Exercise limitation in hypertrophic cardiomyopathy: combined stress echocardiography and cardiopulmonary exercise test.

AIMS: The study aims to investigate exercise-limiting factors in hypertrophic cardiomyopathy (HCM) using combined stress echocardiography and cardiopulmonary exercise test. METHODS AND RESULTS: A symptom-limited ramp bicycle exercise test was performed in the semi-supine position on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation at each activity level. Thirty-six HCM patients (mean age 67 ± 6 years, 72% men, 18 obstructive HCM) were compared with age and sex-matched 29 controls. At rest, compared with controls, E/E' ratio (6.26 ± 2.3 vs. 14 ± 2.5, P < 0.001) and systolic pulmonary artery pressures (SPAP) (22.6 ± 3.4 vs. 34 ± 6.2 mmHg, P = 0.023) were increased. Along with the stages of exercise (unloaded; anaerobic threshold; peak), diastolic function worsened (E/e' 8.9 ± 2.6 vs. 13.8 ± 3.6 P = 0.011; 9.4 ± 2.3 vs. 18.6 ± 3.3 P = 0.001; 8.7 ± 1.9 vs. 21.5 ± 4, P < 0.001), SPAP increased (23 ± 2.7 vs. 33 ± 4.4, P = 0.013; 26 ± 3.2 vs. 40 ± 2.9, P < 0.001; 26 ± 3.5 vs. 45 ± 7 mmHg, P < 0.001), and oxygen consumption (6.6 ± 1.7 vs. 6.8 ± 1.6, P = 0.86; 18.1 ± 2.2 vs. 14.6 ± 1.5, P = 0.008; 20.3 ± 3 vs. 15.1 ± 2.1 mL/kg/min, P = 0.01) was reduced. Oxygen pulse was blunted (6.3 ± 1.8 vs. 6.2 ± 1.9, P = 0.79; 10 ± 2.1 vs. 8.8 ± 1.6, P = 0.063; 12.2 ± 2 vs. 8.2 ± 2.3 mL/beat, P = 0.002) due to an insufficient increase in both stroke volume (92.3 ± 17 vs. 77.3 ± 14.5 P = 0.021; 101 ± 19.1 vs. 87.3 ± 15.7 P = 0.06; 96.5 ± 12.2 vs. 83.6 ± 16.1 mL, P = 0.034) and oxygen extraction (0.07 ± 0.03 vs. 0.07 ± 0.02, P = 0.47; 0.13 ± 0.02 vs. 0.10 ± 0.03, P = 0.013; 0.13 ± 0.03 vs. 0.11 ± 0.03, P = 0.03). Diastolic dysfunction, elevated SPAP, and the presence of atrial fibrillation were associated with reduced exercise capacity. CONCLUSIONS: Both central and peripheral cardiovascular limitations are involved in exercise intolerance in HCM. Diastolic dysfunction seems to be the main driver for this limitation.

Sodium-glucose co-transporter-2 inhibitors in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the prognosis of cancer. Diabetes mellitus (DM) has been shown to have a negative effect on patients treated with ICIs. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective antidiabetic therapies associated with reduced all-cause mortality and cardiovascular (CV) outcomes. OBJECTIVE: To evaluate the prognostic value of SGLT2i on all-cause mortality and cardiotoxicity among patients treated with ICIs. METHODS: We performed a retrospective analysis of patients diagnosed with cancer and type 2 DM (DM2) and treated with ICIs at our center. Patients were divided into two groups according to baseline treatment with or without SGLT2i. The primary endpoint was all-cause mortality and the secondary endpoint was MACE, including myocarditis, acute coronary syndrome, heart failure, and arrhythmia. RESULTS: The cohort included 119 patients, with 24 (20%) patients assigned to the SGLT2i group. Both groups exhibited a comparable prevalence of cardiac risk factors, although the SGLT2i group displayed a higher incidence of ischemic heart disease. Over a median follow-up of 28 months, 61 (51%) patients died, with a significantly lower all-cause mortality rate in the SGLT2i group (21% vs. 59%, p = 0.002). While there were no significant differences in MACE, we observed zero cases of myocarditis and atrial fibrillation in the SGLT2i, compared to 2 and 6 cases in the non-SGLT2i group. CONCLUSIONS: SGLT2i therapy was associated with a lower all-cause mortality rate in patients diagnosed with cancer and DM2 and treated with ICIs. Further studies are needed to understand the mechanism and evaluate its benefit on cardiotoxicity.

The prognostic value of beta-1 blockers in patients with non-small-cell lung carcinoma treated with pembrolizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of metastatic non-small cell lung cancer (mNSCLC). Beta-adrenergic activation contributes to cancer initiation and progression. While non-selective beta-blocker were found to improve the efficacy of ICIs therapy, the role of beta-1 (ß1)-selective -blocker (ß1B) in lung cancer patients is unknown. OBJECTIVE: To evaluate the effect of ß1B on overall survival (OS) and progression-free survival (PFS) in patients diagnosed with mNSCLC and treated with pembrolizumab. METHODS: We performed a retrospective analysis of patients diagnosed with mNSCLC and treated with first-line pembrolizumab at our center. RESULTS: Of 200 eligible patients, 53 (27%) were pretreated with ß1B. Patients in the ß1B cohort were older (73 ± 8 vs. 67 ± 10 years, p < 0.001) with a higher prevalence of cardiac risk factors and cardiovascular (CV) diseases including ischemic heart disease (32% vs. 16%, p = 0.010), heart failure (9% vs. 3%, p = 0.043) and atrial fibrillation (23% vs. 3%, p < 0.001). Compared to the non-ß1B group, patient pretreated with ß1B had a significant shorter median OS (12 vs. 24 months, p = 0.004) and PFS (6 vs. 8 months, p < 0.001). In a multivariate analysis, including all CV risk factors and diseases, the use of baseline ß1B was a strong and independent predictor for accelerated disease progression (HR 1.92, 95%CI 1.32-2.79, p < 0.001) and shorter OS (HR 1.8, 95%, CI 1.18-2.75, p = 0.007). CONCLUSIONS: The use of baseline ß1B showed a strong and independent association for shorter OS and PFS in patients diagnosed with mNSCLC and treated with pembrolizumab.

Immune Checkpoint Inhibitor-Induced Myocarditis vs. COVID-19 Vaccine-Induced Myocarditis-Same or Different?

Immune checkpoint inhibitor (ICI) and coronavirus disease 2019 (COVID-19) vaccine-induced myocarditis possibly share common mechanisms secondary to overactivation of the immune system. We aimed to compare the presenting characteristics of ICIs and COVID-19 vaccine-induced myocarditis. We performed a retrospective analysis of characteristics of patients diagnosed with either ICIs or COVID-19 vaccine-induced myocarditis and compared the results to a control group of patients diagnosed with acute viral myocarditis. Eighteen patients diagnosed with ICIs (ICI group) or COVID-19 vaccine (COVID-19 vaccine group)-induced myocarditis, and 20 patients with acute viral myocarditis (Viral group) were included. The ICI group presented mainly with dyspnea vs. chest pain and fever among the COVID-19 vaccine and Viral groups. Peak median high sensitivity Troponin I was markedly lower in the ICI group (median 619 vs. 15,527 and 7388 ng/L, p = 0.004). While the median left ventricular (LV) ejection fraction was 60% among all groups, the ICI group had a lower absolute mean LV global longitudinal strain (13%) and left atrial conduit strain (17%), compared to the COVID-19 vaccine (17% and 30%) and Viral groups (18% and 37%), p = 0.016 and p = 0.001, respectively. Despite a probable similar mechanism, ICI-induced myocarditis's presenting characteristics differed from COVID-19 vaccine-induced myocarditis.

Intermittent inotropic therapy with levosimendan vs. milrinone in advanced heart failure patients.

AIMS: Routine, intermittent inotropic therapy (IIT) is still applied in advanced heart failure (HF) patients either as a bridge to definitive treatment or as a mean to improve quality of life (QOL), despite limited evidence to support its' use. Given recent reports of improved QOL and reduced HF hospitalization, with levosimendan compared with placebo in advanced HF patients, we aimed to assess the effects of switching a small group of milrinone-treated patients to levosimendan. This was performed as part of a protocol for changing our ambulatory HF clinic milrinone-based IIT to levosimendan. METHODS AND RESULTS: Single-centre study of consecutive ambulatory advanced HF patients that received ≥4 cycles of once-weekly milrinone IIT at our HF outpatient clinic, who were switched to levosimendan IIT. All patients had left ventricular ejection fraction ≤35%, elevated B-natriuretic peptide (BNP), and were in New York Heart Association Classes III-IV despite maximally tolerated guideline directed medical therapy. Patients were evaluated using BNP levels, echocardiography, cardio-pulmonary exercise test, and HF QOL questionnaire before and after 4 weeks of levosimendan IIT. The cohort included 11 patients, 10 (91%) were male and the mean age was 76 ± 12 years. After 4 weeks of levosimendan therapy, maximal O2 consumption improved in 8/9 (89%) by a mean of 2.28 mL/kg [95% CI -0.22-3.38, P = 0.05]. BNP levels decreased in 9/11 (82%) levosimendan treated patients, from a median of 1015 ng/L [261-1035] to 719 ng/L [294-739], (P < 0.01). QOL as measure by the EQ-5D-5L questionnaire improved in 8/11 (82%) patients after levosimendan IIT, by a median of two points [95% CO -4.14-0.37, P = 0.09]. On echocardiography, peak systolic annular velocity (S') increased after levosimendan IIT by an average of 3 cm/s [95% CI 0.16-2.10, P = 0.03]. CONCLUSIONS: In this small-scale study of ambulatory advanced HF patients, we observed improvements in right ventricular systolic function, maximal O2 consumption, and BNP after switching from milrinone to levosimendan based IIT.

Diastolic function as an early marker for systolic dysfunction and all-cause mortality among cancer patients.

BACKGROUND: Increased survival among active cancer patients exposes a wide range of side effects, including cardiotoxicity, manifested by systolic dysfunction and associated with morbidity and mortality. Early diagnosis of subclinical function changes and cardiac damage is essential in the management of these patients. Diastolic dysfunction is considered common among cancer patients; however, its effect on systolic dysfunction or mortality is still unknown. METHODS: Data were collected as part of the Israel Cardio-Oncology Registry, enrolling and prospectively following all patients evaluated in the cardio-oncology clinic in the Tel Aviv Sourasky Medical Center. All patients underwent echocardiographic examinations including evaluation of diastolic parameters and global longitudinal strain (GLS). Systolic dysfunction was defined as either an absolute reduction >10% in left ventricular ejection fraction to a value below 53% or GLS relative reduction >10% between the 1st and 3rd echocardiography examinations. RESULTS: Overall, 190 active cancer patients were included, with a mean age of 58 ± 15 years and a female predominance (78%). During a median follow-up of 243 days (interquartile ranges [IQR]: 164-401 days), 62 (33%) patients developed systolic dysfunction. Over a median follow-up of 789 days (IQR: 521-968 days), 29 (15%) patients died. There were no significant differences in baseline cardiac risk factors between the groups. Using multivariate analysis, E/e' lateral and e' lateral emerged as significantly associated with systolic dysfunction development and all-cause mortality (P = .015). CONCLUSION: Among active cancer patients, evaluation of diastolic function may provide an early marker for the development of systolic dysfunction, as well as all-cause mortality.

Acute pulmonary pressure change after transition to sacubitril/valsartan in patients with heart failure reduced ejection fraction.

AIMS: Sacubitril/valsartan combines renin-angiotensin-aldosterone system inhibition with amplification of natriuretic peptides. In addition to well-described effects, natriuretic peptides exert direct effects on pulmonary vasculature. The effect of sacubitril/valsartan on pulmonary artery pressure (PAP) has not been fully defined. METHODS AND RESULTS: This was a retrospective case-series of PAP changes following transition from angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to sacubitril/valsartan in patients with heart failure reduced ejection fraction and a previously implanted CardioMEMS™ sensor. Pre-sacubitril/valsartan and post-sacubitril/valsartan PAPs were compared for each patient by examining averaged consecutive daily pressure readings from 1 to 5 days before and after sacubitril/valsartan exposure. PAP changes were also compared between patients based on elevated trans-pulmonary gradients (trans-pulmonary gradient ≥ 12 mmHg) at time of CardioMEMS™ sensor implantation. The cohort included 18 patients, 72% male, mean age 60.1 ± 13.6 years. There was a significant decrease in PAPs associated with transition from ACEI/ARB to sacubitril/valsartan. The median (interquartile range) pre-treatment and post-treatment change in mean, systolic and diastolic PAPs were -3.6 (-9.8, -0.7) mmHg (P < 0.001), -6.5 (-15.0, -2.0) mmHg (P = 0.001), and -2.5 (-5.7, -0.7) (P = 0.001), respectively. The decrease in PAPs was independent of trans-pulmonary gradient (F(1,16) = 0.49, P = 0.49). CONCLUSIONS: In this retrospective case series, transition from ACEI/ARB to sacubitril/valsartan was associated with an early and significant decrease in PAPs.

Angiotensin Receptor-Neprilysin Inhibition.

The novel combination sacubitril/valsartan represents a new therapeutic approach in the management of heart failure. With the simultaneous blockage of the enzyme neprilysin (by sacubitril) and angiotensin II receptors (by valsartan), this combination reduces the degradation of natriuretic peptides and other counterregulatory peptide systems while avoiding the deleterious effect of angiotensin II receptors activation and thereby encompasses a beneficial impact of 2 important neurohormonal pathways activated in heart failure. As opposed to previously tested neprilysin inhibitors, sacubitril/valsartan represents a more effective method in reducing morbidity and mortality in heart failure, while preserving a safety profile comparable to well-established, standard, angiotensin-converting enzyme inhibitor's therapy.

Pregnancy and the Risk of Spontaneous Coronary Artery Dissection: An Analysis of 120 Contemporary Cases.

BACKGROUND: Because of the rarity of this condition, information on pregnancy-associated spontaneous coronary artery dissection is limited. We reviewed a large number of contemporary pregnancy-associated spontaneous coronary artery dissection cases in an attempt to define the clinical characteristics and provide management recommendations. METHODS AND RESULTS: A literature search for cases of pregnancy-associated spontaneous coronary artery dissection reported between 2000 and 2015 included 120 cases; 75% presented with ST-segment-elevation myocardial infarction, and 80% had anterior myocardial infarction. Left anterior descending coronary artery was involved in 72% of cases, left main segment in 36%, and 40% had multivessel spontaneous coronary artery dissection. Ejection fraction was reduced to <40% in 44% of cases. Percutaneous coronary intervention was successful in only 50% of cases. Coronary artery bypass surgery was performed in 44 cases because of complex anatomy, hemodynamic instability, or failed percutaneous coronary intervention. Maternal complications included cardiogenic shock (24%), mechanical support (28%), urgent percutaneous coronary intervention (28%), urgent coronary artery bypass surgery (27.5%), maternal mortality (4%), and fetal mortality (2.5%). During follow-up for 305±111 days, there was a high incidence of symptoms because of persistent or new spontaneous coronary artery dissections, and 5 women needed heart transplantation or ventricular assist device implantation. CONCLUSIONS: Pregnancy-associated spontaneous coronary artery dissection is commonly associated with left anterior descending, left main, and multivessel involvement, which leads to a high incidence of reduced ejection fraction, and life-threatening maternal and fetal complications. Percutaneous coronary intervention is associated with low success rate and high likelihood of complications, and coronary artery bypass surgery is often required. Recurrent ischemic events because of persistent or new spontaneous coronary artery dissection are common during long-term follow-up.

A Tale of 2 Diseases: The History of Long-QT Syndrome and Brugada Syndrome.

The Brugada syndrome (BrS) and long-QT syndrome (LQTS) present as congenital or acquired disorders with diagnostic electrocardiograms (ST-segment elevation and prolonged QT interval, respectively) and increased risk for malignant arrhythmias. Our understanding of the 2 disease forms (congenital vs. acquired) differs. A female patient on quinidine for atrial fibrillation who develops ventricular fibrillation is diagnosed with "acquired LQTS" and is discharged with no therapy other than instructions to avoid QT-prolonging medications. In contrast, an asymptomatic male patient who develops a Brugada electrocardiogram on flecainide is diagnosed with "asymptomatic BrS" and could be referred for an electrophysiological evaluation that could result in defibrillator implantation. The typical patient undergoing defibrillator implantation for BrS is asymptomatic but has a Brugada electrocardiogram provoked by a drug. The authors describe how the histories of LQTS and BrS went through the same stages, but in different sequences, leading to different conclusions.

Risk stratification in Brugada syndrome: Clinical characteristics, electrocardiographic parameters, and auxiliary testing.

Risk stratification in Brugada syndrome remains a clinical challenge because the event rate is low but the presenting symptom is often cardiac arrest (CA). We review the data on risk stratification. A history of CA or malignant syncope is a strong predictor of spontaneous ventricular fibrillation (VF), whereas the prognostic value of a history of familial sudden death and the presence of a SCN5A mutation are less well defined. On the electrocardiogram, the presence of spontaneous type I electrocardiogram increases the risk for VF in all studies, whereas the presence of fragmented QRS complexes and early repolarization correlates with increased risk in several studies. Signal-averaged techniques using late potentials and microscopic T-wave alternans show some promising results in small studies that need to be confirmed. The value of electrophysiologic studies for predicting spontaneous VF remains controversial, and this includes programmed stimulation protocols that avoid a third extrastimuli or stimulation from the right ventricular outflow. Risk prediction is particularly challenging in children and women.

Forced diuresis with matched hydration in reducing acute kidney injury during transcatheter aortic valve implantation (Reduce-AKI): study protocol for a randomized sham-controlled trial.

BACKGROUND: Acute kidney injury (AKI) is observed in up to 41% of patients undergoing transcatheter aortic valve implantation (TAVI) and is associated with increased risk for mortality. The aim of the present study is to evaluate whether furosemide-induced diuresis with matched isotonic intravenous hydration using the RenalGuard system reduces AKI in patients undergoing TAVI. METHODS/DESIGN: Reduce-AKI is a randomized sham-controlled study designed to examine the effect of an automated matched hydration system in the prevention of AKI in patients undergoing TAVI. Patients will be randomized in a 1:1 fashion to the RenalGuard system (active group) versus non-matched saline infusion (sham-controlled group). Both arms receive standard overnight saline infusion and N-acetyl cysteine before the procedure. DISCUSSION: The Reduce-AKI trial will investigate whether the use of automated forced diuresis with matched saline infusion is an effective therapeutic tool to reduce the occurrence of AKI in patients undergoing TAVI. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01866800, 30 April 30 2013.

Effect of vitamin D analogues on acute cardiorenal syndrome: a laboratory rat model.

BACKGROUND: Vitamin D has been shown to induce beneficial effects on cardiovascular and renal morbidity by regulating inflammation and tissue fibrosis. OBJECTIVES: To evaluate the effect of vitamin D analogues on cardiac function and fibrosis in an animal model of cardiorenal syndrome. METHODS: Unilateral nephrectomy was performed and myocardial infarction induced in rats. The rats were treated with vitamin D receptor activator (VDRA, paricalcitol, 40 ng/250 g x 3/week) versus a vehicle. A third group of animals, which served as the control, underwent sham surgery and received no treatment. After 4 weeks of treatment, cardiac function and fibrosis were assessed by trans-thoracic echo and histology, respectively. As a parameter of systemic inflammation, previously shown to be altered in acute coronary syndrome, T regulatory (Treg) cell levels were measured by flow cytometry. Renal dysfunction was documented by standard laboratory tests. RESULTS: After 4 weeks of treatment, no significant improvement in cardiac function parameters was noted following VDRA administration. VDRA treatment did not significantly alter Treg cell systemic levels. Consistently, despite a trend toward less extent of myocardial fibrosis, we found no clear beneficial effects of VDRA on myocardial tissue inflammation and remodeling. CONCLUSIONS: Vitamin D treatment showed no beneficial effects on cardiac function parameters and fibrosis in an animal model of cardiorenal syndrome.