined as T-wave inversion in leads V4 through V6) and LVH, assessed by Sokolow-Lyon voltage criteria (RV5–6+SV1 ≥35 mV) and Cornell voltage-duration criteria {[RaVL+SV3+(6 mV in women)]×QRS duration ≥2440 mV · ms}, was evaluated by adjustment for other prognostic covariates. A total of 1533 patients were followed for 4.3±0.8 years (6592 patient-years of follow-up), and 627 cardiovascular events occurred. ECG strain was present in 340 patients (23.6%), with LVH by Sokolow-Lyon voltage in 260 (17.1%) and by Cornell voltage-duration product in 220 (14.6%). In multivariable analyses, ECG left ventricular strain was associated with 3.1-fold higher risk of in-study myocardial infarction (95% confidence interval, 1.4–6.8; P=0.004). Similarly, ECG LVH by both criteria predicted, compared with no ECG LVH, 5.8-fold higher risk of heart failure (95% confidence interval, 2.0–16.8), 2.0-fold higher risk of aortic valve replacement (95% confidence interval, 1.3–3.1; both P=0.001), and 2.5-fold higher risk of a combined end point of myocardial infarction, heart failure, or cardiovascular death (95% confidence interval, 1.3–4.9; P=0.008). Conclusions— ECG left ventricular strain and LVH were independently predictive of poor prognosis in patients with asymptomatic aortic stenosis. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Impact of QRS duration and morphology on the risk of sudden cardiac death in asymptomatic patients with aortic stenosis: the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Study.

OBJECTIVES The aim of the study was to examine the predictive value of QRS duration and morphology during watchful waiting in asymptomatic patients with aortic stenosis (AS). BACKGROUND QRS duration and morphology are associated with poor prognosis in many different populations, but the predictive value, particularly of the risk of sudden cardiac death (SCD), in asymptomatic patients with AS has not been well studied. METHODS Data were obtained in asymptomatic AS patients randomized to simvastatin/ezetimibe combination versus placebo in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. The impact of QRS duration, evaluated as a categorical variable of <85 ms versus 85 to 99 ms and ≥100 ms (excluding bundle branch block [BBB]) and QRS morphology in those with BBB, on cardiovascular morbidity and mortality was assessed by adjusting for clinical and echocardiographic covariates. RESULTS QRS data were available in 1,542 patients who were followed for a mean of 4.3 ± 0.8 years (6,631 patient-years of follow-up). There were 68 cardiovascular deaths (4.6%), including 27 SCDs (1.8%). QRS duration was <85 ms in 900 patients (58.4%), 85 to 99 ms in 396 (25.7%), ≥100 ms in those without BBB in 144 (9.3%), and 102 (6.6%) in those with BBB. In multivariable analyses, those with QRS duration ≥100 ms had, compared with those with QRS duration <85 ms, a 5-fold higher risk of SCD (95% confidence interval: 1.8 to 13.7, p = 0.002) and a 2.5-fold higher risk of cardiovascular death (95% confidence interval: 1.2 to 5.1, p = 0.01). CONCLUSIONS QRS duration and morphology in asymptomatic patients with AS are independently associated with a poor prognosis, particularly the risk of SCD.

Prognostic importance of atrial fibrillation in asymptomatic aortic stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis study

BACKGROUND The frequency and prognostic importance of atrial fibrillation (AF) in asymptomatic mild-to-moderate aortic stenosis (AS) has not been well described. METHODS Clinical examination, electrocardiography and echocardiography were obtained in asymptomatic patients with mild-to-moderate AS and preserved left ventricular (LV) systolic function, randomized to simvastatin/ezetimibe combination vs. placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. At inclusion, AF was categorized as episodic or longstanding. Rhythm change was assessed on annual in-study electrocardiograms. Impact of AF on cardiovascular morbidity and mortality was determined by adjusting for biomarkers, clinical- and echocardiographic covariates. RESULTS Mean follow-up was 4.3 ± 0.8 years (6,721 patient-years of follow-up). At baseline, episodic AF was present in 87 patients (5.6%), longstanding AF in 55 (3.5%) and no AF in 1,421 (90.9%). Incidence of new-onset AF was 1.2%/year; highest in those with impaired LV function. In multivariable analysis, longstanding AF was compared to no AF at baseline, associated with a 4.1-fold higher risk of heart failure (CI 1.2 to 13.8, p=0.02) and a 4.8-fold higher risk of non-hemorrhagic stroke (CI 1.7 to 13.6, p=0.003). CONCLUSION Rate of AF is moderate in asymptomatic AS. Longstanding but not episodic AF was, independently predictive of increased risk of heart failure and non-hemorrhagic stroke. New-onset AF was associated with cardiac decompensation.

Left atrial size and function as predictors of new-onset of atrial fibrillation in patients with asymptomatic aortic stenosis: The simvastatin and ezetimibe in aortic stenosis study

BACKGROUND Left atrial (LA) size and function change with chronically increased left ventricular (LV) filling pressures. It remains unclear whether these variations in LA parameters can predict new-onset atrial fibrillation (AF) in asymptomatic patients with aortic stenosis (AS). METHODS Data were obtained in asymptomatic patients with mild-to-moderate AS (2.5 ≤ transaortic Doppler velocity ≤ 4.0m/s), preserved LV ejection fraction (EF), no previous AF, and were enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. Peak-aortic velocity, LA(max) volume & LAmin volume were measured by echocardiography. LA conduit (LA(con)) volume was defined as LV stroke volume-LA stroke volume. LA function was expressed as LA-EF (LA(max)-LAmin volume/LA(max)). RESULTS In the 1159 patients included, new-onset AF occurred in 71 patients (6.1%) within a mean follow-up of 4.2 ± 0.9 years. Mean age was 66 ± 9.7 years, aortic valve area index 0.6 ± 0.2 cm(2)/m(2), LV mass 99.2 ± 29.7 g/m(2), LA(max) volume 34.6 ± 12.0 mL/m(2), LAmin volume 17.9 ± 9.3 mL/m(2), LA-EF 50 ± 15% and LA(con) volume 45 ± 21 mL/m(2). Baseline LAmin volume predicted new-onset AF in Cox multivariable analysis (HR:2.3 [95%CI:1.3-4.4], P<0.01), and added prognostic information on AF development beyond conventional risk factors (likelihood ratio, P<0.01). In comparison of c-indexes LAmin volume was superior to all other LA measurements. Net reclassification index improved by 15.9% when adding LAmin volume to a model with classic risk factors for AF (P=0.01). CONCLUSION LAmin volume independently predicted new-onset AF in patients with asymptomatic AS and was superior to LA-EF, LA(con) and LA(max) volumes and conventional risk factors.

New-Onset Atrial Fibrillation is Associated With Cardiovascular Events Leading to Death in a First Time Myocardial Infarction Population of 89 703 Patients With Long-Term Follow-Up: A Nationwide Study

Background New‐onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients. Methods and Results All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new‐onset AF on all‐cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re‐infarction and noncardiovascular death, were analyzed by multiple time‐dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow‐up of 5.0±3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus‐rhythm (n=78 992): all‐cause mortality 173.9 versus 69.4 per 1000 person‐years, cardiovascular death 137.2 versus 50.0 per 1000 person‐years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person‐years, fatal/nonfatal re‐infarction 29.0/60.7 versus 14.2/37.9 per 1000 person‐years. In time‐dependent multiple Cox analyses, new‐onset AF remained predictive of increased all‐cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re‐infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non‐ cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P<0.001). Propensity‐score matched analyses yielded nearly identical results (all P<0.001). Conclusions New‐onset AF after first‐time MI is associated with increased mortality, which is largely explained by more cardiovascular deaths. Focus on the prognostic impact of post‐infarct AF is warranted.

Differences in Cardiovascular Risk Profile Between Electrocardiographic Hypertrophy Versus Strain in Asymptomatic Patients With Aortic Stenosis (from SEAS Data)

Electrocardiograms are routinely obtained in clinical follow-up of patients with asymptomatic aortic stenosis (AS). The association with aortic valve, left ventricular (LV) response to long-term pressure load, and clinical covariates is unclear and the clinical value is thus uncertain. Data from clinical examination, electrocardiogram, and echocardiogram in 1,563 patients in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study were used. Electrocardiograms were Minnesota coded for arrhythmias and atrioventricular and intraventricular blocks; LV hypertrophy was assessed by Sokolow-Lyon voltage and Cornell voltage-duration criteria; and strain by T-wave inversion and ST-segment depression. Degree of AS severity was evaluated by echocardiography as peak aortic jet velocity and LV mass was indexed by body surface area. After adjustment for age, gender, LV mass index, heart rate, systolic and diastolic blood pressures, blood glucose, digoxin, antiarrhythmic drugs, drugs acting on the renin-angiotensin system, diuretics, β blockers and calcium receptor blockers; peak aortic jet velocity was significantly greater in patients with electrocardiographic strain (mean difference 0.13 m/s, p <0.001) and LV hypertrophy by Sokolow-Lyon voltage criteria (mean difference 0.12 m/s, p = 0.004). After similar adjustment, LV mass index was significantly greater in patients with electrocardiographic strain (mean difference 14.8 g/cm(2), p <0.001) and LV hypertrophy by Sokolow-Lyon voltage criteria and Cornell voltage-duration criteria (mean differences 8.8 and 17.8 g/cm(2), respectively, p <0.001 for the 2 comparisons). In multiple comparisons patients with electrocardiographic strain had increased peak aortic jet velocity, blood glucose, and uric acid, whereas patients with LV hypertrophy by Sokolow-Lyon voltage criteria were younger and patients with LV hypertrophy by Cornell voltage-duration criteria more often were women. In conclusion, electrocardiographic criteria for LV hypertrophy and strain are independently associated with peak aortic jet velocity and LV mass index. Moreover, clinical covariates differ significantly between patients with electrocardiographic strain and those with LV hypertrophy by Sokolow-Lyon voltage criteria and Cornell voltage-duration criteria.

The preventive effect of statin therapy on new-onset and recurrent atrial fibrillation in patients not undergoing invasive cardiac interventions: A systematic review and meta-analysis

BACKGROUND Previous meta-analyses suggest that pre-procedural use of statin therapy may reduce atrial fibrillation (AF) following invasive cardiac interventions (coronary artery by-pass grafting and percutaneous coronary intervention). However, the current evidence on the benefit of statins unrelated to invasive cardiac interventions has not been clarified systematically. METHODS Through a systematic literature search, trials examining the effect of statin therapy on AF were selected. Trials using statins before any percutaneous or surgical cardiac interventions were excluded. RESULTS The search identified 11 randomized and 16 observational eligible studies, totaling 106,640 patients receiving statin therapy and 129,305 serving as controls. Fourteen studies investigated the effect of statins on new-onset AF, 13 studies investigated the effect of statins on recurrent AF and one in both new-onset and recurrent AF. In the statin versus control group the mean age was 60.7 ± 8.3 versus 68.6 ± 6.2 years and females comprised 8.4% versus 10.3%. Statin therapy was associated with significant reduction of AF (Risk ratio (RR): 0.81 [95% confidence interval (CI): 0.80-0.83], p<0.001) combining all studies. Assessing exclusively randomized trials, statin therapy showed no significant risk reduction (RR: 0.97 [95%CI: 0.90-1.05], p=0.509), heterogeneity p>0.05. Assessing exclusively observational studies the risk reduction of new-onset AF was 12% (RR: 0.88 [95%CI: 0.85-0.91], p<0.001) and recurrent AF 15% (RR: 0.85 [95%CI: 0.80-0.90], p<0.001), heterogeneity p<0.001. CONCLUSION The hitherto published randomized clinical trials do not support a beneficial effect of statins on AF in patients not undergoing invasive cardiac interventions. This is in contrast to the results of observational and interventional studies.

Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance

Background Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.

Mechanisms for overestimating acute myocardial infarct size with gadolinium-enhanced cardiovascular magnetic resonance imaging in humans: a quantitative and kinetic study †

Aims It remains controversial whether cardiovascular magnetic resonance imaging with gadolinium only enhances acutely infarcted or also salvaged myocardium. We hypothesized that enhancement of salvaged myocardium may be due to altered extracellular volume (ECV) and contrast kinetics compared with normal and infarcted myocardium. If so, these mechanisms could contribute to overestimation of acute myocardial infarction (AMI) size. Methods and results Imaging was performed at 1.5T ≤ 7 days after AMI with serial T1 mapping and volumetric early (5 min post-contrast) and late (20 min post-contrast) gadolinium enhancement imaging. Infarcts were classified as transmural (>75% transmural extent) or non-transmural. Patients with non-transmural infarctions (n = 15) had shorter duration of symptoms before reperfusion (P = 0.02), lower peak troponin (P = 0.008), and less microvascular obstruction (P < 0.001) than patients with transmural infarcts (n = 22). The size of enhancement at 5 min was greater than at 20 min (18.7 ± 12.7 vs. 12.1 ± 7.0%, P = 0.003) in non-transmural infarctions, but similar in transmural infarctions (23.0 ± 10.0 vs. 21.9 ± 9.9%, P = 0.21). ECV of salvaged myocardium was greater than normal (39.5 ± 5.8 vs. 24.1 ± 3.1%) but less than infarcted myocardium (50.5 ± 6.0%, both P < 0.001). In kinetic studies of non-transmural infarctions, salvaged and infarcted myocardium had similar T1 at 4 min but different T1 at 8–20 min post-contrast. Conclusion The extent of gadolinium enhancement in AMI is modulated by ECV and contrast kinetics. Image acquisition too early after contrast administration resulted in overestimation of infarct size in non-transmural infarctions due to enhancement of salvaged myocardium.

Renin–angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis

BACKGROUND Renin-angiotensin system inhibition (RASI) is frequently avoided in aortic stenosis (AS) patients because of fear of hypotension. We evaluated if RASI with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) increased mortality in patients with mild to moderate AS. METHODS All patients (n=1873) from the Simvastatin and Ezetimibe in Aortic Stenosis study: asymptomatic patients with AS and preserved left ventricular (LV) ejection fraction were included. Risks of sudden cardiac death (SCD), cardiovascular death and all-cause mortality according to RASI treatment were analyzed by multivariable time-varying Cox models and propensity score matched analyses. RESULTS 769 (41%) patients received RASI. During a median follow-up of 4.3 ± 0.9 years, 678 patients were categorized as having severe AS, 545 underwent aortic valve replacement, 40 SCDs, 103 cardiovascular and 205 all-cause deaths occurred. RASI was not associated with SCD (HR: 1.19 [95%CI: 0.50-2.83], p=0.694), cardiovascular (HR: 1.05 [95%CI: 0.62-1.77], p=0.854) or all-cause mortality (HR: 0.81 [95%CI: 0.55-1.20], p=0.281). This was confirmed in propensity matched analysis (all p>0.05). In separate analyses, RASI was associated with larger reduction in systolic blood pressure (p=0.001) and less progression of LV mass (p=0.040). CONCLUSIONS RASI was not associated with SCD, cardiovascular or all-cause mortality in asymptomatic AS patients. However, RASI was associated with a potentially beneficial decrease in blood pressure and reduced LV mass progression.