Citations

Background: Graves’ disease (GD) can both aggravate pre-existing cardiac disease and cause de novo heart failure (HF). Due to the rarity of thyrotoxic HF, population-based studies are lacking, and data from smaller studies are widely variable. Methods: We reviewed the medical records of 1371 consecutive patients with GD evaluated at our clinic between 2009 and 2019. HF was defined according to Framingham criteria. GD-related HFrEF was defined by left ventricular ejection fraction of <50%, while HFpEF was defined according to the Heart Failure Association of the European Society of Cardiology. Outcomes of major cardiovascular events, all-cause mortality, and cardiac hospitalizations were analyzed with adjustments for age, gender, and history of coronary artery disease (CAD). 1:1 matching with controls (age, gender, and CAD) was additionally done. Results: HF occurred in 74 patients (31 HFrEF; 43 HFpEF). Incidence of GD-related HF, HFrEF, and HFpEF was 5.4%, 2.3%, and 3.1%, respectively. In HFrEF, atrial fibrillation (AF) (RR 10.05, p <0.001) and thyrotropin receptor antibodies (TRAb) level (RR 1.05 per unit, p=0.005) were independent predisposing factors. In HFpEF, independent risk factors were COPD (RR 5.78, p < 0.001), older age (RR 1.48 per 10 years, p = 0.003), overt hyperthyroidism (RR 5.37, p = 0.021), higher BMI (1.06 per unit, p = 0.003), and HTN (RR 3.03, p = 0.011). Rates of cardiac hospitalizations were higher in HFrEF (41.9% vs 3.2%, p <0.001) and HFpEF (44.2% vs 4.7%, p < 0.001) compared to controls. Furthermore, while both increased risk of strokes (HFrEF: RR 4.12, p = 0.027; HFpEF: RR 4.64, p = 0.009), only HFrEF increased risk of all-cause mortality (RR 3.78, p = 0.045). Conclusion: De novo HF occurs in 5.4% of patients with GD and increases the rate of cardiovascular events. HF occurs more frequently in GD patients with AF, higher TRAb, higher BMI, and overt hyperthyroidism, suggesting that these may be targets for treatment to prevent cardiovascular complications, especially in older multimorbid patients.

Background: Hyperthyroidism is associated with atrial fibrillation (AF) with a reported prevalence of 16-60%. However, risk factors for onset of AF with hyperthyroidism are not well defined. We sought to identify patients with hyperthyroidism most likely to develop AF. Methods: We reviewed the medical records of 1371 consecutive patients with GD evaluated at our clinic between 2009 and 2019. GD-related AF was defined as AF diagnosed up to 30 days before or at any time after Grave’s disease (GD). Spontaneous recovery was defined as sinus rhythm after attainment of euthyroidism without the need for pharmacologic or electrical cardioversion. Outcomes of major cardiovascular events, all-cause mortality, and cardiac hospitalizations were compared between cases and controls (GD without AF) matched 1:1 for age, gender, and history of coronary artery disease. Results: AF occurred in 140 patients with an incidence of 10.2%. Older age (RR 1.63 per 10 years, p <0.001), male gender (RR 2.06, p < 0.001), overt hyperthyroidism (RR 2.48, p = 0.002), COPD (RR 2.14, p =0.006), and higher BMI (RR 1.03 per unit, p=0.023) were independent risk factors for AF. Spontaneous AF recovery occurred in 44 of 128 (34.6%) patients with adequate follow up. The multivariate risk factor for failed recovery was the presence of heart failure (HF) (OR =3.52, p= 0.004). GD patients with AF had higher rates of cardiac hospitalizations (Figure) that persisted even after adjusting to HF presence (27.9% vs 2.9%, p < 0.001). Conclusion: Risk factors for AF in GD are similar to those in the general population, although overt hyperthyroidism conferred the highest risk. These data argue for careful monitoring of GD patients with multimorbidity who may be at high risk of developing AF.

Calf muscle pump (CMP) promotes venous return from the lower extremity and contributes to preload and cardiac output. Impaired CMP function may reflect a measure of frailty or cumulative disease burden or may impede cardiac function. The study objective was to test the hypothesis that impaired CMP negatively impacts survival. Consecutive adult patients who underwent venous strain gauge plethysmography at the Mayo Clinic Gonda Vascular Laboratory (January 1, 1998 – December 31, 2011) were assessed for overall survival. Patients with venous incompetence, venous obstruction or unilateral calf pump dysfunction were excluded. Risk of mortality was assessed with Cox proportional hazard ratios and after adjusting for Charlson Comorbidity Index variables. Over the study period, 2728 patients were included in the analysis. Compared to patients with normal CMP, those with impaired CMP were older ( p < 0.001), predominantly female ( p = 0.01) and had higher mean Charlson scores ( p < 0.001). Patients with impaired CMP had a higher mortality rate at 5 (8.9% vs 2.4%), 10 (17.5% vs 5.9%), and 15 years (22.8% vs 8.3%) compared to those with normal CMP ( p < 0.001 for each comparison). Of patients with heart failure, those with impaired CMP had worse survival at each 5-year increment compared to those with normal CMP ( p < 0.05 at each increment). In conclusion, impaired CMP appears to be an independent predictor of poor outcomes after adjusting for variables within the Charlson Comorbidity Index. The association between impaired CMP, heart failure, and mortality may represent a negative impact on circulatory function or a surrogate measure of frailty.

AbstractQTc interval prolongation can lead to life‐threatening complications such as Torsade de Pointes (TdP), ventricular tachycardia (VT) and sudden cardiac death (SCD). It can occur with tyrosine kinase inhibitors (TKIs) but comparative real‐world analyses on the incidence and complication rates are scarce. We retrospectively reviewed all cancer patients treated with TKI therapy at Mayo Clinic between January 2005 and December 2018 and had at least two ECGs (before and after TKI). For each TKI type, we determined the administration rate and incidence of QTc prolongation. QTc prolongation was defined as a corrected QT interval (by Fridericia formula) ≥450 ms in men and ≥470 ms in women. A total of 618 cancer patients were included with 902 TKI administrations, of which 654 (72.5%) were accounted for by pazopanib, sunitinib, imatinib, nilotinib and dasatinib. QTc prolongation (any grade) was reported in 28.8%, most commonly with nilotinib (38.7%) and dasatinib (41.7%). A QTc interval ≥500 ms and a QTc increase ≥60 ms was documented in 46 and 63 administrations, respectively. Life‐threatening toxicity was seen in 14 cases (5.4% of QTc prolongation cases) including VT in 9, SCD in 3 and TdP in two administrations. The response to QTc prolongation was: discontinuation in 68%, dose reduction in 13.5%, temporary hold in 8.1% and no action in 10.4%. In conclusion, QTc prolongation with TKI therapy is very common (∼1/3 of cases) and in 5% (1.7% overall) associated with life‐threatening complications. These data support recommendations for careful ECG monitoring in cancer patients undergoing TKI therapy.

Background and Aims Portopulmonary hypertension (POPH) was previously associated with a single‐nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. Approach and Results We performed a multicenter case‐control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn‐sec/cm−5, and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome‐wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12‐4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2‐hydroxyestrogen/16‐α‐hydroxyestrone (OR per 1‐ln decrease = 2.04; 95% CI, 1.16‐3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone‐sulfate (OR per 1‐ln decrease = 2.38; 95% CI, 1.56‐3.85; P < 0.001), and higher plasma levels of 16‐α‐hydroxyestradiol (OR per 1‐ln increase = 2.16; 95% CI, 1.61‐2.98; P < 0.001) were associated with POPH. Conclusions Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Abstract Aims: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.Methods and Results: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A <0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A <0.6 and >1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke.Conclusions: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Abstract Aims: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.Methods and Results: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A <0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A <0.6 and >1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke.Conclusions: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

ABSTRACT Aims Mild to moderate functional mitral regurgitation (MR) is common in patients with heart failure and preserved ejection fraction (HFpEF) where it is usually considered as an innocent bystander. We hypothesized that MR in HFpEF reflects greater left atrial (LA) myopathy, leading to more adverse haemodynamics and poorer exercise reserve. Methods and results Patients with HFpEF (n = 280) with and without MR underwent echocardiography, invasive haemodynamic exercise testing, and expired gas analysis. As compared to non-MR-HFpEF (n = 163), patients with MR-HFpEF (n = 117; 78 mild and 39 moderate, central jet in 90%) were older, more likely female, with lower body mass and higher prevalence of atrial fibrillation (AF). HFpEF patients with MR displayed greater LA volume, reduced LA strain and compliance, and greater mitral annular dilatation, which was strongly correlated with LA dilatation (r = 0.63, P &lt; 0.0001) but was only weakly related to left ventricular remodelling (r = 0.37). Patients with MR-HFpEF displayed worse biventricular function, more adverse pulmonary haemodynamics, impaired pulmonary vasodilatation, blunted right ventricular reserve, and reduced cardiac output with exercise as compared to non-MR-HFpEF. Importantly, these findings were maintained after excluding patients with HFpEF and AF, suggesting a role for LA myopathy in contributing to MR in HFpEF, independent of rhythm. Conclusions Functional MR in patients with HFpEF reflects LA myopathy, even in the absence of AF, and is associated with greater haemodynamic severity of disease and poorer functional capacity. Further study is required to better define causal mechanisms and potential treatments for MR and LA dysfunction in patients with HFpEF.