Introduction
Hypertrophic cardiomyopathy is commonly attributed to genetic mutations affecting sarcomeric proteins, but it can also be linked to secondary causes such as infiltrative diseases, including amyloidosis.
Amyloid light-chain (AL) amyloidosis is a multiorgan disease. It most commonly affects the kidney with clinical cardiac involvement as the second most frequent manifestation. Although, isolated cardiac amyloidosis can serve as a primary manifestation of underlying hematologic disorders, such as multiple myeloma through the deposition of immunoglobulin high chains in cardiac tissue. The prevalence of this condition is rare, and is likely that it has been underdiagnosed due the rapid progression to death in undiagnosed patients [ 1 ].
Multiple myeloma is a hematologic malignancy characterized by clonal proliferation of plasma cells, starting with a precursor state of monoclonal gammopathy of undetermined significance and progressing to Smoldering MM (SMM), which eventually becomes symptomatic (symptomatic MM).
Here, we discuss a rare case of a patient presenting wit decompensated heart failure associated with hypertrophic cardiomyopathy, secondary to isolated cardiac amyloidosis, which ultimately unveiled a previously undiagnosed multiple myeloma without any other clinical features of multiple myeloma. This case highlights the critical role of thorough diagnostic evaluation in patients with hypertrophic cardiomyopathy as early recognition of multiple myeloma to improve overall prognosis.
Case report
A 65-year-old man with hypertension and diabetes mellitus as cardiovascular risk factors and a 4-month history of diabetic nephropathy, with no particular family history of sudden death was admitted to the hospital complaining of progressive dyspnea with minimal exertion, fatigue, bilateral lower extremities edema over the preceding several days.
On general examination, the patient was afebrile and with a blood pressure of 112/56 mmHg, a regular heart rate of 64 beats per minute, a respiratory rate of 18 breaths per minute with an Oxygen saturation on room air around 94%. Cardiovascular exam revealed signs of right-sided heart failure, including jugular vein distension with hepatojugular reflux, bilateral lower extremity pitting edema extending to the knees, hydrocele and abdominal distension. On lung auscultation, diminished breath sounds were noted ( Fig. 1 ).
His electrocardiogram revealed first degree atrioventricular block, a QS pattern in V1 to V4 and low voltage in precordial leads.
A 48-h ECG showed a first degree atrioventricular block ( Fig. 2 ). No rhythm pauses longer than 2 seconds, No episodes of ventricular tachycardia or nonsustained ventricular tachycardia.
A transthoracic 2D echocardiogram was performed in our center, showing granular sparkling of the myocardium, bi-ventricular hypertrophy without gradient with an interventricular septal thickness of 2.7 cm, a left ventricular posterior wall thickness of 2.5 cm, a right ventricular wall thickness of 1.2 cm ( Fig. 3 ), left ventricular systolic function was altered with a left ventricular ejection fraction (LVEF) of 45% with global longitudinal strain impairment at −4.2% ( Fig. 4 ). There was severe diastolic dysfunction with an E wave velocity of 66 cm/s, E’ wave velocity of 2 cm/s, A wave velocity of 46 cm/s, E/A ratio of 1.43, E/E’ ratio of 33, and a deceleration time of 176 ms, a thickening of interatrial septum measuring 0.7cm, a left atrial enlargement. The echocardiogram also revealed an alteration of right ventricular systolic function with a tricuspid annular plane systolic excursion (TAPSE) of 9 mm. There was a small pericardial effusion.
Considering this picture -a non obstructive type III hypertrophic cardiomyopathy with a granular sparkling of the septum wall and the small pericardial effusion-, provisional diagnosis of cardiac amyloidosis was considered.
Chest X-ray showed a cardiomegaly, a blunting of the costophrenic angles with bilateral alveolointerstitial syndrome ( Fig. 5 ).
Laboratory assays revealed a normal complete blood count, electrolytes and liver function tests, an increased levels of circulating N-terminal probrain natriuretic peptide (70,000 pg/ml) and ultra-sensitive troponin (856,7 ng/mL).
The patient had severe renal failure with creatinine clearance at 21.17 mL/mn/1.73 m², and a positive proteinuria (4527.38 mg/24 h). A renal biopsy was performed, showing diffuse and nodular glomerulosclerosis with 10% diffuse interstitial fibrosis, 10% tubular atrophy, and atherosclerotic lesions, suggestive of diabetic nephropathy.
An alpha-galactosidase assay was performed to exclude Fabry disease as a cause of hypertrophic cardiomyopathy, which was negative.
Protein electrophoresis showed hypo albuminemia with hyper alpha 1 globulinemia ( Fig. 6 ). These results were followed by immunofixation electrophoresis for serum and urine proteins, which revealed a low-intensity monoclonal band of the lambda light chain associated with free lambda light chains.
Based on the results obtained, cardiac amyloidosis was suspected and salivary gland biopsy was done, showing amyloid depositions with a positive congo red staining. The bone marrow biopsy and aspiration revealed 13% of clonal plasma cells, the Bence-Jones protein in the urine was also positive. A diagnosis of light chain multiple myeloma with cardiac AL amyloidosis was made.
Cardiac MRI was not performed because it was unlikely to provide any additional information.
The patient was initially treated with intravenous furosemide and sodium-glucose cotransporter 2 inhibitors with marked improvement in symptoms (regression of congestive signs) and in renal function with a discharge of clearance of 37.3 mL/mn/1.73 m².
The patient was referred to the internal medicine department for additional management and passed away a few weeks later before starting chemotherapy.
Discussion
Amyloidosis is a rare systemic disorder characterized by extracellular deposition of insoluble fibrils composed of misfolded proteins in various organs including the kidneys, liver, and heart [ 2 ]. It can be classified into 4 subtypes based on the nature of the precursor protein that composes the fibrils: (1) AL or primary amyloidosis caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells, (2) transthyretin amyloidosis (ATTR) or familial amyloidosis, a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein, (3) systemic senile amyloidosis, (4) serum amyloid A (AA) or secondary amyloidosis [ 3 ]. AL amyloidosis is the most common type with an approximate prevalence of 0.3 cases per 100,000 [ 4 ].
In AL amyloidosis, renal, neural, and/or dermatologic involvement often coexists with heart involvement. Although, in only 5% of cases, a rare manifestation of the disease, such as isolated cardiac amyloidosis, is observed [ 5 ], as in the case of our patient.
The association between cardiac amyloidosis and multiple myeloma arises from the excessive production of monoclonal immunoglobulin light chains in myeloma, which deposit as amyloid fibrils within myocardial tissue, leading to hypertrophic cardiomyopathy. However, only 10% of the patients with multiple myeloma develop AL amyloidosis, their prognosis is very poor, mainly in the presence of cardiac involvement [ 6 ].
It is unusual that multiple myeloma appears initially as decompensated heart failure. Its most frequent clinical manifestations are bone pain due to osteolysis, hypercalcemia, anemia, and renal insufficiency [ 7 ]. Our patient had none of these classical symptoms. This highlights the importance that a step-by-step diagnostic flow chart and a multidisciplinary clinical evaluation are crucial to obtain the right diagnosis.
The spectrum of presentation can varies from asymptomatic ventricular dysfunction to congestive heart failure, with either preserved or reduced ejection fraction [ 8 ].
The electrocardiogram feature suggestive of cardiac amyloidosis is QS pattern in precordial leads, low voltage and arrythmias. However, it should not be considered as a sensitive marker of the disease [ 9 ]. Echocardiographic imaging typically shows left ventricular thickening with granular sparkling appearance, often associated with right ventricular thickening, and rarely with thickened interatrial, along with diastolic dysfunction and in some cases, pericardial effusion. Left ventricular ejection fraction is preserved for a long time, leading to heart failure with initially preserved then reduced ejection fraction. The apical longitudinal strain is near-normal, with marked impairment at the base. To be noted, the strain has a major pronostic value.
Cardiac magnetic resonance finding has proven its usefulness in determining the diagnosis and prognosis in several forms of cardiac amyloidosis. It usually demonstrates global and subendocardial late gadolinium enhancement of the myocardium [ 10 ]. The absence of this late gadolinium enhancement does not rule out the diagnostic and is not 100% specific, but has a prognosis significance [ 11 ].
As for the laboratory testing, NT-proBNP is disproportionally elevated due to direct damage to myocytes caused by amyloid deposition, in addition to high ventricular filling pressure. The troponin is frequently elevated at a low level and may lead to a misdiagnosis of myocardial infarction.
Protein electrophoresis and immunofixation of urine and serum, along with free light chain assays, remain the gold standard for detecting gammapathies and usually demonstrate a monoclonal band. A bone marrow biopsy is systematically performed in all patients with AL amyloidosis to determine the percentage of plasma cells and to eliminate concomitant multiple myeloma or other hematologic disorders that may cause amyloid deposition such as Waldenström macroglobulinemya and lymphomas. However, the definitive diagnostic modality for cardiac amyloidosis remains an endomyocardial biopsy, and should be considered in ambiguous cases.
In our case, there was no need for magnetic resonance imaging or endomyocardial biopsy to prove the diagnosis, because using clinical, laboratory testing, ECG and echocardiographic findings allowed us to prove the diagnosis.
The treatment of AL cardiac amyloidosis associated with multiple myeloma is based on a multidisciplinary approach by oncologist/hematologist and cardiologist/cardio-oncologist, relies on the optimization of heart failure treatment and the reduction of amyloid-producing light chains, with 1 target ; improving overall survival and patients’ quality of life. Although, there were very few available treatment options for cardiac amyloidosis. Among them, chemotherapy, Autologous Stem Cell Transplantation that is only applicable to 20% of newly diagnosed AL patients [ 12 ] because of the high treatment related mortality in patients with severe cardiac involvement, such as our patient.
The heart transplantation should be considered in carefully selected patients with cardiac amyloidosis and minimal extracardiac involvement. A study performed either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center showed that cardiac transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure [ 13 ]. Unfortunately, our patient passed away a few weeks after the diagnosis was made, before starting the treatment.
As for the prognosis of AL cardiac amyloidosis, the median survival rate in patients with cardiac AL amyloidosis and heart failure does not exceed 67 months [ 14 ]. The biomarkers such as troponin, NTproBNP and free light chains have been proposed as outcome predictors in light-chain amyloidosis. The Mayo Clinic developed a staging system incorporating all 3 of these biomarkers [ 15 ].
In summary, this case drew attention to the significance of isolated cardiac amyloidosis as first presentation of multiple myeloma, and the importance of both multi-disciplinary cooperation and early diagnosis through a structured evaluation, allowing for timely treatment, which improve patient’s survival and quality of life since patients with advanced heart disease are unsuitable candidates for modern, effective hematological treatment including autologous stem cell transplantation.
Patient consent
Written informed consent for the publication of this case report was obtained from the patient.
Footnotes
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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