The biology underlying the problem begins with the receptor itself. HER2 is overexpressed in roughly 25 to 30 percent of breast cancers, and since its amplification was first linked to aggressive disease and poor survival in the 1980s, it has served as the archetype of a druggable oncogenic target. The monoclonal antibody trastuzumab, clinically available since the early 2000s, dramatically improved survival outcomes, an effect consolidated in landmark trials such as HERA, which reported asymptomatic declines in left ventricular ejection fraction in about 7 percent of patients, and BCIRG-006, where the figure climbed to 18.6 percent. A 2019 pooled analysis of the major adjuvant trastuzumab trials, encompassing HERA, NSABP B-31, and N9831, placed the prevalence of trastuzumab-related cardiotoxicity at 11.3 percent asymptomatic and 8.7 percent mildly symptomatic. Broader analyses put the incidence of cardiotoxicity at 14.3 percent with trastuzumab alone, rising to 17.9 percent when the dual antibody blockade of trastuzumab and pertuzumab is added.

The mechanistic explanation for this cardiac vulnerability is now reasonably well understood. Cardiomyocytes depend on HER2 signaling for survival and repair, and blocking the receptor triggers cardiomyocyte death through mitochondrial dysfunction and reactive oxygen species-dependent pathways, while also shifting the balance of anti-apoptotic and pro-apoptotic proteins within heart muscle cells. Trastuzumab additionally works through antibody-dependent cellular cytotoxicity, an immune mechanism that contributes to its anticancer potency but may compound cardiac injury. For patients whose left ventricular ejection fraction remains above 40 percent, the prospective SAFE-HEaRt study demonstrated that trastuzumab can be delivered with acceptable safety. Below that threshold, however, the evidence base thins dramatically, and trastuzumab is considered contraindicated. Guidance on preventing and monitoring cardiac dysfunction in cancer survivors exists, but for patients starting treatment with established cardiomyopathy and an ejection fraction below 40 percent, published guidance is scarce and the literature is sparse.

It was into this evidentiary vacuum that the Bengaluru patient arrived. A frail 65-year-old woman weighing just 38.5 kilograms, she had lived with ischemic cardiomyopathy since 2014 and was managing New York Heart Association class II heart failure with a regimen that included furosemide, aspirin, spironolactone, atorvastatin, carvedilol, digoxin, and nitroglycerin. In July 2023 she noticed a lump in her right breast. Biopsy revealed invasive breast carcinoma of grade 2, estrogen receptor positive in 15 percent of cells, progesterone receptor negative, HER2-positive with 3-plus staining in 95 percent of cells, and a Ki67 proliferation index of 25 percent. Imaging confirmed a heterogeneously enhancing lobulated mass in the lower inner quadrant of the right breast, along with necrotic deep pectoral lymph nodes, establishing early-stage disease that had not invaded skin or muscle. Baseline echocardiography, however, recorded a left ventricular ejection fraction of just 32 percent, placing trastuzumab and pertuzumab, the mainstays of HER2-positive breast cancer therapy, off the table.

The clinical team turned instead to lapatinib, an oral small-molecule tyrosine kinase inhibitor that dually targets HER2 and HER1. The pharmacological argument for this choice is layered. Pooled data from 3,689 patients across clinical trials, along with a meta-analysis of 26 studies, established that lapatinib carries a markedly lower cardiac risk, with reductions in ejection fraction, arrhythmia, and other cardiac adverse events occurring in roughly 3 percent of patients, and individual reports ranging between 1.6 and 4.5 percent. Unlike trastuzumab, lapatinib does not induce antibody-dependent cellular cytotoxicity, and it lacks the apoptosis-inducing property that contributes to cardiomyocyte death. Critically, its pharmacokinetic profile is far more forgiving: while trastuzumab circulates for a half-life of 16 days, pertuzumab for 18 days, and the antibody-drug conjugate T-DM1 for 4 days, lapatinib’s half-life is just 14.2 hours. That short duration means any adverse effect on the heart can be reversed rapidly, and the dose can be titrated or withheld entirely at short notice, an impossibility with long-acting antibodies that linger in the circulation for weeks.

The treatment plan was built around these pharmacological advantages. The patient received 12 weekly doses of nanoparticle albumin-bound paclitaxel together with lapatinib 250 milligrams once daily, with intravenous fluids restricted to avoid volume overload in her failing heart. A dedicated cardio-oncologist monitored her with weekly clinical assessments and monthly echocardiograms. After four weeks, the breast lump had shrunk from 4 by 3 centimeters to 2 by 2 centimeters, axillary nodes had diminished, and her ejection fraction held steady at 32 percent. Encouraged by her tolerance, the team escalated lapatinib to 500 milligrams daily and added weekly carboplatin. By eight weeks the tumor measured under 1 centimeter and cardiac function remained stable at 31 percent. A further escalation to 750 milligrams proved too much, producing increasing diarrhea that forced a return to the 500-milligram dose, a textbook illustration of how the oral agent’s dose flexibility allows real-time optimization in a way infusible antibodies cannot match.

After the full 12 weeks of neoadjuvant therapy, the patient requested a break to pursue local treatments. Positron emission tomography-computed tomography demonstrated a complete metabolic response, confirming that the tumor had been eradicated morphologically and metabolically. Surgery, however, presented an unacceptable risk. Given her ejection fraction of 32 percent with dilated cardiomyopathy, the Seattle Heart Failure Model predicted a five-year mortality of 35 percent, and the patient declined to accept the high probability of peri-operative cardiac complications even after cardiology clearance. The team pivoted to definitive external beam radiation to the right breast, supraclavicular fossa, and axilla, delivering 40 Gy in 15 fractions with a 12.5 Gy boost in 5 fractions to the tumor bed, followed by hormonal therapy with an aromatase inhibitor for five years and continued lapatinib for up to two years. At two years of follow-up, she remains free of disease on clinical examination and imaging, with her cardiac function never having deteriorated during treatment.

The case carries implications beyond a single patient. The authors note that to their knowledge this is the first published description of neoadjuvant lapatinib-based therapy for HER2-positive breast cancer in a patient with pre-existing cardiomyopathy and an ejection fraction below 40 percent, and they frame it as highlighting a genuine gap in the literature. Newer and more potent HER2-targeted kinase inhibitors may extend this strategy: neratinib and tucatinib have both shown cardiac dysfunction rates below 3 percent in pivotal trials, suggesting a growing armamentarium of heart-sparing oral agents for this vulnerable population. The authors also acknowledge the trade-off candidly, noting that lapatinib may be less effective than monoclonal antibodies at engaging immune pathways through antibody-dependent cellular cytotoxicity. In this patient, however, that pharmacological compromise proved more than sufficient, delivering a complete metabolic response without a single beat of additional cardiac damage. For the growing cohort of cancer patients with compromised hearts, the case offers a practical roadmap: choose agents with short half-lives, titrate carefully under dedicated cardio-oncology surveillance, and let pharmacokinetics do the protective work that antibodies cannot.

As targeted cancer therapy continues to expand, the intersection of oncology and cardiology will only grow more crowded. Cardio-oncology, the discipline embodied by the monthly echocardiographic monitoring in this case, is rapidly becoming an essential partner in curative cancer care. The Bengaluru report demonstrates that a contraindication on a drug label need not translate into a forgone chance at cure. By understanding the molecular reasons why HER2 blockade injures the heart, and by selecting inhibitors whose kinetics allow rapid withdrawal, clinicians can walk the tightrope between tumor and myocardium, and occasionally, as in this case, reach the other side with both the cancer and the heart intact.

Subject of Research: Use of the HER2-targeted tyrosine kinase inhibitor lapatinib to treat HER2-positive breast cancer in a patient with pre-existing cardiac dysfunction

Article Title: Targeting HER-2 pathway in presence of cardiac dysfunction: the walk on a tight rope

Article References: Simha, V., Raj, B., Munirathna, V., & Anantharamu, S. (2026). Targeting HER-2 pathway in presence of cardiac dysfunction: the walk on a tight rope. Clinical Cancer Bulletin, 5(1), Article 12. https://doi.org/10.1007/s44272-026-00064-4

Image Credits: AI Generated

DOI: 10.1007/s44272-026-00064-4

Keywords: HER2-positive breast cancer, lapatinib, cardiotoxicity, trastuzumab, cardiac dysfunction, tyrosine kinase inhibitor, neoadjuvant chemotherapy, cardio-oncology, ejection fraction, pertuzumab, drug safety, clinical case report

A portal cavernoma is defined as a network of veins, initially millimetric or even microscopic in size, that progressively dilates and through which hepatoportal blood continues to flow. It represents the body’s workaround for a problem: chronic occlusion of the extrahepatic portal system lasting more than three weeks. When the portal vein—the major vessel that channels nutrient-rich blood from the digestive organs to the liver—becomes irreversibly thrombosed, the surrounding tissue sprouts a tortuous meshwork of collateral channels to bypass the obstruction. First described in 1955 during the autopsy of a patient who died of mesenteric venous thrombosis, the condition has since become recognized as a significant cause of portal hypertension, but it remains sparsely documented in the African literature, particularly in sub-Saharan Africa, where only scattered case reports exist.

The patient’s initial presentation was deceptively ordinary. He had no particular medical history, yet he arrived with hematemesis—vomiting of blood—that had begun two days earlier, followed a day later by moderate diarrhea with blackish stools, a classic sign of digested blood passing through the gastrointestinal tract. There was no indication that he had consumed contaminated food or toxic substances. Clinical examination recorded a blood pressure of 100/60 mmHg, a heart rate elevated to 110 beats per minute, and a respiratory rate of 20 cycles per minute. His body mass index had fallen to 18 kg/m², signaling weight loss. Palpation revealed tenderness in the epigastric region, moderate ascites—fluid accumulating in the abdominal cavity—and an enlarged spleen consistent with Hackett stage II splenomegaly. Cardiac auscultation confirmed regular tachycardia at 110 beats per minute, a physiological compensation for volume loss.

Endoscopy performed shortly after admission revealed more than just the bulbar ulcer. The examination also identified grade IIa esophageal varices—dilated veins in the lining of the esophagus—without red signs, the endoscopic markers that predict imminent rupture. Additionally, the mucosa displayed a mosaic appearance, a hallmark of moderate portal hypertension. This combination should have raised a flag: peptic ulcers do not cause esophageal varices or mosaic mucosa, and both findings point toward elevated pressure in the portal venous system. Nevertheless, given the prominence of the ulcer and the positive H. pylori stool antigen test, the initial diagnosis of a bulbar ulcer was made, and eradication therapy was commenced. It was a reasonable start, but it addressed a contributor rather than the underlying engine of the disease.

The diagnostic turning point arrived two days later with an abdominal ultrasound. The study was consistent with heterogeneous portal vein thrombosis, accompanied by abundant ascites and, notably, a normal-sized, non-dysmorphic liver—an important observation, because cirrhosis is by far the most common cause of portal hypertension, and its absence demanded an alternative explanation. An abdominal computed tomography scan performed with portal vein injection then delivered the decisive findings. Contrast imaging revealed a heterogeneous filling defect in the portal trunk and its branches, with dilation of the vessels upstream of the obstruction, consistent with a thrombotic lesion of the portal trunk. The heterogeneous center of the lesion did not take up contrast, a pattern suggesting a portal cavernoma. The scan also demonstrated thrombosis of the splenic vein, a splenic nodule suggestive of an angioma, and an atrophic pancreas with a 9-millimeter dilation of the Wirsung duct, the main pancreatic duct.

Laboratory workup added nuance rather than contradiction. Transaminases were only slightly elevated, with AST at 44 IU/L and ALT at 48 IU/L, while the blood ionogram, complete blood count, and prothrombin level were all normal. Serology for HIV, hepatitis B, and hepatitis C came back negative, ruling out the viral infections that account for much of chronic liver disease worldwide. The etiological investigation, however, hit a practical wall: thrombophilia testing—including assays for protein C and S, antithrombin III, factor V Leiden, and the JAK2 mutation—could not be performed because these tests were simply unavailable in the clinical setting. This gap matters, because in adults the onset of portal vein thrombosis most often results from a combination of local and systemic prothrombotic factors, and guidelines call for systematic investigation of underlying thrombophilic disease.

With the imaging and clinical picture aligned, the team made their diagnosis: portal cavernoma revealed by gastrointestinal hemorrhage. The mechanism is elegant yet perilous. The portal obstruction creates a network of collateral veins of varying caliber through which hepatoportal blood is rerouted, but these fragile channels—and the varices they feed—operate under elevated pressure. In this patient, the hemorrhage was driven by rupture-prone esophageal varices, which occur in 90 to 95 percent of portal cavernoma cases, making variceal bleeding both the most common mode of presentation and the most feared complication. Other manifestations, including splenomegaly, abdominal pain, ascites, and transit disorders such as the patient’s diarrhea, are frequent but neither constant nor specific. The authors also point to portal hypertensive enteropathy and pancreatic atrophy as contributors to exocrine pancreatic insufficiency, which produces mucosal congestion, malabsorption, and diarrhea—a chain of physiological consequences that links seemingly unrelated symptoms back to the obstructed portal vein.

Treatment proceeded on several fronts simultaneously. The patient received 40 mg of injectable omeprazole every 12 hours to suppress acid and protect the ulcer, 40 mg of propranolol per day—a nonselective beta blocker that lowers portal pressure and provides primary or secondary prevention of variceal hemorrhage—and one sachet of Gaviscon every 8 hours. Endoscopic band ligation was performed to control the bleeding varices directly, and once hemorrhage was arrested, anticoagulation was initiated with 0.8 mL of enoxaparin every 12 hours, later transitioned to 4 mg of acenocoumarol daily with a target International Normalized Ratio of 2 to 3. Anticoagulation in portal cavernoma aims to prevent extension of thrombosis and, in some cases, to allow recanalization, though it must be balanced against the risk of rebleeding from varices.

The clinical evolution was favorable. Abdominal pain, ascites, and gastrointestinal bleeding all regressed, and the patient was discharged home after 10 days, following two stable INR readings of 2.3 and 2.5. Remarkably, no blood transfusion was required, as he remained hemodynamically stable with a hemoglobin level of 11 g/dL. He left the hospital on 40 mg of oral omeprazole twice daily and 4 mg of acenocoumarol, with anticoagulation planned for six months. At a three-month follow-up visit, he showed complete resolution of symptoms with a stable INR. Unfortunately, at the six-month mark the patient was lost to follow-up, and the team was unable to obtain follow-up imaging to assess whether the cavernoma had evolved, a sobering reminder of the practical challenges of longitudinal care in resource-limited settings.

The epidemiological context underscores just how unusual this case is. In the United States, the incidence of portal cavernoma is estimated at about 1 percent of the general population, based on large autopsy studies that documented portal vein thrombosis prevalence and lifetime risk across more than 23,000 consecutive examinations. In Africa, the true incidence is unknown but is thought to be below 1 percent according to the available literature. A Tunisian study in 2001 described just 19 observations over 25 years, while a Moroccan series reported 11 cases between 2003 and 2012. Most series show a male predominance, and the condition is overwhelmingly described in pediatric populations, where omphalitis—infection of the umbilical stump—remains a common cause of portal thrombosis in developing countries. In children, portal vein obstruction is also associated with growth retardation, attributed to reduced hepatoportal flow and resistance to growth hormone. Adult presentations in middle age, such as this one, are exceptionally rare in the published record.

The therapeutic hierarchy for portal cavernoma extends well beyond the medical management available to this patient. Beta blockers remain the cornerstone of hemorrhage prevention, but when endoscopic and pharmacological measures fail, ligation or sclerotherapy of varices is indicated, and in cases complicated by biliary symptoms—cavernomas can compress the bile ducts, producing a condition known as portal biliopathy—a porto-systemic shunt, with or without a porto-biliary shunt, may be required. Such surgical options demand infrastructure and expertise that are often unavailable in the settings where the disease is most likely to go undiagnosed. For the authors of this report, the case is a call to vigilance: when a patient presents with gastrointestinal hemorrhage and the endoscopy shows findings that exceed the usual scope of peptic ulcer disease, clinicians must look deeper into the portal vasculature. The ulcer, in this story, was real—but it was the supporting actor, not the star.

Intussusception, a phenomenon classically associated with the gastrointestinal tract, involves the telescoping of one segment of a hollow organ into an adjacent part, commonly invoking acute obstruction and ischemia. Its occurrence within a coronary artery vessel had been hitherto undocumented in human clinical cases, making this report a pioneering revelation. The coronary arteries, responsible for perfusing the myocardium, are critical conduits whose structural integrity is paramount for sustaining life. The unusual inward folding or invagination of a coronary artery segment in this instance led to catastrophic hemodynamic occlusion.

The clinical manifestation culminating in this fatal event was sudden cardiac death (SCD)—a tragic endpoint defined by an abrupt loss of cardiac function leading to death, often within minutes of symptom onset. SCD accounts for a significant proportion of mortality worldwide, predominantly linked to arrhythmias, myocardial infarction, or structural heart defects. However, the underlying causes can be cryptic in numerous cases, emphasizing the value of detailed post-mortem investigations such as this one.

The forensic autopsy unveiled intussusception as the causal lesion by demonstrating the unique morphological alterations within a coronary artery. The segment of the intussuscepted vessel created a mechanical obstruction akin to a physiological trap, severely restricting blood flow to critical myocardial territories. Microscopic examination reinforced the diagnosis by revealing disruption of the intimal layers and vascular wall architecture, hinting at the complex pathophysiological cascade that ensued prior to death.

What renders this case especially compelling is the rarity and diagnostic elusiveness of coronary artery intussusception. Unlike more familiar coronary pathologies such as atherosclerotic plaque rupture or embolism, intussusception lacks hallmark clinical signs and is invisible to conventional imaging techniques employed ante-mortem. The absence of warning symptoms, coupled with sudden occlusion, underscores this entity as a stealthy perpetrator in sudden cardiac fatalities.

The etiology behind the spontaneous intussusception remains speculative but intriguing hypotheses propose localized vessel wall weakness or aberrant contractile forces as contributing factors. Autoimmune or inflammatory processes could render the vascular layers susceptible to delamination, paving the way for telescoping under normal hemodynamic stress. Alternatively, congenital structural variants might predispose individuals to such vascular vulnerabilities.

Understanding these mechanisms not only expands the scientific comprehension of coronary artery diseases but also beckons a paradigm shift in how unexplained sudden cardiac deaths are approached. It challenges forensic pathologists and clinicians to consider uncommon vascular anomalies during autopsy and clinical evaluation, potentially refining protocols and preventative strategies.

The implications span beyond academic fascination; recognizing coronary intussusception can influence medico-legal outcomes and guide family counseling concerning inheritable risks. Genetic investigations alongside detailed histopathological scrutiny could pave the way for identifying at-risk individuals through innovative biomarkers or imaging modalities yet to be developed.

This case report also prompts a reexamination of current cardiovascular imaging technologies. Conventional angiography or computed tomography may not capture subtle intramural vascular distortions characteristic of intussusception. Future advancements like high-resolution intravascular ultrasound or optical coherence tomography might prove indispensable in detecting such elusive vascular phenomena.

Critically, this discovery sparks curiosity regarding potential therapeutic interventions. If identified preemptively, surgical correction or endovascular approaches might prevent catastrophic myocardial ischemia. However, the rarity and unpredictable nature of intussusception pose formidable challenges to the formulation of clinical guidelines.

From an investigative standpoint, the interdisciplinary collaboration between forensic medicine and cardiology was pivotal in unraveling this case. Such synergy exemplifies the importance of diverse expertise converging to decode perplexing medical mysteries, enhancing the collective arsenal against sudden cardiac deaths.

The broader medical community stands to gain immensely from heightened awareness of coronary artery intussusception. Educating clinicians, pathologists, and radiologists about this rare entity could incite more meticulous evaluations and reporting of similar cases globally. A growing database can yield epidemiological insights and inform future research trajectories.

Ultimately, this seminal case report is a clarion call to deepen investigative resolve in cases of sudden cardiac death where common etiologies fall short. It epitomizes the ceaseless quest for knowledge in medicine—unveiling hidden pathologies that lurk beneath the surface, forever reshaping our understanding of human health and disease.

Subject of Research: Sudden cardiac death caused by coronary artery intussusception

Article Title: Sudden cardiac death due to intussusception of a coronary artery: a case report

Article References:
Attico, F., Di Paola, F., De Nadai, M. et al. Sudden cardiac death due to intussusception of a coronary artery: a case report. Int J Legal Med (2025). https://doi.org/10.1007/s00414-025-03632-w

Image Credits: AI Generated