Effect of tafamidis on left atrial function of patients with transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural effects of amyloid infiltration, predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in the left atrium in ATTR-CM patients, but the association of left atrial (LA) myocardial function with cardiovascular events and of changes in LA myocardial function with tafamidis administration have not yet been clarified. Our aim was, therefore, to use speckle-tracking strain for investigating LA myocardial function in patients with ATTR-CM treated with tafamidis. We studied 55 patients with biopsy-proven ATTR-CM who had been treated with tafamidis (age: 76 ± 2 years, male: 93%). For speckle-tracking analysis of LA myocardial function, the systolic LA strain (LA reservoir function) was defined for this study as LA myocardial function from the apical 4-chamber view. The primary endpoint was defined as a composite comprising cardiovascular death and/or heart failure hospitalization after tafamidis administration over a median follow-up period of 28 ± 4 months. Patients with baseline LA strain < 8.6% (median value) experienced significantly more cardiovascular events than those without (log-rank P = 0.002). Moreover, LA strain in 26 patients worsened after tafamidis administration, and multivariate logistic regression analysis showed age, global longitudinal strain and relative apical longitudinal strain index were identified as independent determinants of deterioration of LA strain after tafamidis administration. In conclusion, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration, and could be an additional parameter for the management of patients with ATTR-CM.

Left Ventricular Longitudinal Myocardial Function of Heart Failure Patients With Transition From Reduced to Preserved Ejection Fraction and of Those With Preserved Ejection Fraction.

Background: Left ventricular (LV) longitudinal myocardial function is associated with the outcomes of heart failure (HF) patients. HF with improved ejection fraction (EF), known as HFimpEF, which is defined as current LVEF >40% but any previously documented LVEF ≤40%, has favorable outcomes compared with HF with preserved EF (HFpEF). However, LV longitudinal myocardial function in patients with previously reduced LVEF (<50%) but improved LVEF to within the normal range (≥50%) (HFnorEF) and its association with cardiovascular events remain unclear. Methods and Results: We studied 70 patients with HFpEF and 65 with HFnorEF. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The primary endpoint was defined as cardiovascular death or HF hospitalization during follow-up of 5.6±3.1 years. The GLS of HFpEF patients was significantly lower than that of HFnorEF patients (13.6±3.5% vs. 14.8±2.2%, P=0.02) even when the LVEF was similar. Multivariate Cox proportional hazards analysis showed that GLS was independently associated with cardiovascular events. Furthermore, of the entire study population, patients with GLS >15.0% had fewer cardiovascular events than those without (log-rank P=0.014) among all the patients. Conclusions: LV longitudinal myocardial dysfunction was more frequently observed in patients with HFpEF than in those with HFnorEF, even when LVEF was similar, and was independently associated with cardiovascular events for HF patients with current LVEF ≥50%.

Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure.

Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg.

Effect of increase in heart rate after anthracycline chemotherapy on subsequent left ventricular dysfunction.

BACKGROUND: Anthracycline chemotherapy-related cardiac dysfunction is believed to be refractory to conventional pharmacological therapy and is associated with a poor prognosis. Increased heart rate (HR) is a known marker of cardiovascular outcomes for various categories of heart failure (HF). However, little interest has been expressed regarding increased HR after anthracycline chemotherapy. Aim of this study was to investigate the effect of increased HR soon after completion of anthracycline chemotherapy on subsequent left ventricular (LV) ejection fraction (LVEF) in cancer patients. METHODS: We studied 172 patients with breast cancer and malignant lymphoma with preserved LVEF (≥ 50 %) and sinus rhythm treated with anthracyclines. Electrocardiography was performed before and soon after completion of anthracycline chemotherapy (2.3 months), and echocardiography before and late after completion of anthracycline chemotherapy (10.5 months). RESULTS: HR significantly increased from 74.2 ±â€¯14.2 bpm to 75.9 ±â€¯13.2 bpm (P = 0.05) soon after completion of anthracycline chemotherapy, while LVEF subsequently significantly decreased from 65.3 ±â€¯5.5 % to 62.4 ±â€¯6.1 % (P < 0.01) late after completion of anthracycline chemotherapy. Patients whose HR increased ≥10 bpm subsequently showed a significantly greater decrease in LVEF than those whose HR increased <10 bpm [-4.9 % (-32.7 % - 10.8 %) vs. -2.2 % (-21.2 % - 12.9 %), p = 0.04]. Multivariable logistic regression analysis showed that an increase in HR soon after completion of anthracycline chemotherapy was independently associated with a subsequent decrease in LVEF (odds ratio: 1.022, 95 % confidential interval; 1.008-1.037, P = 0.002). CONCLUSIONS: Our findings may have a novel effect on the management of cancer patients scheduled for anthracycline chemotherapy.

Identification of factors associated with progression of left atrial enlargement in patients with atrial fibrillation.

Left atrial (LA) enlargement frequently occurs in atrial fibrillation (AF) patients, and this enlargement is associated with the development of heart failure, thromboembolism, or atrial functional mitral regurgitation (AFMR). AF patients can develop LA enlargement over time, but its progression depends on the individual. So far, the factors that cause progressive LA enlargement in AF patients have thus not been elucidated, so that the aim of this study was to identify the factors associated with the progression of LA enlargement in AF patients. We studied 100 patients with persistent or permanent AF (aged: 67 ± 2 years, 40 females). Echocardiography was performed at baseline and 12 (5-30) months after follow-up. LA size was evaluated as the LA volume index which was calculated with the biplane modified Simpson's method from apical four-and two-chamber views, and then normalized to the body surface area (LAVI). The deterioration of AFMR after follow-up was defined as a deterioration in severity of mitral regurgitation (MR) by a grade of 1 or more. Multivariate regression analysis demonstrated that hypertension (p = .03) was an independently associated parameter of progressive LA enlargement, as was baseline LAVI. In addition, the Kaplan-Meier curve indicated that patients with hypertension tended to show greater deterioration of AFMR after follow-up than those without hypertension (log-rank p = .08). Hypertension proved to be strongly associated with progression of LA enlargement over time in patients with AF. Our findings provide new insights for better management of patients with AF to prevent the development of AFMR.

Open-chest epicardial ablation of ventricular tachycardia during a left ventricular assist device implantation: a case report.

Background: Ventricular arrhythmias (VAs) are common after a left ventricular assist device (LVAD) implantation. Further, the majority of post-LVAD ventricular tachycardias (VTs) are secondary to a preexisting cardiomyopathy substrate. Intraoperative ablation of patients with recurrent preoperative VTs may reduce post-LVAD VTs. Case summary: A 59-year-old female with advanced heart failure due to non-ischaemic cardiomyopathy (LV ejection fraction = 24%) and recurrent VTs was referred for an LVAD implantation as a bridge to a heart transplant (INTERMACS Profile-5A). The previous endocardial ablation failed due to an epicardial arrhythmogenic substrate. Therefore, open-chest epicardial mapping during the LVAD implantation was indicated and three target areas of the arrhythmogenic substrate were found, which were ablated by radiofrequency applications. To minimize the cardiopulmonary bypass time, cardiopulmonary bypass was initiated after ablation, and then, an LVAD was implanted. An additional 68 min was required for mapping and ablation. All procedures were performed without any complications, and the post-operative course was uneventful. Thereafter, no VT episodes were observed without any anti-arrhythmic drugs during a 15-month follow-up with LVAD support. Discussion: Intraoperative epicardial mapping and ablation during an LVAD implantation can play an important role in the management of LVAD recipients with recurrent VAs.

Impact of Tafamidis on Echocardiographic Cardiac Function of Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The efficacy of a therapy for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has not been proven, but tafamidis has been associated with favorable outcomes. However, echocardiographic details of the association of tafamidis with cardiac morphology remain undetermined. Moreover, whether the efficacy of tafamidis varies with the degree of cardiac involvement remains unknown. Using echocardiography, this study investigated the impact of tafamidis on the cardiac morphology of patients with ATTR-CM.Methods and Results: Of 52 consecutive patients with biopsy-proven ATTR-CM at Kobe University Hospital, we included 41 for whom details of follow-up echocardiographic examinations after the administration of tafamidis were available. All patients underwent standard and speckle-tracking echocardiography before and a mean (±SD) of 16±8 months after the administration of tafamidis. No significant changes were observed in any representative echocardiographic parameters after the administration of tafamidis. Furthermore, there were no significant changes observed in subgroup analyses (e.g., left ventricular [LV] ejection fraction ≥50% vs. <50%; LV mass index <150 vs. ≥150 g/m2; New York Heart Association Class I-II vs. Class III; age ≥80 vs. <80 years). CONCLUSIONS: Tafamidis may prevent worsening of various representative echocardiographic parameters of patients with ATTR-CM. This effect is also seen in patients with relatively advanced disease and in those who are elderly.

A rare case with Uhl's anomaly whose hemodynamics largely dependent on right atrial hyper-contraction and a patent foramen ovale - A "double-edged sword" of ventricularized right atrium.

We report the case of a 31-year-old man with Uhl's anomaly. Echocardiography revealed severely enlarged nonfunctioning right ventricle and unusual findings of the premature opening of the pulmonary valve along with substantial forward flow during late-diastole, indicating that pulmonary circulation was largely dependent on compensatory right atrial contraction. Moreover, right-to-left shunt through the patent foramen ovale (PFO) achieved systemic circulation at the expense of severe hypoxia. During accelerated idioventricular rhythm (AIVR) accompanied by ventriculo-atrial (VA) conduction, hypoxemia deteriorated further because of an increased right-to-left shunt through the PFO. We report the case of an adult with Uhl's anomaly whose hemodynamics was largely dependent on the ventricularized right atrium and PFO. Although the unique hemodynamics contributed to his survival into adulthood, detrimental aspects manifested themselves during AIVR with VA conduction like a "double-edged sword." .

Fibronectin-containing High-Density Lipoprotein is Associated with Cancer Cell Adhesion and Proliferation.

A large amount of evidence suggests that high-density lipoprotein (HDL) has anti-atherosclerotic properties. HDL-cholesterol (HDL-C) has also been widely used as a marker of cardiovascular disease. Recently, it was reported that plasma HDL-C levels are inversely correlated with cancer risk. However, the relationship between HDL and cancer pathophysiology remains unknown. Here, we sought to investigate the effect of HDL on cancer progression. First, we focused on fibronectin-an essential extracellular matrix glycoprotein-as an HDL-associated protein and found that only 7.4% of subjects in this study had fibronectin in HDL isolated from their plasma. The fibronectin-containing HDL (FN-HDL) increased the phosphorylation of focal adhesion kinase (FAK) in HeLa cells compared to HDL without fibronectin, further inducing the phosphorylation in a dose-dependent manner. Second, we found that fibronectin-treated HDL activated the phosphorylation of FAK, and its upstream effector blocked the phosphorylation induced by FN-HDL. Finally, we demonstrated that FN-HDL promoted cancer cell proliferation and adhesion compared to HDL without fibronectin. Our study showed the possible mechanism by which FN-HDL enhanced cancer cell proliferation and adhesion via the FAK signaling pathway. Further investigation of the roles of HDL components in tumorigenesis might provide novel insight into cancer pathophysiology.

Noninvasive Leg-Positive Pressure Stress Echocardiography Reveals Preload Reserve in Adult Patients after Complete Repair of Tetralogy of Fallot.

BACKGROUND: Long-term sequelae such as right ventricular dysfunction and reduced hemodynamic reserve are the main determinants of cardiovascular outcomes after repair of tetralogy of Fallot (TOF). Echocardiographic parameters at rest offer only partial information on impaired hemodynamics in these patients, and data during stress testing are lacking. The leg-positive pressure (LPP) maneuver has recently been reported to be able to apply acute preload stress. The aim of this study was to test the hypothesis that preload reserve is impaired and ventricular interaction is exacerbated in patients with TOF. METHODS: In this prospective cross-sectional study, we recruited 44 consecutive patients with TOF and 30 normal control subjects. Echocardiography was performed both at rest and during LPP stress, and preload reserve was defined as the change between baseline stroke volume (SV) and that obtained during LPP stress. The eccentricity index was calculated as the ratio of the left ventricular anteroposterior to septal-lateral dimensions to quantify ventricular interaction. RESULTS: LPP stress significantly increased SV from 73 ± 14 to 83 ± 16 mL (P < .01) in control subjects, while the increase in SV was significantly blunted (from 75 ± 19 to 79 ± 18 mL; P < .01 for interaction) in patients with TOF. The eccentricity index significantly changed during LPP stress in patients with TOF only from 1.07 ± 0.13 to 1.13 ± 0.14 (P < .01 for interaction). Patients with TOF were subdivided into two subgroups on the basis of the median value of increased response in SV (22 with sufficient and 22 with insufficient preload reserve). Multivariate analysis identified significant pulmonary regurgitation as the only independent determinant factor for insufficient preload reserve (odds ratio, 4.57; 95% CI, 1.048-19.90; P = .04). CONCLUSIONS: In patients after repair of TOF, ventricular interaction was exacerbated and preload reserve was impaired, especially in patients with significant pulmonary regurgitation. LPP stress testing may direct tailored treatment approaches, risk stratification, and clinical decision-making, such as more aggressive pharmacologic therapy, meticulous outpatient follow-up, or earlier reintervention.

Temporary biventricular support with extracorporeal membrane oxygenation: a feasible therapeutic approach for cardiogenic shock with multiple organ failure.

Various strategies using a ventricular assist device (VAD) are applied to rescue Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (Profile-1) patients. However, the optimal use of VAD in Profile-1 patients has not been completely elucidated. We retrospectively reviewed 23 Profile-1 patients [mean age 36.9 ± 16.6 years, 14 males; 11 with non-ischemic cardiomyopathy (NICM), 9 with fulminant myocarditis (FM), 2 with ischemic cardiomyopathy (ICM), and 1 with peripartum cardiomyopathy (PPCM); 18 with pre-operative percutaneous extracorporeal membrane oxygenation (p-ECMO) support] who underwent VAD implantation from 2011 to 2015 at our institution. Nine initially received left VAD (LVAD) alone (NICM in 9, ICM in 2 with ICM, and FM in 1), one with NICM received biventricular VAD (BiVAD; n = 1), and 10 received LVAD combined with right ventricular support using an ECMO circuit (BiVAD-ECMO) (FM in 8, NICM in 1, and PPCM in 1). Paracorporeal VAD was used in all patients. ECMO was used for the patients with severe pulmonary edema, inflammation, anemia, and thrombopenia. The BiVAD patient died 1.4 months after VAD implantation. The overall survival was comparable between patients with BiVAD-ECMO and LVAD (2-year survival, 80.0 and 75.0%, respectively). Three VAD strategies were initially applied in Profile-1 patients. Among them, the BiVAD-ECMO strategy is a promising therapeutic option to rescue Profile-1 patients with multiple organ failure.

Low partial pressure of end-tidal carbon dioxide predicts left ventricular assist device implantation in patients with advanced chronic heart failure.

BACKGROUND: This study aimed to clarify the prognostic impact of partial pressure of end-tidal carbon dioxide (PETCO2) in patients with advanced chronic heart failure (HF). METHODS: Forty-eight patients (mean age 43.1±11.9years, 32 males) with chronic HF (44 with non-ischemic and 4 with ischemic cardiomyopathy) were prospectively enrolled. Echocardiography, blood tests, pulmonary function testing, and PETCO2 measurements were performed as noninvasive tests, whereas right heart catheterization and arterial blood gas analysis were conducted as invasive tests. The primary end point of this study was left ventricular assist device (LVAD) implantation or cardiac death. RESULTS: Eighteen patients underwent LVAD implantation at the Interagency Registry for Mechanically Circulatory Support (INTERMACS) profile 3 during the follow-up period, and no patient died. PETCO2 was significantly lower in a stepwise manner with New York Heart Association functional class (class I or II, 34.2±9.3mmHg vs. class III or IV, 27.7±2.5mmHg; p<0.001). Univariate and multivariate Cox proportional hazard models and time-dependent receiver operating characteristic curve analysis revealed that PETCO2≤31mmHg is an independent noninvasive predictor of LVAD implantation. Univariable and multivariable linear regression analyses showed that pulmonary arterial pressure was independently and highly correlated with PETCO2 (r2=-0.512, p<0.001). CONCLUSIONS: Among various noninvasive clinical parameters investigated, PETCO2 was the independent predictor of LVAD implantation at the INTERMACS profile 3 in patients with chronic HF. Pulmonary congestion may significantly contribute to decreases in PETCO2 in patients with HF.

Donor-Transmitted Atherosclerosis Associated With Worsening Cardiac Allograft Vasculopathy After Heart Transplantation: Serial Volumetric Intravascular Ultrasound Analysis.

BACKGROUND: The influence of preexisting donor-transmitted atherosclerosis (DA) on cardiac allograft vasculopathy (CAV) development remains unclear. METHODS: We performed 3-dimensional intravascular ultrasound (3D-IVUS) analysis in 42 heart transplantation (HTx) recipients at 2.1 ± 0.9 months (baseline) and 12.2 ± 0.4 months post-HTx, as well as consecutive 3D-IVUS analyses up to 3 years post-HTx in 35 of the 42 recipients. Donor-transmitted atherosclerosis was defined as a maximal intimal thickness of 0.5 mm or greater at baseline. Changes in volumetric IVUS parameters were compared in recipients with (DA group) and without DA (DA-free group) at baseline, 1 year, and 3 years post-HTx. RESULTS: Donor-transmitted atherosclerosis was observed in 57.1% of 42 recipients. The DA group exhibited a significantly greater increase in plaque volume at 1 year post-HTx (P < 0.001), leading to increased percent plaque volume (plaque volume/vessel volume, [%]) (P < 0.001) and decreased luminal volume (P = 0.021). Donor-transmitted atherosclerosis was independently associated with a greater increase in percent plaque volume during the first post-HTx year (P = 0.011). From 1 to 3 years post-HTx, the DA group underwent continuous reduction in luminal volume (P = 0.022). These changes resulted in a higher incidence of angiographic CAV at 3 years post-HTx in the DA group (58.8% vs 5.6%, P = 0.002). CONCLUSIONS: This volumetric IVUS study suggests that DA correlates with the worsening change in CAV several years post-HTx. Donor-transmitted atherosclerosis recipients may require more aggressive treatment to prevent subsequent CAV progression.

Risk Stratification for Cardiac Allograft Vasculopathy in Heart Transplant Recipients - Annual Intravascular Ultrasound Evaluation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term success after heart transplant. We assessed the post-transplant risk factors for CAV development. METHODS AND RESULTS: Patients who underwent heart transplant between May 1999 and December 2013 were included in this study. Patients (n=54) were divided into 2 groups according to the presence or absence of CAV progression after transplant. Coronary angiogram and intravascular ultrasound were conducted within 5-11 weeks after transplant, at 12 months, and annually thereafter. Scheduled endomyocardial biopsies were performed after transplant or whenever acute cellular rejection (ACR) or antibody-mediated rejection was suspected. Twenty-five of 54 patients (46.2%) had CAV progression. ACR ≥ International Society for Heart and Lung Transplantation grade 2 (ACR ≥ 2) and donor age >50 years were significantly associated with CAV development compared with ACR <2 and donor age <50 years. Patients with no history of ACR ≥ 2 and donor age ≤50 years had a significantly low risk of developing CAV compared with the other groups. CONCLUSIONS: Donor age and history of ACR ≥ 2 are independent risk factors for CAV development. Identifying patients at risk of developing CAV is important for appropriate direction of resources and intensity of follow-up.

Incidence, etiology, and outcome of primary graft dysfunction in adult heart transplant recipients: a single-center experience in Japan.

Donor and recipient characteristics, as well as donor-recipient matching, affect clinical outcomes after heart transplantation (HTx). This study aimed to clarify how donor and recipient characteristics affect the clinical course after HTx. The medical records of all the patients who underwent HTx at the National Cerebral and Cardiovascular Center from 1999 to 2014 were retrospectively reviewed. Sixty-one patients (48 males) underwent HTx. Six recipients (9.8 %) developed primary graft dysfunction (PGD) determined by criteria recently established at a consensus conference. Development of PGD was associated with high-dose inotropic support for the donor heart and a history of stroke in the recipient (p = 0.04 and p = 0.002, respectively). Recipients with PGD had higher right atrial pressure (RAP) and lower cardiac output (CO) compared with those without PGD at 6 months after HTx (RAP, 6.8 ± 3.6 vs. 2.8 ± 2.2 mmHg, p < 0.001; CO, 4.6 ± 0.8 l vs. 5.8 ± 1.2 l/min, p = 0.02). With respect to survival, patients with PGD had a 5-year survival rate equivalent to those without PGD (83.3 vs. 93.3 %, p = 0.23). High-dose inotropic support for the donor heart and a history of stroke in the recipient are significant predictive factors for the development of PGD. However, recipients with PGD demonstrate mid-term survival comparable to those without PGD.

Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients.

BACKGROUND: Whether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression. METHODS: We retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1 year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2 ± 2.3 years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4 ± 2.2 years after HTx). The EVL group underwent three-dimensional intravascular ultrasound (3D-IVUS) analysis before and 1 year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group. RESULTS: IVUS indices in the EVL group at 1 year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (≥ 2 years) also did not exhibit increased CAV development, while those in the MMF group did. CONCLUSIONS: Conversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices.