Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

Haemodynamic effects of acute intravenous landiolol in Takotsubo cardiomyopathy with dynamic left ventricular outflow tract obstruction.

Takotsubo cardiomyopathy (TCM) leads to serious left ventricular outflow tract (LVOT) obstruction with cardiogenic shock in 6%-20% of cases. The onset of LVOT obstruction, coupled with mitral regurgitation resulting from systolic anterior motion of mitral valve leaflets, can lead to haemodynamic instability in addition to severely impaired systolic function. We describe three patients who experienced chest discomfort following emotional stress. These patients displayed pronounced abnormalities on ECGs, insignificant obstructive coronary disease and haemodynamic instability due to LVOT obstruction. The infusion of landiolol, a short-acting beta blocker, was effective in releasing the gradient. Dynamic outflow obstruction is the major predictor of haemodynamic collapse. We suggested that an early identification of this complication in hypotensive patients with suspected TCM could be of utmost importance to optimise the therapeutic approach in the acute setting.

Perspectivas actuales en el procedimiento de Ross y Ross-Konno: ¿es hora de buscar alternativas? / Current perspectives in Ross and Ross-Konno procedures: Is it time to search for alternatives?

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Bisoprolol for treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy. The BASIC (bisoprolol AS therapy in hypertrophic cardiomyopathy) study.

AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.

Randomized Trial of Metoprolol in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The use of ß-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies. OBJECTIVES: This study aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM. METHODS: This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing. RESULTS: Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg [interquartile range (IQR): 15-58 mm Hg] vs 72 mm Hg [IQR: 28-87 mm Hg]; P = 0.007), at peak exercise (28 mm Hg [IQR: 18-40 mm Hg] vs 62 mm Hg [IQR: 31-113 mm Hg]; P < 0.001), and postexercise (45 mm Hg [IQR: 24-100 mm Hg] vs 115 mm Hg [IQR: 55-171 mm Hg]; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms. CONCLUSIONS: Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).

Mavacamten - a new disease-specific option for pharmacological treatment of symptomatic patients with hypertrophic cardiomyopathy.

Current pharmacotherapy for hypertrophic cardiomyopathy (HCM) is not disease-specific and has suboptimal efficacy, often necessitating interventional treatment. EXPLORER-HCM was a phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial investigating the effects of mavacamten, a first-in-class selective cardiac myosin inhibitor, in patients with HCM, left ventricular outflow tract obstruction (LVOTO) and New York Heart Association (NYHA) class II or III symptoms. The primary endpoint was defined as either a ≥1.5 ml/kg/min increase in peak oxygen consumption (pVO2) and ≥1 NYHA class reduction or a ≥3.0 ml/kg/min pVO2 increase without NYHA class worsening. Secondary endpoints evaluated changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopa-thy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). A total of 251 patients were randomized to receiving mavacamten or placebo. The primary endpoint and all secondary endpoints were met significantly more frequently in the mavacamten arm versus placebo. The safety profile of mavacamten was similar to that of placebo. In conclusion, disease-specific treatment with mavacamten in patients with obstructive HCM led to reduced LVOTO and improvement in both objective functional parameters and patient-related health status.

Echocardiographic features of accessory mitral valve tissue presenting left ventricular outflow tract obstruction in a dog.

In a 3-year-old Samoyed, aortic bulging was found on radiography during a general check-up. On echocardiography, turbulent flow was found in left ventricular outflow tract (LVOT) with high velocity (6.1 m/s). A linear structure was attached to the interventricular septum and connected to the chordae tendineae reaching the papillary muscle. A part of the structure moved during cardiac cycle, similar to mitral motion. This dog was diagnosed with LVOT obstruction caused by accessory mitral valve tissue (AMVT). This is the first report of AMVT in veterinary medicine. AMVT should be considered as a possible cause of LVOT obstruction in dogs.

Vasopressin in Patients with Septic Shock and Dynamic Left Ventricular Outflow Tract Obstruction.

PURPOSE: Left ventricular outflow tract obstruction (LVOTO) is a relatively uncommon but severe condition that may lead to hemodynamic impairment. It can be elicited by morphological (left ventricular hypertrophy, sigmoid septum, prominent papillary muscle, prolonged anterior mitral valve leaflet) and functional (hypovolemia, low afterload, hypercontractility, catecholamines) factors. We sought to determine the incidence of the most severe form of LVOTO in septic shock patients and describe the therapeutic effects of vasopressin. METHODS: Over a period of 29 months, 527 patients in septic shock were screened for LVOTO. All were mechanically ventilated and treated according to sepsis bundles, including pre-load optimization and norepinephrine infusion. Vasopressin was added in addition to norepinephrine to reduce the adrenergic burden and decrease LVOTO. RESULTS: Ten patients were diagnosed with the most severe form of LVOTO, including systolic anterior mitral valve motion (SAM) and severe mitral regurgitation (MR) with pulmonary oedema. The median norepinephrine dosage to obtain a mean arterial pressure of ≥70 mmHg was 0.58 mcg/Kg/min (IQR 0.40-0.78). All patients had a hyper-contractile left ventricle, septal hypertrophy, significant LVOTO (peak gradient 78 [56-123] mmHg) associated with SAM and severe MR with pulmonary oedema. Vasopressin (median 4 IU/h) allowed a significant reduction of norepinephrine (0.18 [0.14-0.30] mcg/kg/min; p = 0.01), LVOT gradient (35 [24-60] mmHg; p = 0.01) and MR with a significant paO2/FiO2 increase (174 [125-213] mmHg; p = 0.01). CONCLUSION: Vasopressin allowed a reduction of norepinephrine with subsequent LVOTO reduction and hemodynamic improvement of the most severe form of LVOTO, which represented 1.9% of all septic shock patients.

Left ventricular outflow tract pressure gradient changes after carvedilol-disopyramide cotherapy in a cat with hypertrophic obstructive cardiomyopathy.

Disopyramide reduces the left ventricular outflow tract (LVOT) pressure gradient and improves symptoms in humans with hypertrophic obstructive cardiomyopathy (HOCM). However, the efficacy of disopyramide in cats has not been reported. We treated a cat with HOCM with carvedilol and disopyramide cotherapy and monitored the changes in LVOT flow velocity and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration. A 10-month-old neutered male Norwegian Forest cat was referred with a moderate systolic cardiac murmur. Echocardiography revealed thickening of the left ventricular wall, systolic anterior motion of the mitral valve leaflets, and turbulent aortic flow in the LVOT at systole. The LVOT flow velocity was 5.6 m/s. The plasma NT-proBNP concentration exceeded 1,500 pmol/L. The cat was diagnosed with HOCM and the ß-blocker carvedilol was started and gradually increased to 0.30 mg/kg, bid. After 57 days, the LVOT flow velocity (4.8 m/s) and plasma NT-proBNP concentration (870 pmol/L) had decreased but remained elevated. Therefore, disopyramide was added at 5.4 mg/kg po bid and increased to 10.9 mg/kg po bid after 22 days. After 141 days of carvedilol and disopyramide treatment, the systolic anterior motion of the mitral valve leaflets had disappeared and the LVOT flow velocity and plasma NT-proBNP concentration had decreased to 0.7 m/s and 499 pmol/L, respectively. No adverse effect has been observed during the follow-up. Disopyramide might relieve feline LVOT obstruction after only partial response to a beta-blocker. Further large-scale studies are required to investigate the efficacy and safety of disopyramide use in cats with moderate to severe HOCM.

Development of Pulmonary Edema Despite Negative Fluid Balance with Diuretics in a Patient with Heart Failure and Sigmoid Septum.

An 87-year-old man was hospitalized due to dyspnea and leg edema. He was diagnosed with heart failure due to anemia with a hemoglobin (Hb) concentration of 6.0 g/dL. Chest X-ray on admission revealed pleural effusion. He was transfused with 400 mL packed red blood cells, which elevated the Hb concentration to 8.6 g/dL. Spironolactone (25 mg/day) and furosemide (20 mg/day, intravenously) were initiated. Despite the negative fluid balance, the patient's dyspnea worsened. Chest X-ray on day 8 revealed pulmonary edema despite decreased pleural effusion. Transthoracic echocardiography (TTE) revealed a sigmoid-shaped interventricular septum and systolic anterior motion of the mitral valve, causing left ventricular outflow tract obstruction (LVOTO; peak pressure gradient, 96 mmHg). Pilsicainide (75 mg/day) was administered to reduce the LVOTO. In addition, furosemide administration was changed to continuous infusion with increased dose of 48 mg/day (2 mg/h). The patient's dyspnea finally abated, with X-ray on day 12 revealing marked reduction in pulmonary congestion. TTE on day 17 revealed marked reduction in LVOTO (peak pressure gradient, 21 mmHg). Hemodynamic change by diuretics in the setting of right-sided heart failure due to anemia and in the presence of LVOTO due to sigmoid septum could be the cause of pulmonary edema.

Pharmacotherapy for the treatment of obstructive hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases and represents a leading cause of sudden cardiac death as well as a prevalent cause of heart failure and stroke. HCM is characterized by a very complex pathophysiology, consisting of heterogeneous clinical manifestations and natural history. Left ventricular outflow tract (LVOT) obstruction has been considered the most knowable feature of HCM since the initial clinical descriptions of the disease.Areas covered: In this review, the authors discuss the most recent reports on the pharmacological treatment of obstructive HCM, mainly based on three different levels of intervention: control of symptoms, cardiac metabolism modulation and disease-modifying approaches, including genetic preventive therapies.Expert opinion: There are presently limited data supporting pharmacological interventions for this complex disease. However, an improved understanding of HCM pathophysiology will allow the development of novel treatment options. Two important key messages are to further study drugs with negative but limited previous results and to design new and larger trials for those molecules that have already produced positive results in HCM, especially for pressure gradients and symptoms control.

Markers of responsiveness to disopyramide in patients with hypertrophic cardiomyopathy.

BACKGROUND: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction. METHODS: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation. RESULTS: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ±â€¯5.6% vs. 59.7 ±â€¯5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ±â€¯2.3% vs. -16.1 ±â€¯2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ±â€¯5.1 ml/m2 vs. 23.2 ±â€¯6.8 ml/m2, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ±â€¯3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ±â€¯11.2% vs. 50.5 ±â€¯12.2%, p = 0.005), systolic LA strain (34 ±â€¯12.4% vs. 25.8 ±â€¯10.6%, p = 0.04), and LA strain-rate (1.34 ±â€¯0.49%/sec vs. 0.99 ±â€¯0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide. CONCLUSIONS: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered.

Takotsubo Cardiomyopathy in a Patient with Previously Undiagnosed Hypertrophic Cardiomyopathy with Latent Obstruction.

A 62-year-old woman with takotsubo cardiomyopathy (TCM) accompanied by cardiogenic shock due to the obstruction of left ventricular outflow tract (LVOT) and massive mitral regurgitation (MR) was admitted to the emergency department. After successful treatment with intensive care, dobutamine stress-echocardiography was performed, which reproduced a dynamic LVOT gradient, severe MR and cardiogenic shock. A histological examination obtained from the right ventricular septum demonstrated hypertrophied and bizarre myocytes, with myocyte disarray. Besides TCM, a diagnosis of preexisting hypertrophic cardiomyopathy with latent obstruction was made. She was discharged with medical therapy including a beta-blocker, which would not be routinely employed in the treatment of a patient with TCM.

Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30mmHg at rest or with provocation. There are no data on whether 30mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes. METHODS: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median follow-up period of 2.1years. RESULTS: Among 536 patients, 131 patients had resting LVOT gradients greater than 30mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients >90mmHg (HR 3.92, 95% CI 1.97-7.79) or <30mmHg (HR 2.15, 95% CI 1.08-4.29) have more events compared to those with gradients between 30 and 89mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with "benign" latent HCM (provoked gradient 30-89mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome. CONCLUSIONS: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups.

Transient left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve: A stunning cause.

Left ventricular outflow tract obstruction (LVOTO) and systolic anterior motion (SAM) of the mitral valve may have various etiologies, of which hypertrophic cardiomyopathy is the most common. More rarely, an acute coronary syndrome, myocardial stunning, and takotsubo cardiomyopathy may give rise to LVOTO and SAM. Here, we present a 70-year-old female patient with a non-ST-elevation acute coronary syndrome treated with percutaneous coronary intervention. Echocardiography the day after, because of dyspnea and hypotension, revealed apical akinesia, LVOTO, and SAM, which proved completely reversible after treatment with a ß-blocker and a 2-month follow-up period. It was concluded that postischemic apical stunning had caused LVOTO and SAM.

Manifestation of Latent Left Ventricular Outflow Tract Obstruction in the Acute Phase of Takotsubo Cardiomyopathy.

Objective Left ventricular outflow tract (LVOT) obstruction is a complication in 15-25% of patients with Takotsubo cardiomyopathy and sometimes leads to catastrophic outcomes, such as cardiogenic shock or cardiac rupture. However, the underlying mechanisms have not been clarified. Methods and Results We experienced 22 cases of Takotsubo cardiomyopathy during 3 years, and 4 of these 22 cases were complicated with LVOT obstruction in the acute phase (mean age 79±5 years, 1 man, 21 women). The LVOT pressure gradient in the acute phase was 100±17 mmHg. Transthoracic echocardiogram (TTE) revealed left ventricular hypertrophy (LVH) in one case and sigmoid-shaped septum without LVH in three cases. The complete resolution of the LVOT obstruction was achieved in a few days with normalization of the left ventricular wall motion following administration of beta-blockers. A dobutamine provocation test after normalization of the left ventricular wall motion reproduced the LVOT obstruction in all cases and revealed the presence of latent LVOT obstruction. Conclusion The manifestation of latent LVOT obstruction in the acute phase of Takotsubo cardiomyopathy is one potential reason for the complication of LVOT obstruction with Takotsubo cardiomyopathy.

Computed tomography imaging to quantify the area of the endocardial subvalvular apparatus in hypertrophic cardiomyopathy - Relationship to outflow tract obstruction and symptoms.

BACKGROUND: Abnormalities of the endocardial subvalvular apparatus (SVA), which includes the papillary muscles directly attached to the mitral leaflet and left ventricular apical-basal muscle bundles, are occasionally identified in hypertrophic cardiomyopathy (HCM). Their associations with left ventricular outflow tract (LVOT) obstruction are unknown. METHODS: We retrospectively reviewed cardiac computed tomography image data sets of 107 consecutive patients with HCM [56 obstructive (HOCM) and 51 non-obstructive (HNOCM)] as well as 53 controls. We evaluated anomalies of the SVA, measured the cross-sectional area of the SVA at the level of the LVOT, and subsequently assessed its correlation with the LVOT pressure gradient with and without medication. RESULTS: The area of the SVA was greater in HOCM than in HNOCM patients and in the control group (2.5 ± 1.3 cm(2), 1.4 ± 0.8 cm(2), and 0.9 ± 0.6 cm(2), respectively; p < 0.0001). Anomalies in the SVA were more often observed in the HOCM group than in the HNOCM patients and controls (abnormal papillary muscles, 14%, 8%, and 0%, respectively; P = 0.010; LV apical-basal muscle bundles, 73%, 65%, and 45%, respectively; P = 0.0094). Among HOCM patients, logistic regression analysis demonstrated that an SVA area of 2.2 cm(2) was an independent risk factor of residual severe LVOT obstruction (≥50 mmHg) after medication (odds ratio, 10.1; 95% confidence interval, 2.05-49.80). CONCLUSION: An increased area of the endocardial subvalvular apparatus could be an independent risk factor for clinically relevant LVOT obstruction refractory to medication.