Casper N. Bang

Four-Group Classification of Left Ventricular Hypertrophy Based on Ventricular Concentricity and Dilatation Identifies a Low-Risk Subset of Eccentric Hypertrophy in Hypertensive Patients

Background—Left ventricular hypertrophy (LVH; high LV mass [LVM]) is traditionally classified as concentric or eccentric based on LV relative wall thickness. We evaluated the prediction of subsequent adverse events in a new 4-group LVH classification based on LV dilatation (high LV end-diastolic volume [EDV] index) and concentricity (mass/end-diastolic volume [M/EDV]2/3) in hypertensive patients. Methods and Results—In the Losartan Intervention for Endpoint Reduction (LIFE) echocardiography substudy, 939 hypertensive patients with measurable LVM at baseline were randomized to a mean of 4.8 years of losartan- or atenolol-based treatment. Patients with LVH (LVM/body surface area ≥116 and ≥96 g/m2 in men and woman, respectively) were divided into 4 groups—concentric nondilated (increased M/EDV, normal EDV), eccentric dilated (increased EDV, normal M/EDV), concentric dilated (increased M/EDV and EDV), and eccentric nondilated (normal M/EDV and EDV)—and compared with patients with normal LVM. Time-varying LVH classes were tested for association with all-cause and cardiovascular mortality and a composite end point of myocardial infarction, stroke, heart failure, and cardiovascular death in multivariable Cox analyses. At baseline, the LVs were categorized as eccentric nondilated in 12%, eccentric dilated in 20%, concentric nondilated in 29%, concentric dilated in 14%, and normal LVM in 25%. Treatment changed the prevalence of 4 LVH groups to 23%, 4%, 5%, and 7%; 62% had normal LVM after 4 years. In time-varying Cox analyses, compared with normal LVM, those with eccentric dilated and both concentric nondilated and dilated LVH had increased risks of all-cause or cardiovascular mortality or the composite end point, whereas the eccentric nondilated group did not. Conclusions—Hypertensive patients with relatively mild LVH without either increased LV volume or concentricity have similar risk of all-cause mortality or cardiovascular events because hypertensive patients with normal LVM seem to be a low-risk group. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260.

Relationship of Sudden Cardiac Death to New- Onset Atrial Fibrillation in Hypertensive Patients With Left Ventricular Hypertrophy

Background—Prevalent atrial fibrillation (AF) is associated with a higher sudden cardiac death (SCD) rate in some populations, and incident AF predicts increased mortality risk in the general population and after myocardial infarction. However, the relationship of SCD to new-onset AF is unclear. Methods and Results—The relationship of SCD to new-onset AF was evaluated in 8831 hypertensive patients with electrocardiographic left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. During 4.7±1.1 years mean follow-up, new-onset AF occurred in 701 patients (7.9%) and SCD in 151 patients (1.7%). In univariate Cox analyses, new-onset AF was associated with a >4-fold higher risk of SCD (hazard ratio, 4.69; 95% CI interval, 2.96–7.45; P<0.001). In multivariate Cox analyses adjusting for age, sex, race, diabetes mellitus, history of heart failure, myocardial infarction, ischemic heart disease, stroke, smoking, serum high-density lipoprotein cholesterol, creatinine, glucose, and urine albumin/creatinine ratio as standard risk factors, and for incident myocardial infarction, in-treatment use of digoxin, systolic and diastolic pressure, heart rate, QRS duration, Cornell voltage-duration product, and Sokolow-Lyon voltage left ventricular hypertrophy treated as time-varying covariates, new-onset AF remained associated with a >3-fold increased risk of SCD (hazard ratio, 3.13; 95% confidence interval, 1.87–5.24; P<0.001). Conclusions—Development of new-onset AF identifies hypertensive patients at increased risk of SCD. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260.

Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction – A LIFE review

Cornell product criteria, Sokolow-Lyon voltage criteria and electrocardiographic (ECG) strain (secondary ST-T abnormalities) are markers for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, the relationship of regression of ECG LVH and strain during antihypertensive therapy to cardiovascular (CV) risk was unclear before the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. We reviewed findings on ECG LVH regression and strain over time in 9193 hypertensive patients with ECG LVH at baseline enrolled in the LIFE study. The composite endpoint of CV death, nonfatal MI, or stroke occurred in 1096 patients during 4.8±0.9years follow-up. In Cox multivariable models adjusting for randomized treatment, known risk factors including in-treatment blood pressure, and for severity ECG LVH by Cornell product and Sokolow-Lyon voltage, baseline ECG strain was associated with a 33% higher risk of the LIFE composite endpoint (HR. 1.33, 95% CI [1.11-1.59]). Development of new ECG strain between baseline and year-1 was associated with a 2-fold increased risk of the composite endpoint (HR. 2.05, 95% CI [1.51-2.78]), whereas the risk associated with regression or persistence of ECG strain was attenuated and no longer statistically significant (both p>0.05). After controlling for treatment with losartan or atenolol, for baseline Framingham risk score, Cornell product, and Sokolow-Lyon voltage, and for baseline and in-treatment systolic and diastolic blood pressure, 1 standard deviation (SD) lower in-treatment Cornell product was associated with a 14.5% decrease in the composite endpoint (HR. 0.86, 95% CI [0.82-0.90]). In a parallel analysis, 1 SD lower in-treatment Sokolow-Lyon voltage was associated with a 16.6% decrease in the composite endpoint (HR. 0.83, 95% CI [0.78-0.88]). The LIFE study shows that evaluation of both baseline and in-study ECG LVH defined by Cornell product criteria, Sokolow-Lyon voltage criteria or ECG strain improves prediction of CV events and that regression of ECG LVH during antihypertensive treatment is associated with better outcome, independent of blood pressure reduction.

Statin Treatment, New-Onset Diabetes, and Other Adverse Effects: A Systematic Review

Statin treatment prevents cardiovascular diseases probably beyond their lipid-lowering effect. Increasing evidence suggests that statins might increase the risk of new-onset diabetes; however, diabetes is known to increase the risk of cardiovascular diseases. The majority of the literature suggests an increased risk of new-onset diabetes in patients treated with statins in a number of different settings and that the risk appears greatest among the more potent statins. Furthermore, a dose-response curve has been shown between statin treatment and the development of diabetes. Possible mechanisms include muscle insulin resistance, lower expression of GLUT-4 in adipocytes impairing glucose tolerance and suppression of glucose-induced elevation of intracellular Ca2+ level. However, other side effects have been reported such as increased risk of myotoxicity, increased liver enzymes, cataracts, mood disorders, dementias, hemorrhagic stroke and peripheral neuropathy, which should maybe be added to the increased risk of new-onset diabetes, when considering the risk- benefit ratio of statin treatment.

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.

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.

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.

Systolic left ventricular function according to left ventricular concentricity and dilatation in hypertensive patients: the Losartan Intervention For Endpoint reduction in hypertension study.

Background: Left ventricular hypertrophy [LVH, high left ventricular mass (LVM)] is traditionally classified as concentric or eccentric based on left ventricular relative wall thickness. We evaluated left ventricular systolic function in a new four-group LVH classification based on left ventricular dilatation [high left ventricular end-diastolic volume (EDV) index and concentricity (LVM/EDV(2/3))] in hypertensive patients. Methods and results: Nine hundred thirty-nine participants in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy had measurable LVM at enrolment. Patients with LVH (LVM/body surface area ≥116 g/m2 in men and ≥96 g/m2 in women) were divided into four groups; ‘eccentric nondilated’ (normal LVM/EDV and EDV), ‘eccentric dilated’ (increased EDV, normal LVM/EDV), ‘concentric nondilated’ (increased LVM/EDV with normal EDV), and ‘concentric dilated’ (increased LVM/EDV and EDV) and compared to patients with normal LVM. At baseline, 12% had eccentric nondilated, 20% eccentric dilated, 29% concentric nondilated, and 14% concentric dilated LVH, with normal LVM in 25%. Compared with the concentric nondilated LVH group, those with concentric dilated LVH had significantly lower pulse pressure/stroke index and ejection fraction; higher LVM index, stroke volume, cardiac output, left ventricular midwall shortening, left atrial volume and isovolumic relaxation time; and more had segmental wall motion abnormalities (all P < 0.05). Similar differences existed between patients with eccentric dilated and those with eccentric nondilated LVH (all P < 0.05). Compared with patients with normal LVM, the eccentric nondilated had higher LV stroke volume, pulse pressure/stroke index, Cornell voltage product and SBP, and lower heart rate and fewer were African-American (all P < 0.05). Conclusion: The new four-group classification of LVH identifies dilated subgroups with reduced left ventricular function among patients currently classified with eccentric or concentric LVH.

Psoriasis is associated with subsequent atrial fibrillation in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint study.

Background: Inflammation contributes to the pathogenesis of psoriasis as well as atrial fibrillation. The impact of psoriasis and its association with new-onset atrial fibrillation was assessed in hypertensive patients with left ventricular hypertrophy (LVH). Methods: The predictive value of baseline or incident psoriasis for new-onset atrial fibrillation was evaluated in 7099 hypertensive patients with electrocardiographic LVH with no history of atrial fibrillation or other cardiovascular disease, in sinus rhythm on their baseline electrocardiogram. Results: A total of 154 patients (2.2%) had or developed psoriasis and new-onset atrial fibrillation occurred in 506 patients (7.1%) during a mean follow-up of 4.7 ± 1.1 years. At baseline, the psoriasis patients were younger (65 ± 7 vs. 67 ± 7 years) and had less left ventricle hypertrophy by ECG Sokolow-Lyon voltage (27.6 ± 9.7 vs. 30.1 ± 10.4 mm); higher hemoglobin (6.3 ± 2.2 vs. 6.0 ± 2.7 mmol/l) and prevalence of diabetes (20.6 vs. 12.8%, P ⩽ 0.004) than patients without psoriasis. In multivariable Cox analysis, adjusting for age, sex, hemoglobin, diabetes, time-varying SBP, heart rate, study treatment and Sokolow-Lyon hypertrophy, psoriasis, treated as a time-varying covariate, was associated with a two-fold higher risk of new-onset atrial fibrillation [hazard ratio: 1.97 (95% confidence interval (CI): 1.18–3.30), P = 0.01]. Propensity-matched analysis yielded similar results (odds ratio: 3.49, 95% CI 1.24–9.81, P = 0.018). Conclusion: Psoriasis has a similar prevalence in hypertensive patients as in the general population. Psoriasis independently predicted new-onset atrial fibrillation despite lower age and electrocardiographic LVH in psoriasis patients than in patients without psoriasis.