Abstract Background Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. Objectives The goal of this study was to describe ATTR ...in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. Methods Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189). Results U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival. Conclusions In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey THAOS; NCT00628745 )
Whether a normal electrocardiogram excludes left ventricular (LV) diastolic dysfunction (DD) and whether electrocardiographic parameters are associated with DD is unknown. We therefore sought to ...investigate the relation between electrocardiographic parameters and DD. We first evaluated 75 consecutive patients referred for echocardiography for clinical suspicion of heart failure (phase 1). Electrocardiography and comprehensive echocardiography were performed on all patients and were analyzed separately in a blinded fashion. Receiver operating characteristic curves and multivariate regression analyses were used to determine which electrocardiographic parameters were most closely associated with DD. Next, we prospectively validated our results in 100 consecutive, unselected patients undergoing echocardiography (phase 2). In phase 1 of our study, the mean age was 59 ± 14 years, 41% were women, 31% had coronary disease, 53% had hypertension, and 25% had diabetes. The mean ejection fraction was 54 ± 15%, and 64% had DD. Of all the electrocardiographic parameters, the QTc interval was most closely associated with DD. QTc was inversely associated with E′ velocity (r = −0.54, p <0.0001), and the area under the receiver operating characteristic curve for QTc as a predictor of DD was 0.82. QTc prolongation was independently associated with reduced E′ velocity (p = 0.021 after adjustment for age, gender, medications, QRS duration, and ejection fraction). In phase 2 of our study QTc was the electrocardiographic parameter most associated with reduced E′ velocity (435 ± 31 vs 419 ± 24 ms; p = 0.004), confirming our phase 1 study findings. In conclusion, QTc prolongation was the electrocardiographic marker most predictive of DD and was independently associated with DD.
Serial electrocardiographic monitoring of ΔQTc as an assumed harbinger of proarrhythmia is currently recommended for dofetilide and sotalol initiation. Markers of repolarization heterogeneity such as ...increased peak to end of T-wave (TpTe) duration and abnormal T-wave morphology may also predict proarrhythmia. We investigated whether such T-wave measurements on baseline electrocardiogram will correlate with ΔQTc after drug initiation. An analysis of 140 consecutive patients with paroxysmal atrial fibrillation hospitalized in sinus rhythm for sotalol or dofetilide initiation was performed. Baseline and serial electrocardiograms were analyzed using QT Guard Plus software (GE Healthcare), which measured QTc and TpTe and scored T-wave morphology for asymmetry, notching, and flatness using T-wave vector magnitude and principal component analysis algorithms. Sotalol and dofetilide were administered in 71% and 29% of patients, respectively. Mean age was 61 ± 14 years, and 34% were women. After a single dose of either drug, there was a statistically significant increase in QTc and TpTe (p <0.01), as well as composite and individual T-wave markers of repolarization heterogeneity (p <0.01). QTc increased by a mean of 19 ± 30 ms after initial antiarrhythmic dose. ΔQTc was inversely related to baseline QTc and TpTe (p <0.01). After controlling for baseline QTc, there was no independent association between T-wave markers of repolarization heterogeneity and ΔQTc. In conclusion, for patients with paroxysmal atrial fibrillation admitted for dofetilide or sotalol loading, T-wave markers of increased repolarization heterogeneity are measurable within hours after initiation. A shorter baseline QTc is associated with an increased ΔQTc; however, there is no independent relation between baseline T-wave markers of repolarization heterogeneity and ΔQTc.
Abstract Objective Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial ...Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF. Methods The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction ≥40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest or ≥25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization. Conclusion Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF.
Chronotropic incompetence (CI) is common in heart failure with preserved ejection fraction (HFpEF) and may be a key reason underlying exercise intolerance in these patients. However, the determinants ...of CI in HFpEF are unknown. We prospectively studied 157 patients with consecutive HFpEF who underwent cardiopulmonary exercise testing and defined CI according to specific thresholds of the percent heart rate reserve (%HRR). CI was diagnosed as present if %HRR <80 if not taking a β blocker and <62 if taking β blockers. Participants who achieved inadequate exercise effort (respiratory exchange ratio ≤1.05) on cardiopulmonary exercise testing were excluded. Multivariable-adjusted logistic regression was used to determine the factors associated with CI. Of the 157 participants, 108 (69%) achieved a respiratory exchange ratio >1.05 and were included in the final analysis. Of these 108 participants, 70% were women, 62% were taking β blockers, and 38% had chronic kidney disease. Most patients with HFpEF met criteria for CI (81 of 108; 75%). Lower estimated glomerular filtration rate (GFR), higher B-type natriuretic peptide, and higher pulmonary artery systolic pressure were each associated with CI. A 1-SD decrease in GFR was independently associated with CI after multivariable adjustment (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4, p = 0.02). The association between reduced GFR and CI persisted when considering a variety of measures of chronotropic response. In conclusion, reduced GFR is the major clinical correlate of CI in patients with HFpEF, and further study of the relation between chronic kidney disease and CI may provide insight into the pathophysiology of CI in HFpEF.
Abstract Pulmonary hypertension (PH) secondary to heart failure with preserved ejection fraction (HFpEF) is an increasingly recognized cause of PH due to an emerging epidemic of HFpEF. The mechanisms ...underlying the pathogenesis of PH in HFpEF are not well established, but the presence of PH and right ventricular dysfunction in HFpEF is associated with worse prognosis. Currently, it is unclear whether PH is just a marker of underlying disease severity or whether it could be a target of treatment in HFpEF. Although PH-HFpEF and pulmonary arterial hypertension share several clinical characteristics, the evidence supporting the use of pulmonary arterial hypertension-specific therapies in PH-HFpEF is limited. Here, we review the disease classification, epidemiology, proposed pathophysiology, and treatments for PH-HFpEF. Our limited understanding highlights an urgent need for more research to elucidate the pathogenesis of PH in HFpEF and to develop novel therapies for this challenging syndrome.
There are well-documented changes in thyroid hormone metabolism that accompany heart failure (HF). However, the frequency of thyroid hormone abnormalities in HF with preserved ejection fraction ...(HFpEF) is unknown, and no studies have investigated the association between triiodothyronine (T3 ) and markers of HF severity (B-type natriuretic peptide BNP and diastolic dysfunction DD) in HFpEF. In this study, 89 consecutive patients with HFpEF, defined as symptomatic HF with a left ventricular ejection fraction >50% and a left ventricular end-diastolic volume index <97 ml/m2 , were prospectively studied. Patients were dichotomized into 2 groups on the basis of median T3 levels, and clinical, laboratory, and echocardiographic data were compared between groups. Univariate and multivariate linear regression analyses were performed to determine whether BNP and DD were independently associated with T3 level. We found that 22% of patients with HFpEF had reduced T3 . Patients with lower T3 levels were older, were more symptomatic, more frequently had hyperlipidemia and diabetes, and had higher BNP levels. Severe (grade 3) DD, higher mitral E velocity, shorter deceleration time, and higher pulse pressure/stroke volume ratio were all associated with lower T3 levels. T3 was inversely associated with log BNP (p = 0.004) and the severity of DD (p = 0.039). On multivariate analysis, T3 was independently associated with log BNP (β = −4.7 ng/dl, 95% confidence interval −9.0 to −0.41 ng/dl, p = 0.032) and severe DD (β = −16.3 ng/dl, 95% confidence interval −30.1 to −2.5 ng/dl, p = 0.022). In conclusion, T3 is inversely associated with markers of HFpEF severity (BNP and DD). Whether reduced T3 contributes to or is a consequence of increased severity of HFpEF remains to be determined.
Abstract Objective Pulmonary hypertension (PHT) has been considered a risk factor for mortality in cardiac surgery. Among mitral valve surgery (MVS) patients, we sought to determine if severe PHT ...increases mortality risk and if patients who undergo concomitant tricuspid valve surgery (TVS) incur additional risk. Methods Preoperative PHT was assessed in 1571 patients undergoing MVS, from 2004 to 2013. Patients were stratified into PHT groups as follows (mm Hg): none (<35); moderate (35-49); severe (50-79); and extreme (≥80). Propensity-score matching resulted in a total of 430 patients, by PHT groups, and 384 patients, by TVS groups. Results Patients with severe PHT had higher mortality, both 30-day (4% PHT vs 1% no PHT, P < .02) and late (defined as survival at 5 years): 75.5% severe versus 91.9% no PHT ( P < .001). In propensity-score–matched groups, severe PHT was not a risk factor for 30-day (3% each, P = 1.0) or late mortality (86.2% severe vs 87.1% no PHT; P = .87). TVS did not increase 30-day (4.7% TVS vs 4.2% no TVS, P = .8) or late mortality (78.7% TVS vs 75.3% no TVS, P = .90). Late survival was lower in extreme PHT (75.4% vs no PHT 91.5%, P = .007), and a trend was found in 30-day mortality (11% extreme vs 3% no PHT, P = .16). Conclusions Mortality in MVS is unaffected by severe PHT or the addition of TVS, yet extreme PHT remains a risk factor. Severe PHT (50-79 mm Hg) should not preclude surgery; concomitant TVS does not increase mortality.
Abstract Objectives The purpose of this study was to determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). ...Background Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. Methods We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. Results The mean age was 66 ± 11 years, 62% were female, and 42% were African American. Higher UACR was associated with greater left ventricular mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher 95% confidence interval: 0.05 to 0.14 mm; p = 0.001, adjusted p = 0.01) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower 95% confidence interval: 0.14 to 0.98%; p = 0.01, adjusted p = 0.03. The association between UACR and RV parameters persisted after the exclusion of patients with macroalbuminuria (UACR >300 mg/g). Increased UACR was also independently associated with worse outcomes. Conclusions In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and left ventricular remodeling and longitudinal systolic dysfunction. (Classification of Heart Failure With Preserved Ejection Fraction; NCT01030991 )