with AF because S4 depends on effective atrial contraction. In patients with an atrial septal defect, there is fixed splitting of the second heart sound because there is equalisation of volume loads between the two atria occurring through the defect. A loud S1 can occur in AF due to reduced diastolic filling time so the mitral valve remains widely open at the end of diastole. S3 is a mid‐diastolic sound. It can occur in children and young people due to rapid diastolic filling. A pathologic S3 is present in patient with congestive heart failure (CCF) and other heart disorders due to reduced ventricular compliance and rapid diastolic filling.
Voin V, Oskouian R, Loukas M, Tubbs R. Auscultation of the heart. Clinical Anatomy. 2016;30(1):58–60.
https://www.ncbi.nlm.nih.gov/pubmed/27576554
3. Answer: B
Anthracyclines such as doxorubicin and idarubicin exhibit an anti‐cancer action through inhibition of topoisomerase (Top) 2α in cancer cells, and their toxicity is largely through inhibition of Top 2β in cardiac myocytes. Topoisomerases are highly expressed in proliferating eukaryotic cells and are involved in detangling and relegating aberrant DNA coils. By binding Top 2α in cancer cells' DNA, anthracyclines facilitate the cleavage function of topoisomerase, but not the religation, which leads to accumulation of double stranded DNA breaks and initiates programmed cell death pathways. Anthracyclines also cause mitochondrial dysfunction and excessive intracellular reactive oxygen species, which results in increased apoptosis. This process is promoted by high intracellular iron availability. Both of these pathways are thought to contribute to the death of cardiac myocytes, and result in cardiomyopathy.
Patient factors predictive of higher risk for anthracycline cardiomyopathy include lifetime cumulative dose, age less than 18 or over 65, female gender, renal failure, radiotherapy involving the heart, pre‐existing cardiac disease, carbonyl reductase gene polymorphisms, and carrier status for haemochromatosis genes. Exposure to anthracycline chemotherapy also increases risk of cardiotoxicity with trastuzumab. Trials evaluating the pharmaceutical prevention of anthracycline related cardiomyopathy have found small but statistically significant differences in deterioration of left ventricular function for ACE inhibitors, beta‐blockers, aldosterone antagonists and angiotensin 2 receptor blockers in predominantly low‐exposure and low‐risk patients. These results may or may not be clinically significant.
Trials that target those at highest risk of cardiomyopathy are most likely to yield more meaningful clinical results. For example, in one trial patients receiving high dose chemotherapy were randomised to receive placebo or ramipril should they have a troponin rise after their first cycle of chemotherapy. The results of the study found that the treatment arm had a roughly stable left ventricular ejection fraction over the trial period, but the placebo arm decreased by around 14%, which could translate to meaningful patient‐centred outcomes. Dexrazoxane competitively binds Top 2β, preventing anthracycline binding, and very effectively prevents anthracycline cardiomyopathy. Previous concerns regarding increased risk of secondary cancers with dexrazoxane are being re‐evaluated as the result of multiple influential trials, and it is now available for use in a number of settings.
Henriksen P. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart. 2017;104(12):971–977.
https://heart.bmj.com/content/104/12/971.long
4. Answer: B
Most patients with symptomatic severe aortic stenosis (AS) have a valve area <1.0 cm2 and/or a mean transvalvular pressure gradient >40 mmHg. Low gradient AS is defined as severe AS (valve area <1.0 cm2) with a transvalvular pressure gradient <30 mmHg. Low gradient AS is seen in patients with left ventricular (LV) systolic dysfunction with reduced left ventricular ejection fraction (LVEF). A challenging clinical task in those with low gradient AS is differentiating who will survive and improve after aortic valve replacement surgery and those who will not. There is a subset of patients with AS and low transvalvular gradients who do not benefit from aortic valve replacement and are at considerable risk of operative death. These patients have a significant degree of LV dysfunction but only mild to moderate AS. They are considered to have pseudo‐stenosis because their symptoms are primarily due to poor LV function, not significant valvular disease.
Dobutamine Stress Echocardiography (DSE) is useful to differentiate true aortic stenosis from pseudo‐aortic stenosis. Patients with severe AS and secondary LV dysfunction that leads to a low transvalvular pressure gradient are considered to have true stenosis. In this setting, the severe stenotic lesion results in excessive afterload and a reduced LVEF, thereby producing both a markedly decreased stroke volume and low transvalvular pressure gradient. It is logical to assume that aortic valve replacement will be beneficial in these patients. In pseudostenosis, patients have a low transvalvular pressure gradient because of the combination of moderate AS and low cardiac output. The low output reduces the valve opening forces, resulting in limited mobility of a valve that is not severely diseased. The calculated valve area may mistakenly suggest severe stenosis because of valve area equation limitations when applied to low flow rate conditions. In contrast to true stenosis, surgical correction in these patients is unlikely to be beneficial.
There are no other clinical or haemodynamic variables that are helpful to stratify risk in such patients and determine the appropriate therapy. The aortic valve calcium score (determined by CT) has been associated with AS haemodynamic severity, progression rate, and clinical outcomes but not validated in patients with low ejection fraction. Patients with contractile reserve have a much better outcome after surgery.
Annabi M, Touboul E, Dahou A, et al. Dobutamine Stress Echocardiography for Management of Low‐Flow, Low‐Gradient Aortic Stenosis. Journal of the American College of Cardiology. 2018;71(5):475–485. https://www.sciencedirect.com/science/article/pii/S0735109717417785?via%3Dihub
5. Answer: D
There is an increased prevalence of AS in an ageing population. Severe AS is defined on transthoracic echocardiogram as a reduced aortic valve area (AVA) of < 1.0 cm2, peak velocity of > 4 m/s and a mean gradient of greater than 40 mmHg across the valve. Patients with less severe aortic stenosis may remain asymptomatic for years. Once the symptoms of syncope, angina, or heart failure develop, average survival reduces rapidly, with an increased risk of sudden cardiac death. Until transcatheter aortic valve implantation (TAVI) became available, the options to treat severe AS include medical (palliative management), surgical aortic valve replacement (SAVR), or a Ross procedure (where a diseased aortic valve is replaced by a patient's own pulmonary valve). SAVR involves a midline sternotomy, general anaesthetic, cardiopulmonary bypass, typically requires 24 to 48 hours stay in an intensive care unit (ICU) and 10 to 14 days as an inpatient for post‐op recovery and mobilisation, and an even longer hospital stay for rehabilitation in the frail and elderly. Patients who are greater than 75 years old have an increased morbidity and mortality associated with SAVR.
Since the advent of TAVI in 2002, elderly patients who were not suitable candidates for SAVR, can now be considered for TAVI if appropriate, provided they do not have severe COPD, debilitating stroke, active malignancy, and dementia
