Avinainder Singh

Coronary Artery Disease Detected by Coronary Computed Tomographic Angiography Is Associated With Intensification of Preventive Medical Therapy and Lower Low-Density Lipoprotein Cholesterol

Background—Coronary computed tomographic angiography (CCTA) is an accurate test for the identification of coronary artery disease (CAD), yet the impact of CCTA results on subsequent medical therapy and risk factors has not been widely reported. Methods and Results—We identified consecutive patients aged >18 years without prior CAD who underwent CCTA from 2004 to 2011 and had complete data on medications before and after CCTA. CCTA results were categorized as no CAD, <50% stenosis, and ≥50% stenosis. Based on the number of involved segments, extent of disease was categorized as nonextensive (⩽4 segments) or extensive CAD (>4 segments). Electronic medical records and patient interviews were reviewed blinded to CCTA findings to assess initiation of aspirin and intensification of lipid-lowering therapies. Survival analysis was performed to evaluate intensification of lipid therapy as a predictor of cardiovascular death or nonfatal myocardial infarction. Among 2839 patients with mean follow-up of 3.6 years, the odds of physician intensification of lipid-lowering therapy significantly increased for those with nonobstructive CAD (odds ratio, 3.6; 95% confidence interval, 2.9–4.9; P<0.001) and obstructive CAD (odds ratio, 5.6; 95% confidence interval, 4.3–7.3; P<0.001). Low-density lipoprotein cholesterol levels declined significantly in association with intensification of lipid-lowering therapy after CCTA in all patient subgroups. In a hypothesis-generating analysis, among patients with nonobstructive but extensive CAD, statin use after CCTA was associated with a reduction in cardiovascular death or myocardial infarction (hazards ratio, 0.18; 95% confidence interval, 0.05–0.66; P=0.01). Conclusions—Abnormal CCTA findings are associated with downstream intensification in statin and aspirin therapy. In particular, CCTA may lead to increased use of prognostically beneficial therapies in patients identified as having extensive, nonobstructive CAD.

Prevalence of Monoclonal Gammopathy in Wild-Type Transthyretin Amyloidosis

Objective: To evaluate the prevalence of monoclonal gammopathy (MG) in patients with wild‐type transthyretin amyloidosis (ATTRwt) (formerly known as senile amyloidosis). Patients and Methods: We retrospectively analyzed the serum protein electrophoresis and serum immunofixation results, free light chain (FLC) levels, and renal function of 113 consecutive patients with ATTRwt seen at the Brigham and Womens Hospitals Cardiac Amyloidosis Program between February 21, 2006, and November 9, 2016. Monoclonal gammopathy was defined as a monoclonal protein present in the serum. Light chain MG was defined as an abnormal serum FLC &kgr;/&lgr; ratio with an elevated FLC level in the absence of a monoclonal protein. In patients with renal dysfunction, the renal FLC reference range was used. Results: The mean age of the population was 75 years, 3 of the 113 patients (3%) were female, and 110 (97%) were white. Monoclonal gammopathy was present in 26 patients (23%), 24 of whom had monoclonal protein present and 2 others who met criteria for light chain MG. Most clones (12 of 20 [60%]) were &lgr; restricted. Another 7 patients had an abnormal FLC &kgr;/&lgr; ratio in the setting of renal dysfunction. Conclusion: In this study, MG was present in 23% of patients with ATTRwt. The finding of MG or an abnormal FLC &kgr;/&lgr; ratio in an elderly man may cause diagnostic confusion during subtyping of amyloidosis. A high degree of clinical suspicion for ATTRwt and precise tissue typing using mass spectrometry may overcome such diagnostic challenges. Abbreviations and Acronyms: AL amyloidosis = light chain amyloidosis; ATTRwt = wild‐type transthyretin amyloidosis; FLC = free light chain; LC‐MG = light chain monoclonal gammopathy; MG = monoclonal gammopathy; MGUS = monoclonal gammopathy of undetermined significance; SPEP = serum protein electrophoresis

Novel Pharmacotherapies for Cardiac Amyloidosis

&NA; Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis.

Study of young patients with myocardial infarction: Design and rationale of the YOUNG-MI Registry

The YOUNG‐MI registry is a retrospective study examining a cohort of young adults age ≤ 50 years with a first‐time myocardial infarction. The study will use the robust electronic health records of 2 large academic medical centers, as well as detailed chart review of all patients, to generate high‐quality longitudinal data regarding the clinical characteristics, management, and outcomes of patients who experience a myocardial infarction at a young age. Our findings will provide important insights regarding prevention, risk stratification, treatment, and outcomes of cardiovascular disease in this understudied population, as well as identify disparities which, if addressed, can lead to further improvement in patient outcomes.

Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis

Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis Wild-type transthyretin amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF), affecting 13% in a consecutive series of cardiology and internal medicine patients admitted to a university hospital.1 However, the diagnosis is often not considered due to the perceived rarity of the disease. Although the primary manifestation of ATTRwt is cardiac, approximately 50% of patients have a history of carpal tunnel syndrome,2 with amyloid deposits in the flexor tenosynovium.3 Spontaneous rupture of the distal biceps tendon (RBT) is uncommon, with an estimated prevalence of less than 1 per 1000 persons aged 56 to 74 years.4 We observed RBT in several patients with ATTRwt cardiomyopathy, and performed a cross-sectional study to further evaluate.

‘A new staging system for cardiac transthyretin amyloidosis’: is it already on the verge of obsolescence?

Transthyretin (TTR) amyloidosis is considered a rare disease by many cardiologists, yet the past decade has seen a substantial increase in diagnosis, suggesting that it is more common than previously thought. In addition to greater awareness and recognition of typical echocardiographic abnormalities, the use of simple but highly sensitive and specific imaging with bone tracers [Tc-3,3-diphosphono1,2-propanodicarboxylic (DPD) in Europe and Tc-pyrophosphate (PYP) in the USA] or more advanced imaging such as cardiac magnetic resonance imaging have rendered the diagnosis more easily made. Thus many cardiologists, particularly those with an interest in cardiomyopathy, will have experienced a recent surge in diagnosis of wild-type TTR amyloidosis (ATTRwt), and probably a more frequent diagnosis of the Afro-Caribbean amyloidogenic TTR variant, Val122Ile, which is carried by 1 in 30 subjects of African descent living in Europe and the USA. The burden of TTR amyloidosis among heart failure patients is not small. Small series of patients have tantalizingly implied that >10% of patients with diastolic heart failure may have a contributing component of ATTRwt amyloid, and that the Val122Ile variant TTR amyloidosis is the fourth most common cause of heart failure in Afro-Caribbean patients in London. A diagnosis of TTR cardiac amyloidosis as a cause of heart failure may not, until recently, have helped the individual patient much, except for avoidance of potentially harmful drug therapy such as calcium channel blockers and possibly beta-blockade. However, this is changing rapidly. Amyloidogenesis can be slowed or prevented by stabilizing the precursor protein (TTR) or by significantly lowering TTR levels, two very different mechanisms. The first trial of a TTR stabilizer, tafamadis, is expected to report results by mid-2018, and transthyretinlowering drugs for TTR cardiomyopathy are likely to enter clinical trials in the same year. Progress in gene silencing therapy and protein stabilization have led to major therapeutic advances, and recently reported clinical trials in hereditary familial amyloid polyneuropathy have demonstrated very strong positive effects on stabilizing, and possibly even improving, the neuropathy (NCT0196034 and NCT01737398). Transthyretin cardiomyopathy may present as new-onset heart failure or atrial arrhythmia, or may be identified in an asymptomatic patient investigated for an abnormal electrocardiogram. However, the rapid advances in understanding and diagnosis of TTR cardiomyopathy have been ahead of our ability to offer an accurate prognosis at the time of diagnosis. For example, while there is no doubt that untreated cardiac TTR amyloidosis has a far better prognosis than untreated cardiac light-chain (AL) amyloidosis, there remains debate as to whether ATTRwt and mutant TTR (ATTRm) cardiomyopathies differ in prognosis (and, if so, why) and whether subgroups of ATTRm amyloidosis cardiomyopathy with differing prognoses can be identified. Although TTR amyloidosis is increasingly diagnosed, it is still relatively uncommon, and clinical trials, current and planned, are by necessity quite small. Given the rapidly emerging novel therapies, the ability to precisely determine prognostic groups for risk stratification in clinical trials becomes critical, in order to avoid a false-negative outcome of an effective drug. It is for this and other reasons that an accurate staging system would be of great value. A staging system for AL amyloidosis was developed some years ago by the Mayo Clinic. It included patients with a spectrum of cardiac and non-cardiac disease, but of the three prognostic factors on multivariate analysis, two (NT-proBNP and troponin T) are markers of cardiac involvement, with the third a haematological marker. Based on the subsequent use and utility of this staging system, the same group published data showing that NT-proBNP and troponin T are useful in stratifying risk in ATTRwt using similar cut-off values.

Reply: Cardiovascular Risk Models and Statin Therapy

We thank Dr. DuBroff for his interest in our paper from the YOUNG-MI registry showing that most patients who experienced a myocardial infarction below the age of 50 years would not have been considered eligible for statin therapy by current guidelines [(1)][1]. We completely agree that better

Type 2 Myocardial Infarction and the Hospital Readmission Reduction Program

Central Illustration: The Potential Implications of Including Type 2 Myocardial Infarction in the Hospital Readmission Reduction Program. Abbreviations: CABG= Coronary Artery Bypass Grafting, COPD= Chronic Obstructive Pulmonary Disease, HF= Heart Failure, HRRP= Hospital Readmissions Reduction Program, ICD: International Statistical Classification of Diseases and Related Health Problems, T1MI= Type 1 Myocardial Infarction, T2MI= Type 2 Myocardial Infarction.

Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis

Importance Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection. Objective To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States. Design, Setting, and Participants In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention’s Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed. Exposures Region of residence. Main Outcomes and Measures Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence. Results Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals. Conclusions and Relevance The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.

True, true unrelated? Coexistence of Waldenström macroglobulinemia and cardiac transthyretin amyloidosis

Waldenstrom’s macroglobulinemia (WM) is an indolent disorder that may not always require treatment. Among the indications for treatment is the co-existence of light chain (AL) amyloidosis,[1][1] reported to affect nearly 3% of patients.[2][2] In a multicenter study of 72 individuals with IgM-