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- J Cardiol Cases
- v.28(3); 2023 Sep
- PMC10477047
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J Cardiol Cases. 2023 Sep; 28(3): 105–108.
Published online 2023 Jun 13. doi:10.1016/j.jccase.2023.04.011
PMCID: PMC10477047
PMID: 37671260
Dane M. Rucker, MD,a,⁎ Omar K. Siddiqi, MD,b David R. Pimentel, MD,b and Ivan Luptak, MD, PhDb
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Abstract
Cardiac amyloidosis is a restrictive cardiomyopathy for which diuretics are frequently used, but vasodilators have classically been relatively contraindicated due to side effects of hypotension. In the setting of decompensated heart failure, this may not be the case. We report a man with advanced cardiac amyloidosis who presented to the hospital with decompensated heart failure, in part, due to elevated systemic vascular resistance. Through the use of invasive hemodynamic testing, we were able to demonstrate an increase in cardiac output in response to a nitroprusside challenge. In turn, the patient had an improvement in his symptoms and was sent home on afterload reducing medications. This discerns a subpopulation of cardiac amyloidosis patients in decompensated heart failure who benefit from medications that reduce systemic vascular resistance, and can benefit from hemodynamic testing, especially when diuretics fail to control symptoms.
Learning objective
Medications that cause peripheral vasodilation are standard therapy for patients with reduced ejection fraction, however, they are seldom used for patients with cardiac amyloidosis due to adverse effects. In some cases, there may be value in using hemodynamic measurements in patients with advanced cardiac amyloidosis to guide management as some patients may have hemodynamics that resemble those of systolic heart failure. This may offer a novel approach to symptomatic treatment of advanced cardiac amyloidosis.
Keywords: Cardiomyopathy, Restrictive, Hemodynamics, Heart failure with preserved ejection fraction, Amyloidosis
Introduction
Cardiac amyloidosis is a restrictive cardiomyopathy marked by extracellular accumulation of misfolded proteins. In most cases of cardiac amyloidosis, these amyloid fibrils originate from monoclonal light chains (AL amyloidosis), or transthyretin (TTR, formerly known as prealbumin) from the liver. Rarely, transthyretin (ATTR) amyloidosis is caused by a mutation in the TTR gene, resulting in hereditary or variant transthyretin (ATTRv) amyloidosis. More commonly, ATTR amyloidosis is caused by the age-related accumulation of amyloidogenic fibrils from genetically normal (wild-type) transthyretin (ATTRwt). Interstitial deposition of amyloid fibrils results in increased biventricular wall thickness and ventricular stiffness. These phenotypic changes are the hallmark of restrictive cardiomyopathy, and thus, the hemodynamics of patients with cardiac amyloidosis often resemble those of patients with other causes of restrictive cardiomyopathy. This hemodynamic profile is characterized by markedly elevated filling pressures and a profound inability to augment cardiac output with exercise resulting in significant exertional intolerance [1].
Patients with cardiac amyloidosis often present with decompensated heart failure. While diuretics address symptoms, tetramer stabilizers such as tafamidis and diflunisal have been used to slow down disease progression [2]. In the setting of reduced ejection fraction, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists have also been successfully used, however, there is often intolerance of these therapies due to hypotension resulting from frequent comorbid neuropathy [3]. Thus, vasodilators are considered to be relatively contraindicated for amyloid, however, other diseases with abnormal ventriculo-arterial coupling such as aortic stenosis and
hypertrophic cardiomyopathy have been shown to benefit from vasodilatory therapy in selective sub groups [4]. These findings were confirmed by using invasive hemodynamic measurements with the administration of a pure afterload agent nitroprusside [5].
It is unknown if there are sub-categories of patients with cardiac amyloid disease that can benefit from vasodilation. We present a case of a patient with ATTRwt cardiac amyloidosis who presented with severe dyspnea and hypertension. Acute vasodilation with nitroprusside markedly improved his cardiac output suggesting that patients may benefit from long-term vasodilation.
Case report
A 76-year-old Caucasian male with ATTRwt amyloidosis and history of hypertension, New York Heart Association class III heart failure, chronic kidney disease stage III, 1st-degree atrioventricular (AV) block, and carpal tunnel presented with progressive dyspnea. Three years before admission, he presented to his primary care physician with the complaint of dyspnea on exertion. At that time, his electrocardiogram (ECG) showed normal sinus rhythm (NSR) with low voltage and 1st-degree AV block. B-type natriuretic peptide (BNP) was 304 pg/mL. He was referred to the cardiology department and had a negative stress test, but with exercise intolerance on a beta-blocker. He had previously tried an ACEi, which he could not tolerate due to hypotension. A transthoracic echocardiogram showed grade II diastolic dysfunction with left ventricular ejection fraction of 50 %, along with severely increased wall thickness. Cardiac magnetic resonance imaging showed severe concentric left ventricular hypertrophy raising the suspicion for amyloidosis. Serum and urine protein electrophoresis, and serum free light chains were all normal. Technetium pyrophosphate scan was done, which was consistent with ATTR cardiac amyloidosis, with a Perugini score of 3. He denied genetic testing and endomyocardial biopsy. He was started on furosemide 40 mg daily and diflunisal 250 mg BID.
After 3 years, he developed subacute worsening of his exertional dyspnea refractory to increase of his home diuretic to bumetanide 1 mg BID, and was admitted to the hospital with decompensated heart failure. He denied orthostasis or peripheral neuropathy. His admission vital signs were significant for a blood pressure of 139/100 mmHg. His weight was 68.0 kg, which was 5.8 kg higher than his previous discharge weight. Physical examination revealed jugular venous pressure to the angle of the mandible, decreased breath sounds in the bases, and no lower extremity edema.
Laboratory results showed a creatinine of 1.84 mg/dL (baseline 1.7 mg/dL), BNP of 1534 pg/mL, and troponin of 0.220 ng/mL. Notably, he had a persistent troponin elevation to this level. Chest X-ray showed cardiomegaly, cephalization, and interstitial edema. ECG was NSR with low voltage and new t-wave flattening in V5/V6 (Fig. 1). Echocardiogram showed sinus tachycardia with severely increased wall thickness of the left ventricular cavity, an ejection fraction of 50 %, global hypokinesis, grade III diastolic dysfunction, reduced right ventricular systolic function, and a severely dilated left atrium (Table 2). Additionally, a dilated inferior vena cava with blunted respirophasic variation was noted.
Fig. 1
Parameters measured before, during, and after hospitalization
A) Vitals and medications before, during, and after hospitalization; B) EKG on admission;
C) Posteroanterior view chest x-ray on admission; D) Lateral view chest x-ray on admission
qD, daily; TID, three times daily; PO, by mouth; IV, intravenously
*He was switched to Bumetanide 1 mg BID, 2 days prior to admission.
Table 2
Transthoracic Echocardiogram measurements prior to admission and immediately prior to discharge.
| Transthoracic echocardiogram measurements | 2 years prior to admission | 9 months prior to admission | Prior to discharge, on Hydralazine |
|---|---|---|---|
| LA (mm) | 36 | 37 | 34 |
| IVSd (mm) | 16 | 18 | 18 |
| LVIDd (mm) | 37 | 35 | 39 |
| LVPWd (mm) | 16 | 18 | 18 |
| LVIDs (mm) | 31 | 26 | 32 |
| Fractional shortening | Not obtained | 26 % | 18 % |
| Global longitudinal strain | (−8 %) | Not obtained | Not obtained |
| Aortic ascending (mm) | 30 | 26 | 29 |
| LV mass index (gm/m2) | 132.44 | 143.56 | 174.71 |
| Regurgitation | None | 1+ TV | 1+ AV, 1+ MV, 1+ TV |
| Stenosis | None | None | None |
| Wall motion | Normal | Normal | Normal |
| Ejection fraction | 45–50 % | 50–55 % | 45–50 % |
| Valves | Normal | Normal | Normal |
| Diastolic dysfunction | Grade II | Grade III | Grade III |
| Pericardial effusion | None | Trace | Trace |
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LA, left atrium; IVSd, interventricular septum diameter; LVIDd, left ventricular internal diameter end diastole; LVPWd, left ventricular posterior wall diameter; LVIDs, left ventricular internal diameter end systole.
Treatment
The patient was initially diuresed with furosemide IV 40 mg. This resulted in a net output of 960 mL, but increased his creatinine to 2.15 mg/dL. Due to a difficult volume examination, right heart catheterization (RHC) was scheduled. The results showed a high-normal right heart pressure (10 mmHg), an elevated pulmonary capillary wedge pressure (19 mmHg), low cardiac index (1.5 mL/min/m2), and elevated systemic vascular resistance (SVR) (2900 dyn·s/cm5) (Table 1).
Table 1
Catheterization measurements before and after administration of nitroprusside.
| Air rest | Post-nitroprusside (3 μg/kg/min) | |
|---|---|---|
| RAP (mmHg) | 9 | 5 |
| mPAP (mmHg) | 37 | 26 |
| PCWP (mmHg) | 26 | 17 |
| MAP (mmHg) | 103 | 71 |
| SV (mL) | 35.3 | 41.8 |
| SVI (mL/m2/beat) | 19.40 | 22.97 |
| CI ((mL/min)/m2) | 1.84 | 2.3 |
| SVR (dyn·s/cm5) | 2245 | 1263 |
| PVR (dyn·s/cm5) | 263 | 172 |
| RVSWI (g·m/m2) | 10.34 | 8.60 |
| LVSWI (g·m/m2) | 20.30 | 16.86 |
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RAP, right atrial pressure; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; MAP, mean arterial pressure; SV, stroke volume; SVI, stroke volume index; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; RVSWI, right ventricular stroke work index; LVSWI, left ventricular stroke work index.
With knowledge of the patient's high SVR, we decided to reduce afterload with hydralazine 25 mg TID, a pure afterload reduction agent, and isosorbide dinitrate 25 mg TID. Despite the elevated pulmonary capillary wedge pressure, his creatinine increased with diuresis, so we also started low-dose IV dopamine at 2.5 μg/kg/min to increase cardiac output and renal blood flow. RHC with nitroprusside challenge was then planned to have an objective assessment of the patient's hemodynamic response to pure afterload reduction.
Initial RHC showed a normal right atrial pressure (9 mmHg), an elevated pulmonary capillary wedge pressure (26 mmHg), low cardiac index (1.84 mL/min/m2), elevated SVR (2245 dyn·s/cm5), and elevated aortic pressure (103 mmHg). After nitroprusside administration, RHC showed decreased right atrial pressure (5 mmHg), a decreased pulmonary capillary wedge pressure (17 mmHg), increased cardiac index (2.3 mL/min/m2), decreased SVR (1263 dyn·s/cm5), and decreased aortic pressure (71 mmHg) (Table 1).
With these findings, we planned to increase his vasodilators to the maximum tolerated dose. The patient was discharged the next day on hydralazine 100 mg TID, isosorbide mononitrate 60 mg daily, and torsemide 10 mg daily with close follow up.
Discussion
Cardiac amyloidosis is a restrictive cardiomyopathy that is highly preload dependent and generally requires avoidance of vasodilator therapy. In our patient, we performed invasive hemodynamics with a nitroprusside challenge and found that his cardiac output was limited by high SVR and improved with nitroprusside, a pure afterload reducing agent. Therefore, hydralazine, which is also a pure afterload reducing agent, was chosen for long-term therapy. This case presentation demonstrates that in patients with cardiac amyloidosis, 1) peripheral vasoconstriction may lead to reductions in cardiac output that can be improved with vasodilation, and 2) acute vasodilator therapy may discern sub-populations of cardiac amyloidosis patients who may benefit from long-term vasodilator therapy.
Patients with reduced systolic function have demonstrated benefit from afterload reduction. In fact, a nitroprusside challenge has been used in systolic heart failure to evaluate responsivity of pulmonary hypertension in left heart disease, and this responsiveness may suggest improved mortality [4]. This is in contradistinction to patients with heart failure with preserved ejection fraction (HFpEF) in whom vasodilator therapy seems to minimally change cardiac output [6]. Cardiac amyloidosis is felt to be an extreme case of HFpEF best treated with diuretics. However, in cardiac amyloidosis, there is abnormal ventriculo-arterial coupling. This is manifested in both a reduction in stroke volume and arterial compliance, with an increase in total peripheral resistance [7]. It has not been demonstrated, however, whether a vasodilator improves these findings and symptoms. To our knowledge, this is the first report of the use of an intravenous vasodilator in a patient with cardiac amyloidosis. After administration of nitroprusside, our patient markedly improved his cardiac index with less dyspnea. If decreased stroke volume was purely due to impaired filling, he would have likely developed severe hypotension to nitroprusside with no increase in cardiac output. Thus, our findings suggest that despite preserved ejection fraction, myocardial contractility was depressed in our patient.
Such finding of vascular dependency is not particularly surprising when other disease states with “fixed” low output or restrictive physiology and lower contractility are examined. For example, in aortic stenosis with left ventricular dysfunction, there is improvement after vasodilator therapy. In addition, in certain subsets of hypertrophic cardiomyopathy with hypertension, vasodilator therapy may be beneficial in allaying symptoms and its diagnosis would be made with a vasodilator challenge [5]. This case raises the issue of whether a prospective study of invasive hemodynamics with maneuvers would help define the physiology of cardiac amyloidosis and its responsiveness to systemic vasodilation and afterload reduction.
The dogma regarding cardiac amyloidosis is that vasodilator therapy should be avoided if feasible. However, previous studies question whether this is universally true [8]. Albeit small, these studies have shown that ACEi/ARBs have been tolerable in patients with cardiac amyloidosis and reduced systolic function [9]. In our patient, we started a dose of afterload reduction that he tolerated well. In fact, he required lower doses of diuretic after the medication change. Whether a vasodilator challenge can be used to help stratify amyloidosis patients who can benefit symptomatically is another hypothesis generating question that this case raises.
Consent
Consent was obtained directly from the patient prior to submission.
Declaration of competing interest
The authors declare no conflict of interest.
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