This report describes an adult who survived cancer as a young adult but had risk factors for increased cardiac dysfunction (high-dose ATC chemotherapy and post-exposure hypertension) and experienced acute HF 20 years post-chemotherapy, along with two WHF episodes post-discharge [2]. The onset of the second episode of WHF symptoms occurred during quadruple therapy induction, necessitating ivabradine initiation. The patient improved to NYHA class IIm with a trend of decreasing BNP levels due to the five-drug combination. However, the sixth HF drug, vericiguat, was introduced six weeks after starting the five-drug combination due to the increased risks of severe cardiovascular events associated with ongoing AS requiring imminent invasive therapy, as well as the poor prognosis of ATC-induced cardiomyopathy, with a five-year survival rate of < 50% after the onset of symptomatic HF [8]. The multidrug combination therapy improved the WHF with ATC-induced cardiomyopathy, and the patient uneventfully survived AVR and showed significant cardiac reverse remodeling (CRR).

ATC-based chemotherapy is associated with irreversible dose-dependent cardiac damage. The specific mechanisms of ATC cardiotoxicity remain unclear; however, the major cellular targets are cardiomyocytes, among others, such as cardiac progenitor cells, cardiac fibroblasts, endothelial cells, smooth muscle cells, endothelial progenitor cells, and mesenchymal stromal cells. The main pathophysiological mechanisms include oxidative stress, DNA damage, senescence, and cell death, with potentially different effects and degrees of involvement in different cell types [9, 10]. The patient developed colon and rectal cancer after chemotherapy, and the initial 2DE during the first hospitalization revealed significant aortic valve sclerosis relative to the patient’s age. Considering this, the senescence-associated secretory phenotype associated with ATC may have played a role as the hinge between cancer and cardiovascular disease induced by senescent cardiovascular cells [11]. Furthermore, hypertension requiring antihypertensive drugs occurred less than five years after chemotherapy treatment, suggesting a potential association with this phenomenon. ATC cardiotoxicity is potentially a continuous phenomenon, beginning at the myocardial cell level, followed by progressive functional decline (asymptomatic cardiotoxicity in months) and overt HF (symptomatic cardiotoxicity in years), all manifesting as different evolutionary stages of the same phenomenon. The time to onset of symptomatic HFrEF varies among patients [10], indicating that the activation of cardiac compensatory mechanisms, including survival factors, typically delays symptomatic cardiac dysfunction for years. However, cardiac function progressively declines several years to more than 10 years after chemotherapy due to the exhaustion of compensatory mechanisms and the onset of additional stressors, such as hypertension and coronary artery disease, eventually leading to a symptomatic state [12]. One factor delaying overt HF in our patient was the use of angiotensin receptor blockers (ARB) for hypertension, which concomitantly acted as HF therapy. The patient's blood pressure, which was not controlled based on contemporary hypertension guidelines, atherosclerotic AS, and aging constituted additional stressors. Consequently, the collapse of cardiac compensatory mechanisms caused acute HF 20 years post-chemotherapy.

The VICTORIA trial, a double-blind, randomized, controlled trial comparing vericiguat to placebo in patients with a history of GDMT use and severe HFrEF, including those with WHF, demonstrated the clinical benefit of vericiguat for reducing cardiovascular death or HF hospitalization, without severe adverse effects [13]. Intracellular cyclic guanosine monophosphate (cGMP) levels are decreased in patients with HF, and increased cGMP levels inhibit cardiac remodeling, vascular injury, fibrosis, and inflammation. This increase in cGMP results from the nitric oxide (NO)-soluble guanylyl cyclase (GC)-cGMP signaling pathway stimulated by vericiguat and the natriuretic peptide-particulate GC-cGMP signaling pathway triggered by sacubitril/valsartan in different compartments [14]. Therefore, future clinical trials should investigate the clinical efficacy of combining these two drugs in HFrEF. Additionally, vericiguat directly stimulates soluble GC (sGC) in a NO-independent manner and enhances the sensitivity of sGC to endogenous NO, which may be effective in HF due to atherosclerosis with impaired endothelial function, such as in this case. Animal experiments have shown that sGC activity decreases in DOX-mediated cardiomyopathy, and this reduced activity exacerbates reactive oxygen species generation and cardiac dysfunction [15]. This reduced sGC activity is permanent; therefore, activating sGC is considered to have therapeutic potential in treating symptomatic ATC-induced CTRCD.

Recent recommendations suggest quadruple therapy as the standard of care in WHF, prioritizing rapid sequence or simultaneous initiation of key agents rather than escalating their doses. Furthermore, early up-front vericiguat use is recommended for patients with WHF alongside quadruple therapy, as tolerated, to further reduce the risk of residual adverse clinical outcomes [16]. Based on our experience with vericiguat use, we formulated the following policy regarding the timing of adding this drug. Early initiation of vericiguat in WHF should be based on an individualized residual risk assessment. Even if clinical symptoms remain stable with quadruple therapy, vericiguat should be initiated under the following conditions: when there is a high likelihood of future adverse events due to, such as in this case, ongoing AS or ACT-induced cardiomyopathy with a poor prognosis. Vericiguat should also be initiated when the decrease in BNP or N-terminal pro-BNP (NT-proBNP) levels is unacceptable (a reduction rate of 30% or less) [17, 18], or when the LVEF has not recovered to baseline or remains less than 50% after approximately three months.

CRR is a surrogate measure for HFrEF improvement, which is an important goal in HFrEF treatment. BBs are known to achieve the highest CRR, with gradual dose increases recommended while monitoring for HF or bradycardia occurrence. According to the package insert for the carvedilol used in this case in Japan, the dosage starts at 1.25 mg two times daily, and the dose is gradually increased at intervals of at least one week, if tolerated, with a maintenance dose of 2.5–10 mg two times daily. This is considerably lower than the dosages in package inserts from Western countries. Specifically, this is because clinical trials conducted in Japan have confirmed sufficient efficacy of BBs, even at low doses, and fewer side effects have been observed. This background relates to the fact that WHF and intolerance were frequently observed in the early stages of BB introduction in Japan. In our case, up-titration of carvedilol was halted at 7.5 mg/day, during which BNP levels ranged between 1,100–1,900 pg/mL, and clinical inertia may have occurred due to concerns about complications from further dosage increases. Therefore, titrating to the maximum tolerated dose in line with GDMT is advisable. The patient was in a congested and unstable state during the second episode of WHF, classified as NYHA class III, and dosage increases during this period were discouraged according to both Japanese and Western guidelines. Additionally, during the coronavirus disease 2019 pandemic, when hospital bed availability was limited and outpatient treatment was necessary, increasing BB dosage in an outpatient setting posed a risk of further HF deterioration. Therefore, ivabradine, which lowers heart rate without decreasing LV dp/dt, was selected. Ivabradine has a CRR effect and can control the increased heart rate resulting from sympathetic excitation in HF, without depressing cardiac function [19, 20]. Benstoem et al. in their recent meta-analysis reported no difference in cardiovascular mortality and severe adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with HFrEF [21]. Additionally, Bryan et al. reported that ivabradine improved LVEF with CRR, reduced rehospitalizations due to WHF, further lowered the heart rate, and improved exercise capacity; however, it did not improve quality of life. No reduction in cardiovascular mortality or increase in severe adverse events was observed [22]. Therefore, further investigation is required to understand the lack of improvement in cardiovascular mortality despite inducing CRR. In the VICTORIA trial, the incidence of CRR did not differ between the groups [23]. However, several reports recently demonstrated CRR by vericiguat [24]. In our case, CRR development was attributed to the additive effect of the sixth drug, the complementary vericiguat.

The PARADIGM-HF trial and its substudy revealed that sacubitril/valsartan significantly reduced cardiovascular mortality and HFrEF hospitalization compared to angiotensin-converting enzyme inhibitors (ACEi). Furthermore, the event rate was significantly lower in the dose-maintenance group than in the dose-reduction group for both agents [25]. A retrospective study of symptomatic ATC-induced CTRCD replaced ACEi/ARB with sacubitril/valsartan and observed greater CRR, improved NYHA class, and decreased NT-proBNP. Additionally, sacubitril/valsartan demonstrated greater CRR in the low- and medium/high-dose groups [26]. Therefore, sacubitril/valsartan is the first-line RASi drug for ATC-induced CTRCD and should be increased to maximally tolerated doses.

The patient’s post-chemotherapy cardiovascular monitoring was inadequate according to the current GDMT [27], including ECG and CXR performance. 2DE monitoring was performed post-acute HF admission. Interestingly, the AVPG increased with increasing CRR. The progression of LV strain on ECG over approximately two years indicated severe AS progression, which may have been caused by aortic valve calcification based on CT and 2DE findings. The increase in AVPG may have been associated with improved LV function because myocardial contractility accelerates the speed of blood flow through the aortic valve orifice. The improvement in LV function and the timely resolution of PH outweighed AS progression. This was a valuable case in which the 2DE findings captured the pathophysiology and drug effects over time.

The long-term prognosis for patients undergoing multidrug therapy remains unknown and requires continued careful follow-up. In conclusion, this report demonstrates the potential of multidrug treatment with vericiguat and ivabradine add-ons based on quadruple therapy for the successful treatment of WHF in high-risk cancer survivors with severe ACT-induced cardiomyopathy.