Nitin Mahajan

Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A Mendelian Randomization Analysis

OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). BACKGROUND LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. RESULTS All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)). CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Diagnostic accuracy of myocardial perfusion imaging and stress echocardiography for the diagnosis of left main and triple vessel coronary artery disease: a comparative meta-analysis

Objectives Compare the diagnostic performance of stress echocardiography (SE) and myocardial perfusion imaging (MPI) for the diagnosis of left main disease (LM) and triple vessel disease (TVD). Background Limited comparative data on MPI and SE for the detection of LM and TVD (high-risk coronary artery disease) exist in the literature. Methods Quantitative meta-analysis was performed using studies identified by systematic electronic literature search. Articles were included if they reported data on exercise, dobutamine SE or exercise, adenosine, dipyridamole, thallium201, technetium 99m sestamibi MPI and used coronary angiography as the reference test. Summary receiver-operating characteristic (SROC) curves were constructed for each imaging modality. Additionally, pooled sensitivity, specificity and likelihood ratios were calculated per modality. Meta-regression was performed to adjust for patient and study characteristics. Results Thirty-two studies met inclusion criteria; 23 (MPI-15; SE-14; Common studies-6) provided sufficient data for analysis. In a SROC model comparing the two imaging modalities, SE was associated with higher area under curve (0.82 (0.03) vs 0.73 (0.02), p=0.01) and index Q* value (0.75 (0.02) vs 0.67 (0.02), p=0.01). Using pooled summary point estimates, SE had higher pooled sensitivity (94% vs 75%, p<0.001) and lower negative likelihood ratio (0.21 vs 0.47, p<0.001) compared to MPI. No evidence of a difference in the pooled specificity (40% vs 48%, p=0.16) and positive likelihood ratio (1.52 vs 1.58, p=0.36) was seen between the two stress modalities. Pooled diagnostic OR on meta-regression (9.78 vs 4.06, p=0.02) remained significantly higher for SE compared to MPI for identification of LM and TVD even after adjustment for study characteristics. Conclusions Since LM alone or in combination with TVD are categorised as representing potentially life-threatening variants of CAD, a screening test with high sensitivity, low negative likelihood ratio or higher discriminatory capacity would be desirable for risk stratification. In the absence of a direct head-to-head comparison of the diagnostic accuracies of SE and MPI, our findings indicate that SE appears to be the preferred screening modality for high-risk coronary artery disease.

Clinical Effect of Naturally Random Allocation to Lower Systolic Blood Pressure Beginning Before the Development of Hypertension

Systolic blood pressure (SBP) rises approximately linearly with age in most societies. The cause of this rise is unclear. We tested the hypothesis that SBP is causally associated with the rate of rise in SBP with age by evaluating the effect of 12 polymorphisms associated with lower SBP on the age-related rate of rise in SBP in a series of meta-regression analyses involving ⩽199 477 participants in 63 studies. We then evaluated the effect of these polymorphisms on the odds of coronary heart disease in 22 223 case and 64 762 control subjects and compared it with the effect of lower SBP observed in both prospective cohort studies and blood pressure–lowering randomized trials. All 12 polymorphisms were associated with both lower SBP and a slower age-related rise in SBP. The weighted mean effect of these 12 polymorphisms was associated with a 0.32-mm Hg lower SBP (P=1.79×10−7) and a 0.093-mm Hg/decade slower age-related rise in SBP (P=3.05×10−5). The effect of long-term exposure to lower SBP on coronary heart disease mediated by these polymorphisms was 2-fold greater than that observed in prospective cohort studies (P=0.006) and 3-fold greater than that observed in short-term blood pressure treatment trials (P=0.001). We conclude therefore that SBP seems to be causally associated with the rate of rise in SBP with age and has a cumulative effect on the risk of coronary heart disease.

The Role of Early LDL Lowering to Prevent the Onset of Atherosclerotic Disease

Coronary atherosclerosis is a chronic progressive disease that begins early in life and progresses slowly over several decades before becoming clinically manifest. The causal relationship between low-density lipoprotein cholesterol (LDL-C) and the risk of coronary atherosclerosis is well established. Multiple randomized trials have demonstrated that lowering LDL-C levels during treatment with a statin reduces the risk of major atherosclerotic coronary events. However, individuals being treated with a statin continue to experience a high residual risk of events. Here we review the evidence that lowering LDL-C levels beginning earlier in life, and therefore earlier in the atherosclerotic disease process, can prevent or substantially delay the development of atherosclerosis and thereby substantially improve the clinical benefit of therapies that lower LDL-C levels. We focus on providing a critical appraisal of the naturally randomized evidence that is emerging from recently conducted genetic association studies.

Cardiac Magnetic Resonance Imaging in Peripartum Cardiomyopathy

Background:Peripartum cardiomyopathy (PPCM) is a rare life-threatening condition of unclear etiology. Data on the use of cardiac magnetic resonance (CMR) imaging to characterize PPCM are limited. This study was done to assess the role of CMR imaging for the diagnosis and prognostication of patients with PPCM. Methods:Medical records of a tertiary medical center were screened for PPCM patients with CMR imaging done within the past 5 years (2006–2011). Images were reviewed by 2 expert radiologists (blinded to clinical data) using cine sequences for chamber function and size, T2-weighted images for the determination of edema (T2-ratio), and late gadolinium enhancement (LGE) sequences for myocardial tissue characterization. Results:Ten PPCM patients (aged 28 ± 6 years, 90% African American) had a total of 15 CMR examinations: 4 in the acute phase (within 7 days of diagnosis) and 11 during follow-up (median, 12 months; range, 1–72 months). Left ventricular ejection fraction was decreased in all 4 initial scans. Elevated T2 ratio (>2) seen in 1 patient decreased on follow-up imaging. LGE was seen in 1 of the 4 acute-phase scans and in 4 of the 11 follow-up phase scans. These 4 patients had multiple readmissions because of heart failure exacerbations and persistently low left ventricular ejection fraction on subsequent echocardiograms. Conclusions:LGE seems to be associated with a poor prognosis in the setting of PPCM. CMR imaging seems to have promising practical implications in the diagnosis and prognostication of PPCM patients.

Role of Non-High-Density Lipoprotein Cholesterol in Predicting Cerebrovascular Events in Patients Following Myocardial Infarction

Although there appears to be a role for statins in reducing cerebrovascular events, the exact role of different lipid fractions in the etiopathogenesis of cerebrovascular disease (CVD) is not well understood. A secondary analysis of data collected for the placebo arm (n = 2,078) of the Cholesterol and Recurrent Events (CARE) trial was performed. The CARE trial was a placebo-controlled trial aimed at testing the effect of pravastatin on patients after myocardial infarction. Patients with histories of CVD were excluded from the study. A Cox proportional-hazards model was used to evaluate the association between plausible risk factors (including lipid fractions) and risk for first incident CVD in patients after myocardial infarction. At the end of 5 years, 123 patients (6%) had incident CVD after myocardial infarction (76 with stroke and 47 with transient ischemic attack). Baseline non-high-density lipoprotein (HDL) cholesterol level emerged as the only significant lipid risk factor that predicted CVD; low-density lipoprotein cholesterol and HDL cholesterol were not significant. The adjusted hazard ratios (adjusted for age, gender, hypertension, diabetes mellitus, and smoking) for CVD were 1.28 (95% confidence interval [CI] 1.06 to 1.53) for non-HDL cholesterol, 1.14 (95% CI 0.96 to 1.37) for low-density lipoprotein cholesterol, and 0.90 (95% CI 0.75 to 1.09) for HDL cholesterol (per unit SD change of lipid fractions). This relation held true regardless of the level of triglycerides. After adjustment for age and gender, the hazard ratio for the highest natural quartile of non-HDL was 1.76 (95% CI 1.05 to 2.54), compared to 1.36 (95% CI 0.89 to 1.90) for low-density lipoprotein cholesterol. In conclusion, non-HDL cholesterol is the strongest predictor among the lipid risk factors of incident CVD in patients with established coronary heart disease.

Calcific aortic valve and spontaneous embolic stroke: a review of literature.

Aortic valve calcification is common in the elderly and in patients with congenital bicuspid aortic valve but unlike calcific mitral valve disease it is not a well recognized risk factor for stroke. Although autopsy studies have revealed evidence of systemic embolism in one-third of cases with calcific aortic valves, there is conflicting data from larger clinical studies examining the association between calcific aortic valve and stroke. There are only 8 reported cases of symptomatic stroke from spontaneous cerebral thromboembolism associated with calcific aortic valve in the literature. Computerized tomography (CT) angiography and CT without contrast are modalities of choice to diagnose calcific embolism, while MRI may be useful in delineating the extent of ischemia. Ideal management strategy, the role of antiplatelet therapy, anticoagulation or recommendations for valve replacements are poorly defined. We present a focused literature review on this topic.

Stroke secondary to calcific bicuspid aortic valve: Case report and literature review

BACKGROUND Aortic valve calcification is common in rheumatic endocarditis, elderly patients, and congenital bicuspid aortic valve. It is not a recognized risk factor for stroke. We report a case of non-calcific embolization from calcified bicuspid aortic valve. METHODS A 52-year-old male with bicuspid aortic valve presented with aphasia and right arm weakness of less than 3h duration. CT head revealed hypodensity in the left middle cerebral artery (MCA) distribution and laboratory testing showed factor V leiden heterozygosity. The patient improved after intra-arterial tissue plasminogen activator (t-PA), but developed recurrence of right sided hemiparesis and silent myocardial infarction (MI). Cerebral angiography revealed clot in the left MCA. The patient received t-PA followed by transcatheter clot retrieval and was started on anticoagulation. CONCLUSIONS Embolization from calcific bicuspid aortic valves can lead to stroke and MI. Conservative management with anticoagulation for treatment of associated poststagnation thrombosis or aortic valve replacement as treatment is debatable. This patient was successfully managed with anticoagulation.

Predictors of stroke in patients with severe systolic dysfunction in sinus rhythm: Role of echocardiography

BACKGROUND Congestive heart failure in sinus rhythm ranks second after atrial fibrillation (AF) among cardiogenic risk-factors for stroke. Clinical and echocardiographic predictors of stroke in this high-risk population remain poorly defined. METHODS Retrospective screening of 1886 consecutive patients with severe systolic dysfunction (LVEF ≤35%) at a tertiary medical center echocardiography database (Nov 2005-Sep 2008) identified 83 patients in sinus rhythm with cardioembolic stroke. Patients with AF on follow-up, prosthetic valve, ventricular arrhythmia and lack of consensus between reviewing neurologists were excluded (n=10). Consecutive age and gender-matched controls in sinus rhythm formed GpII (n=73). RESULTS The incidence of stroke was 3.9% (73/1886) over 35 months in this study. There were no significant differences in prevalence of established clinical risk-factors for stroke. There was a significantly higher prevalence of LV non-compaction (p=0.02), aneurysm (p<0.01), spontaneous echo-contrast (p<0.01) and pulmonary hypertension (p<0.001) in GpI. CONCLUSIONS LV non-compaction, aneurysm, spontaneous echo-contrast and pulmonary hypertension are associated with an increased risk of stroke. While anticoagulation of these high-risk subgroups appears reasonable, further study in a prospective randomized clinical trial merits consideration.

Single-photon emission computed tomography myocardial perfusion imaging in the diagnosis of left main disease

Left main disease (LMD), defined as ≥ 50% lesion stenosis, occurs in 3% to 5% of patients undergoing catheterization. Limited data on the value of single‐photon emission computed tomography (SPECT) imaging for diagnosis of LMD exists.