The effects of bolus isosorbide dinitrate on pulmonary hypertension with cardiopulmonary comorbidities.

Lowering mean pulmonary arterial pressure (mPAP) without reducing cardiac output is essential in treating pulmonary hypertension (PH). Isosorbide dinitrate (ISDN) potentially achieves this in post-capillary PH but can decrease cardiac output and blood pressure (BP), especially in pre-capillary PH. However, post-capillary PH and pre-capillary PH can overlap, and their clear discrimination is difficult. The aim of the study was to examine to what extent bolus ISDN injection reduces mPAP and BP, and changes mixed venous oxygen saturation (SvO2), an indicator of cardiac output in PH with various cardiopulmonary comorbidities in the context of treatment modifications. We retrospectively examined the hemodynamic effects of bolus ISDN injection in patients with PH who underwent right heart catheterization and their subsequent treatment modification. Our sample comprised 13 PH patients. In seven with pre-capillary PH, ISDN significantly lowered mPAP from the median 34 (interquartile range 32-39) to 28 (28-30) mmHg and the mean BP (mBP) from 90 (79-92) to 72 (68-87) mmHg. In six with post-capillary PH, ISDN lowered mPAP from 40 (29-44) to 27 (23-31) mmHg and mBP from 91 (87-110) to 87 (82-104) mmHg. There was a significant decrease in SvO2 from 69.8% (64.9%-78.1%) to 63.9% (60.5%-71.5%) in pre-capillary PH, but not in post-capillary PH including combined post- and pre-capillary PH and some patients showed a large increase in SvO2. In all patients showing an SvO2 increase, diuretics or hemodialysis were up-titrated or continued. Bolus ISDN injection lowered mPAP. However, in pre-capillary PH, it caused a significant decrease in SvO2 and a notable reduction in blood pressure. In post-capillary PH, including combined post- and pre-capillary PH, it clarified whether systemic preload and afterload reduction increased or decreased SvO2 in each patient, which may aid in treatment modification.

Pd/Pa fluctuation with continuous ATP administration indicates inaccurate FFR measurement caused by insufficient hyperemia.

Continuous intravenous adenosine triphosphate (ATP) administration is the standard method for inducing maximal hyperemia in fractional flow reserve (FFR) measurements. Several cases have demonstrated fluctuations in the ratio of mean distal coronary pressure to mean arterial pressure (Pd/Pa) value during ATP infusion, which raised our suspicions of FFR value inaccuracy. This study aimed to investigate our hypothesis that Pd/Pa fluctuations may indicate inaccurate FFR measurements caused by insufficient hyperemia. We examined 57 consecutive patients with angiographically intermediate coronary lesions who underwent fractional flow reverse (FFR) measurements in our hospital between November 2016 and September 2018. Pd/Pa was measured after continuous ATP administration (150 µg/kg/min) via a peripheral forearm vein for 5 min (FFRA); and we analyzed the FFR value variation in the final 20 s of the 5 min, defining 'Fluctuation' as variation range > 0.03. Then, 2 mg of nicorandil was administered into the coronary artery during continued ATP infusion, and the Pd/Pa was remeasured (FFRA+N). Fluctuations were observed in 23 of 57 patients. The cases demonstrating discrepancies of > 0.05 between FFRA and FFRA+N were observed more frequently in the fluctuation group than in the non-fluctuation group (12/23 vs. 1/34; p < 0.0001). The discrepancy between FFRA and FFRA+N values was smaller in the non-fluctuation group (mean difference ± SD; -0.00026 ± 0.04636 vs. 0.02608 ± 0.1316). Pd/Pa fluctuation with continuous ATP administration could indicate inaccurate FFR measurements caused by incomplete hyperemia. Additional vasodilator administration may achieve further hyperemia when Pd/Pa fluctuations are observed.

Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction.

BACKGROUND: Although guideline-directed medical therapy (GDMT), including ß-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, ß-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449-0.778, P=0.001; ß-blockers: OR 0.698, 95% CI 0.529-0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560-0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics. CONCLUSIONS: Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.

Optimal Timing of Serial 18F-Fluoro-2-Deoxyglucose Positron Emission Tomography after Prednisolone Treatment Introduction for Cardiac Sarcoidosis.

Immunosuppressive therapy with prednisolone (PSL) is the first-line treatment for cardiac sarcoidosis (CS), and 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is used to evaluate its efficacy to guide treatment. However, the appropriate timing of FDG-PET in CS remains unknown. This single-center, retrospective, observational study included 15 consecutive CS patients who underwent 3 serial FDG-PET scans (at baseline, in the early phase [1-2 months after PSL introduction], and in the late phase [≥ 5 months after PSL introduction with a maintenance dose of PSL]). We adhered to the PSL tapering protocol by the Japanese Circulation Society even when early FDG-PET showed positive results (SUVmax ≥ 4.0). No patient died during the 908 (644-1600) days of observation. Negative results in the late phase were observed in 3 of 6 early-positive patients, and 3 of 9 early-negative patients showed positive results in the late phase. Changes in echocardiographic parameters from baseline to the late phase were significantly better in late-negative patients than in late-positive patients (left ventricular end-diastolic diameter: -0.7 (-9.3-[-0.5]) mm versus +3.5 (0.8-7.5) mm, P = 0.039; left ventricular end-systolic diameter: -4.2 (-6.9-[-0.1]) mm versus +5.1 (0.5-7.0) mm, P = 0.015; left ventricular ejection fraction: +4.7% (-1.0-9.0%) versus -1.5% (-11.3-1.5%), P = 0.045) ), although early FDG-PET did not predict those consequent changes. An interval of ≥ 5 months after introducing the PSL with a maintenance dose of PSL is long enough for FDG-PET to reflect consequent left ventricular functions, while an interval of 1-2 months can be too short.

Long-Term Outcomes in Patients with Not-Retrieval Inferior Vena Cava Filter Under Anticoagulation.

Since permanent inferior vena cava (IVC) filters increase deep vein thrombosis (DVT), filter retrieval should be performed as possible. Despite the guideline recommendation, IVC filters are not always retrieved in clinical practice. To date, many patients with not-retrieval IVC filters have been prescribed anticoagulant therapy, but the long-term prognosis, including venous thromboembolism (VTE) and bleeding events, remains unknown. In this study, 195 patients who underwent IVC filter implantation between 2006 and 2017 at 3 institutions in Niigata City have been investigated about their deaths, VTE recurrence, and bleeding events. After peaking 2009, the number of IVC filter implantation gradually decreased. During observational period, there were 158 patients with not-retrieval IVC filters (the overall retrieval rate of 19.0%). The not-retrieval group included significantly older and more patients with cancer compared to the retrieval group. Anticoagulation therapy was continued in 88% of the not-retrieval group. During a mean follow-up of 5.0 years, 6 symptomatic DVT events associated with inadequate control of anticoagulation and 13 bleeding events were observed. A total of 52 patients died and only the presence of cancer was prognostic risk factor. Although long-term anticoagulation therapy may be associated with bleeding events, there were few recurrent VTE under optimal anticoagulation. It is anticipated that even if the IVC filter cannot be retrieved, appropriate anticoagulation is useful for prevention of DVT recurrence despite the risk of bleeding.

The Risk of Ventricular Tachyarrhythmias in Patients with Antimitochondrial Antibodies-Related Noncardiac Diseases.

Antimitochondrial antibodies (AMA) are serum autoantibodies specific to primary biliary cholangitis and are linked to myopathy and myocardial damage; however, the presence of AMA as a risk factor for ventricular tachyarrhythmias (VTs) has remained unknown. This study aimed to elucidate whether the presence of AMA-related noncardiac diseases indicates VTs risk.This cohort study enrolled 1,613 patients (883 females) who underwent AMA testing to assess noncardiac diseases. The incidence of VTs and supraventricular tachyarrhythmias (SVTs) from a year before the AMA testing to the last visit of the follow-up were retrospectively investigated as primary and secondary objectives. Using propensity score matching, we extracted AMA-negative patients whose covariates were matched to those of 152 AMA-positive patients. In this propensity score-matched cohort, the incidence of VTs and SVTs in the AMA-positive patients were compared with that in AMA-negative patients.The AMA-positive patients had higher estimated cumulative incidence (log-rank, P = 0.013) and prevalence (5.9% versus 0.7%, P = 0.020) of VTs than the AMA-negative patients. The presence of AMA was an independent risk factor for VTs (hazard ratio, 4.02; 95% CI, 1.44-20.01; P = 0.005). Meanwhile, AMA were associated with atrial flutter and atrial tachycardia development. In AMA-positive patients, VTs were associated with male sex, underlying myopathy, high creatine kinase levels, presence of chronic heart failure or ischemic heart disease, left ventricular dysfunction, presence of SVTs, and the electrocardiographic parameters indicating atrial disorders.The presence of AMA-related noncardiac diseases is an independent risk factor for VTs.

Incidence and Risk Factors of Future Need for Long-Term Care Insurance in Japanese Elderly Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

Long-Term Prognosis of Patients Who Underwent Percutaneous Transvenous Mitral Commissurotomy for Mitral Stenosis.

The long-term prognosis for up to 20 years of patients who have undergone percutaneous transvenous mitral commissurotomy (PTMC) for mitral stenosis (MS) is unknown.We examined 77 of 93 patients (83%) with MS and who underwent PTMC from 1989 to 2002 at our institute, as well as the occurrence of either one of the following clinical endpoints until September 1, 2018: all-cause death or repeat intervention for the mitral valve.The mean follow-up duration was 20.5 ± 7.3 years. The mean age was 51 ± 11 years. Overall, the 20-year survival rate was 71% ± 5%; without any intervention, the 20-year survival rate was 40% ± 6%. In patients who achieved good immediate results (i.e., mitral valve area (MVA) of ≥ 1.5 cm2 without mitral regurgitation (MR) of > 2/4 after PTMC), the 20-year survival rate was 80% ± 6%; without any intervention, the 20-year survival rate was 54% ± 7%.In our 20-year observational study, patients who have undergone PTMC for MS had favorable prognosis, especially in those who achieved good immediate results. In those who had poor immediate results, careful follow-up is needed because they might have more clinical event and any intervention for the mitral valve.

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

BACKGROUND: Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. METHODS AND RESULTS: LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. CONCLUSIONS: We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin.

Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans.

BACKGROUND: Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans. METHODS: In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats. RESULTS: MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without. CONCLUSIONS: In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force.

Successful ß-blocker introduction under intra-aortic balloon pumping and ivabradine in a patient with new-onset dilated cardiomyopathy and pulsus alternans: a case report.

Background: Pulsus alternans has been considered a sign of poor prognosis in patients undergoing treatments for heart failure. However, it may be overlooked in patients with intra-aortic balloon pumps (IABPs). The use of IABP and ivabradine for a ß-blocker introduction in a patient with dilated cardiomyopathy (DCM) and pulsus alternans and its consequence have never been reported. Case summary: In a 16-year-old high school boy with idiopathic DCM [left ventricular end-diastolic diameter (LVDd), 72 mm; left ventricular ejection fraction (LVEF), 18%], the introduction of carvedilol therapy failed, causing cardiogenic shock under inotropes. Therefore, an IABP support was provided, and he was transferred to our hospital. The arterial pressure waveform under IABP demonstrated pulsus alternans with sinus tachycardia at 135/min. Ivabradine reduced the heart rate to ∼100/min and eliminated the pulsus alternans neither decreasing the cardiac index nor increasing the pulmonary artery wedge pressure. Subsequently, carvedilol was reintroduced, and IABP and inotropes were discontinued. Then, 112 days after his transfer to our hospital, left ventricular reverse remodelling was confirmed (LVDd, 54 mm; LVEF, 44%), and he returned to school. The carvedilol dose reached 20 mg/day in 4 months after discharge, and further improvement was observed a year after discharge (LVDd, 54 mm; LVEF, 52%). Discussion: Pulsus alternans is considered a predictor of poor prognosis. However, IABP and ivabradine may stabilize the haemodynamics in pulsus alternans, leading to a successful ß-blocker introduction.

Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

Estimation of paracrine signaling using quantitative RT-PCR from multiple patchy lesion samples.

We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo.