Preservation of Circumferential and Radial Left Ventricular Function as a Mitigating Mechanism for Impaired Longitudinal Strain in Early Cardiac Amyloidosis.

BACKGROUND: In patients with cardiac amyloidosis (CA), left ventricular ejection fraction (LVEF) is frequently preserved, despite commonly reduced global longitudinal strain (GLS). We hypothesized that nonlongitudinal contraction may initially serve as a mitigating mechanism to maintain cardiac output and studied the relationship between global circumferential (GCS) and radial (GRS) strain with LVEF and extracellular volume (ECV), a marker of amyloid burden. METHODS: Patients with CA who underwent cardiac magnetic resonance (CMR; n = 140, 70.7 ± 11.5 years, 66% male) or echocardiography (n = 67, 71 ± 13 years, 66% male) and normal controls (CMR, n = 20; echocardiography, n = 45) were retrospectively identified, and GCS, GLS, and GRS were quantified using feature-tracking CMR or speckle-tracking echocardiography and compared between CA patients with preserved and reduced LVEF (CAHFpEF, CAHFrEF) and controls. The prevalence of impaired strain (magnitudes <2.5th percentile of the controls) was compared between CAHFpEF and CAHFrEF and between ECV quartiles. RESULTS: While echocardiography-derived GLS was impaired in both CAHFpEF (-13.4% ± 3.1%, P < .003) and CAHFrEF (-9.1% ± 3.2%, P < .003), compared with controls (-20.8% ± 2.4%), GCS was more impaired in CAHFrEF compared with both controls (-15.6% ± 5.0% vs -32.3% ± 3.3%, P < .003) and CAHFpEF (-30.4% ± 5.7%, P < .003) and did not differ between CAHFpEF and controls (P = .24). The prevalence of abnormal CMR-derived GCS (P < .0001) and GRS (P < .0001) but not GLS (P = .054) varied significantly across ECV quartiles. CONCLUSIONS: Among CA patients with preserved LVEF, preserved GCS and GRS, despite near-universally impaired GLS, may be explained by an initial predominantly subendocardial involvement, where mostly longitudinal fibers are located. If confirmed in future studies, these findings may facilitate identification of patients with early stages of CA, when treatments may be most effective.

Non-invasive diagnosis of transthyretin cardiac amyloidosis utilizing typical late gadolinium enhancement pattern on cardiac magnetic resonance and light chains.

AIMS: While cardiac magnetic resonance (CMR) is often obtained early in the evaluation of suspected cardiac amyloidosis (CA), it currently cannot be utilized to differentiate immunoglobulin (AL) and transthyretin (ATTR) CA. We aimed to determine whether a novel CMR and light-chain biomarker-based algorithm could accurately diagnose ATTR-CA. METHODS AND RESULTS: Patients with confirmed AL or ATTR-CA with typical late gadolinium enhancement (LGE) and Look-Locker pattern for CA on CMR were retrospectively identified at three academic medical centres. Comprehensive light-chain analysis including free light chains, serum, and urine electrophoresis/immunofixation was performed. The diagnostic accuracy of the typical CMR pattern for CA in combination with negative light chains for the diagnosis of ATTR-CA was determined both in the entire cohort and in the subset of patients with invasive tissue biopsy as the gold standard. A total of 147 patients (age 70 ± 11, 76% male, 51% black) were identified: 89 ATTR-CA and 58 AL-CA. Light-chain biomarkers were abnormal in 81 (55%) patients. Within the entire cohort, the sensitivity and specificity of a typical LGE and Look-Locker CMR pattern and negative light chains for ATTR-CA was 73 and 98%, respectively. Within the subset with biopsy-confirmed subtype, the CMR and light-chain algorithm were 69% sensitive and 98% specific. CONCLUSION: The combination of a typical LGE and Look-Locker pattern on CMR with negative light chains is highly specific for ATTR-CA. The successful non-invasive diagnosis of ATTR-CA using CMR has the potential to reduce diagnostic and therapeutic delays and healthcare costs for many patients.

T2 mapping in myocardial disease: a comprehensive review.

Cardiovascular magnetic resonance (CMR) is considered the gold standard imaging modality for myocardial tissue characterization. Elevated transverse relaxation time (T2) is specific for increased myocardial water content, increased free water, and is used as an index of myocardial edema. The strengths of quantitative T2 mapping lie in the accurate characterization of myocardial edema, and the early detection of reversible myocardial disease without the use of contrast agents or ionizing radiation. Quantitative T2 mapping overcomes the limitations of T2-weighted imaging for reliable assessment of diffuse myocardial edema and can be used to diagnose, stage, and monitor myocardial injury. Strong evidence supports the clinical use of T2 mapping in acute myocardial infarction, myocarditis, heart transplant rejection, and dilated cardiomyopathy. Accumulating data support the utility of T2 mapping for the assessment of other cardiomyopathies, rheumatologic conditions with cardiac involvement, and monitoring for cancer therapy-related cardiac injury. Importantly, elevated T2 relaxation time may be the first sign of myocardial injury in many diseases and oftentimes precedes symptoms, changes in ejection fraction, and irreversible myocardial remodeling. This comprehensive review discusses the technical considerations and clinical roles of myocardial T2 mapping with an emphasis on expanding the impact of this unique, noninvasive tissue parameter.

Prevalence and haemodynamic profiles of pulmonary hypertension in cardiac amyloidosis.

OBJECTIVES: While cardiac amyloidosis (CA) classically involves the left ventricle (LV), less is known about its impact on the right ventricle (RV) and pulmonary vasculature. We performed a retrospective analysis to identify the prevalence and types of pulmonary hypertension (PH) profiles in CA and to determine haemodynamic and cardiovascular magnetic resonance (CMR) predictors of major adverse cardiovascular events (MACE). METHODS: Patients with CA who underwent CMR and right heart catheterisation (RHC) within 1 year between 2010 and 2019 were included. Patients were assigned the following haemodynamic profiles based on RHC: no PH, precapillary PH, isolated postcapillary PH (IPCPH), or combined precapillary and postcapillary PH (CPCPH). The relationship between PH profile and MACE (death, heart failure hospitalisation) was assessed using survival analysis. CMR and RV parameters were correlated with MACE using Cox-regression analysis. RESULTS: A total of 52 patients were included (age 69±9 years, 85% men). RHC was performed during biopsy in 44 (85%) and for clinical indications in 8 (15%) patients. Rates of no PH, precapillary PH, IPCPH and CPCPH were 5 (10%), 3 (6%), 29 (55%) and 15 (29%), respectively. Haemodynamic PH profile did not correlate with risk of death (p=0.98) or MACE (p=0.67). Transpulmonary gradient (TPG) (HR 0.88, CI 0.80 to 0.97), RV, (HR 0.95, CI 0.92 to 0.98) and LV ejection fraction (HR 0.95, CI 0.92 to 0.98) were significantly associated with MACE. CONCLUSIONS: PH is highly prevalent in CA, even at the time of diagnosis. While IPCPH was most common, CPCPH is not infrequent. TPG and RV ejection fraction (RVEF) are prognostic markers in this population.

Atrial function and geometry differences in transthyretin versus immunoglobulin light chain amyloidosis: a cardiac magnetic resonance study.

To determine the differences in left atrial (LA) function and geometry assessed by cardiac magnetic resonance (CMR) between transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis (CA). We performed a retrospective analysis of 54 consecutive patients (68.5% male, mean age 67 ± 11 years) with confirmed CA (24 ATTR, 30 AL) who underwent comprehensive CMR examinations. LA structural and functional assessment including LA volume, LA sphericity index, and LA strain parameters were compared between both subtypes. In addition, 15 age-matched controls were compared to all groups. Patients with ATTR-CA were older (73 ± 9 vs. 62 ± 10 years, p < 0.001) and more likely to be male (83.3% vs. 56.7%, p = 0.036) when compared to AL-CA. No significant difference existed in LA maximum volume and LA sphericity index between ATTR-CA and AL-CA. LA minimum volumes were larger in ATTR-CA when compared with AL-CA. There was a significant difference in LA function with worse strain values in ATTR vs AL: left atrial reservoir [7.4 (6.3-12.8) in ATTR vs. 13.8 (6.90-24.8) in AL, p = 0.017] and booster strains [3.6 (2.6-5.5) in ATTR vs. 5.2 (3.6-12.1) in AL, p = 0.039]. After adjusting for age, LA reservoir remained significantly lower in ATTR-CA compared to AL-CA (p = 0.03), but not LA booster (p = 0.16). We demonstrate novel differences in LA function between ATTR-CA and AL-CA despite similar LA geometry. Our findings of more impaired LA function in ATTR may offer insight into higher AF burden in these patients.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

[Figure: see text].

Indexed left ventricular mass to QRS voltage ratio is associated with heart failure hospitalizations in patients with cardiac amyloidosis.

In cardiac amyloidosis (CA), amyloid infiltration results in increased left ventricular (LV) mass disproportionate to electrocardiographic (EKG) voltage. We assessed the relationship between LV mass-voltage ratio with subsequent heart failure hospitalization (HHF) and mortality in CA. Patients with confirmed CA and comprehensive cardiovascular magnetic resonance (CMR) and EKG exams were included. CMR-derived LV mass was indexed to body surface area. EKG voltage was assessed using Sokolow, Cornell, and Limb-voltage criteria. The optimal LV mass-voltage ratio for predicting outcomes was determined using receiver operating characteristic curve analysis. The relationship between LV mass-voltage ratio and HHF was assessed using Cox proportional hazards analysis adjusting for significant covariates. A total of 85 patients (mean 69 ± 11 years, 22% female) were included, 42 with transthyretin and 43 with light chain CA. At a median of 3.4-year follow-up, 49% of patients experienced HHF and 60% had died. In unadjusted analysis, Cornell LV mass-voltage ratio was significantly associated with HHF (HR, 1.05; 95% CI 1.02-1.09, p = 0.001) and mortality (HR, 1.05; 95% CI 1.02-1.07, p = 0.001). Using ROC curve analysis, the optimal cutoff value for Cornell LV mass-voltage ratio to predict HHF was 6.7 gm/m2/mV. After adjusting for age, NYHA class, BNP, ECV, and LVEF, a Cornell LV mass-voltage ratio > 6.7 gm/m2/mV was significantly associated with HHF (HR 2.25, 95% CI 1.09-4.61; p = 0.03) but not mortality. Indexed LV mass-voltage ratio is associated with subsequent HHF and may be a useful prognostic marker in cardiac amyloidosis.

Is mitral valve disease treated differently in men and women?

PURPOSE: This study was performed to determine if there is a sex-based bias in referral practices, complexity of disease, surgical treatment, or outcomes in patients undergoing mitral valve surgery at our institution. METHODS: Data were collected from the Cardiovascular Research Database of the Clinical Trial Unit of the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital and they were defined according to the Society of Thoracic Surgeons National Database ( www.sts.org ). All patients who had mitral valve replacement, mitral valve repair with annuloplasty ring placement, and mitral valve annuloplasty alone were evaluated, including patients who underwent concomitant tricuspid valve surgery, atrial fibrillation ablation, patent foramen ovale closure, and coronary artery bypass grafting. An unmatched comparison was made between the 836 men and 600 women in the entire cohort (N = 1436) and propensity score-matching was performed in 423 pairs of men and women. Additional propensity score-matching for 219 pairs of men and women with Type II mitral valve functional class and no coronary artery disease and for 68 pairs of men and women with Type 1 or Type IIIb mitral valve functional class. Propensity score matching was used to compare sex differences involving a greedy algorithm with a caliper of size 0.1 logit propensity score standard deviation units. RESULTS: Between 1 April 2004 and 30 June 2017, 1436 patients (41.8% women, mean age 61.1 ± 12.6 years (men), 62.9 ± 13.3 years (women)) underwent mitral valve surgery. The unmatched comparison for the entire cohort showed that, on average, at the time of surgery, women had higher Society of Thoracic Surgery risk scores, were older and had more heart failure, coronary artery disease, and mitral stenosis than men. Women received proportionately fewer mitral repairs and more atrial fibrillation ablation, and tricuspid valve surgery. Women had longer intensive care unit and hospital stays, required more dialysis, and suffered more transient ischemic attacks and cardiac arrests postoperatively, and 30-day mortality rate was higher for women. However, propensity score-matching of 846 of the patients (423 men; 423 women) indicated that both the surgical approaches and surgical outcomes were comparable for men and women who had similar levels of disease and co-morbidities. Additional propensity score-matching of only those patients with degenerative mitral regurgitation (DMR) (219 men; 219 women) and those with Type 1 or Type III mitral valve disease showed no differences in the surgical procedures performed or in 30-day mortality rates. CONCLUSIONS: Women appear to be referred for mitral valve surgery later in the course of their disease, which could possibly be on the basis of sex bias, but they may also have a more aggressive form of mitral valve disease than men. Regardless of the reasons for the later referral of women for mitral valve surgery, the clinical outcomes are dependent upon the severity of the mitral disease and associated co-morbidities at the time of surgery, not on the basis of sex bias.

Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage.

BACKGROUND: Myocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes. METHOD AND RESULTS: We quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than "nonischemic" MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01). CONCLUSION: MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.

Frequency of clinically unsuspected myocardial injury at a children's hospital.

BACKGROUND: Ill children are at risk but rarely screened for myocardial injury. The frequency of such injury in ill children is unknown. Elevated levels of plasma cardiac troponin I (cTnI) can detect subclinical myocardial injury. METHODS: We measured cTnI levels from 283 Children's Hospital, Boston patients (median age 2.10 years, range 0.13-22.4 years) seen in an outpatient or emergency clinic without clinically apparent cardiac disease. We took > or = 0.5 ng/mL as an indication of myocardial injury. We also measured plasma creatine kinase-MB, total creatine kinase, and myoglobin, and performed a chart review. RESULTS: Fifteen (7.8%) of the 193 acutely ill children and 4 (4.4%) of the 90 well children had an elevated cTnI level (P = .44). Within the acutely ill group, the children with elevated cTnI were younger and had lower mean hemoglobin and hematocrit levels. Cardiac troponin I levels correlated with creatine kinase-MB (r = 0.22; P < .001) but not with creatine kinase or myoglobin. The 4 children with cTnI > 0.89 ng/mL, who also had plasma cardiac troponin T measured, showed cardiac troponin T elevations that were consistent with unstable angina levels in adults. Four children had high-level cTnI elevations (> 2 ng/mL) consistent with acute myocardial infarction levels in adults. CONCLUSIONS: Elevated cTnI levels occur in children without clinically apparent cardiac disease and can be at adult unstable angina or acute myocardial infarction levels. Prospective studies to determine the clinical significance of these findings and their relationship to the development of cardiomyopathy are warranted.

Cardiovascular Complications in Patients with HIV Infection.

As advances in early diagnosis and aggressive therapy, as well as better supportive care, become available to a larger number of patients with HIV infection, survival is being prolonged, and more patients are experiencing cardiac abnormalities. The most common cardiac manifestations of HIV disease are dilated cardiomyopathy, myocarditis, pericardial effusion, endocarditis, pulmonary hypertension, HIV-associated malignant neoplasms, and drug-related cardiotoxicity. The introduction of highly active antiretroviral therapy (HAART) regimens has substantially modified the course of HIV disease by lengthening survival and improving quality of life of HIV-infected patients. However, early data have raised concerns about HAART being associated with an increase in peripheral and coronary arterial disease. This review discusses the principal HIV-associated cardiovascular manifestations and emphasizes new knowledge about their prevalence, pathogenesis, and treatment.