Case of Refractory Hypertension Controlled After Aortic and Mitral Valve Replacement and Coronary Artery Bypass Grafting
A 78-year-old black man presented to the Hypertension Clinic at the University of Alabama at Birmingham for uncontrolled blood pressure (BP). His BP remained uncontrolled (automated office, ≥135/85 mm Hg) from August 2011 to August 2016 in spite of use of 6 antihypertensive agents in adequate doses (Figure 1). During this time period, his average systolic BP was 167.1 mm Hg and average diastolic BP was 68.7 mm Hg.
The patient was on 3 antihypertensive medications on initial presentation to University of Alabama at Birmingham in 2011, including an angiotensin receptor blocker (irbesartan), a calcium channel blocker (amlodipine), and a long-acting thiazide-like diuretic (chlorthalidone). Spironolactone was added as a fourth antihypertensive agent. Eventually, hydralazine—a vasodilator—and clonidine—a centrally acting sympatholytic—were added as the fifth and sixth antihypertensive agents. The patient’s BP remained uncontrolled on 6 different classes of antihypertensive medications (Figure 1).
Comorbidities and secondary causes of hypertension were evaluated by biochemical analysis and imaging.
The patient was diagnosed with mild chronic kidney disease. Mean serum creatinine was 1.35 mg/dL with an estimated glomerular filtration rate of 58 mL/min per 1.73 m2. Diabetes mellitus was excluded (HbA1c was 5.5%), primary aldosteronism was excluded as the plasma aldosterone–renin ratio was <30 (plasma aldosterone was <4 ng/dL, and plasma renin activity was 1.0 ng/mL per hour), and pheochromocytoma was excluded as plasma metanephrine (0.4 nMol/L) and normetanephrine (<0.2 nMol/L) were not elevated.
Renal Ultrasound With Doppler
Renal duplex imaging showed no evidence of renal artery stenosis.
This patient had normal left ventricular systolic function (left ventricular ejection fraction [EF], ≥50%–55%), elevated stroke volume (SV; 93 mL), and severe left ventricular dilation. Valvular lesions identified by transthoracic echocardiograph (TTE) were
Moderate-to-severe mitral valve regurgitation: the mitral valve was myxomatous and thickened; the annulus was dilated (5 cm in diameter), and the jet was eccentrically and posteriorly directed, which caused systolic retrograde flow in the right pulmonary vein. The E/A ratio (ratio of early-to-late ventricular filling velocities to evaluate diastolic performance of the heart) was 1.5.
Moderate-to-severe aortic valve insufficiency: the aortic valve was thickened, and the jet was eccentrically directed toward the anterior mitral valve leaflet.
Mild tricuspid regurgitation and trace pulmonary valve regurgitation.
Left and Right Heart Catheterization
The left main artery had a 60% distal calcified stenosis; the left anterior descending artery had an 80% proximal calcified stenosis with diffuse 60% distal stenosis, and the left circumflex artery had a proximal 40% calcified stenosis. The right coronary artery had a severe diffuse 80% stenosis, and the posterior descending artery had a 60% stenosis. Filling pressures were high: the right atrial pressure was 12 mm Hg; pulmonary artery pressure was 42/21 mm Hg and the pulmonary capillary wedge pressure was 24 mm Hg.
Discussion: Managing the Hypertension
Dr Carey: This is a very interesting case. I would like to go back to the average systolic and diastolic BPs in the office. It appears this was predominantly systolic hypertension, and there was a relatively low diastolic pressure. I would like us all to reflect that a patient with major coronary atherosclerotic disease may be at risk for a myocardial infarction when the diastolic pressure drops below filling pressure. So, one has to be very careful until definitive therapy is achieved.
Dr Phillips: Even though the guidelines give the opportunity to use β-blockers, I would not use β-blockers for this patient. I would not give him all that time for filling. You are giving him time to raise his left ventricular and diastolic pressure with all that aortic insufficiency and he is already demonstrating that he is not able to tolerate that, with regard to diastolic function. As a cardiologist in a surgical hospital, Houston Methodist—the home of still the ghost of Michael DeBakey—I would have probably had him in the operating room a couple days ago.
Professor Bursztyn: I would like to raise an issue with the need for some of the secondary hypertension workup. If someone takes an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, as this patient did, and has severe hypertension, the likelihood that the finding of renal artery stenosis will lead to any helpful therapeutic action is null, given that this is the best prediction of successful renal revascularization. Pheochromocytoma is extremely rare, in general, and in particular, at the age of 78 years, in someone whose hypertension is somewhat justified, and, I think, this is not helpful. Secondary hyperaldosteronism is certainly something that is important in this patient. I would like also to have a word, in terms of what are the benefits of adding hydralazine to a high dose of amlodipine. Some 30 years ago, when nifedipine was an emerging product, my colleagues and myself found, as many others did, that 30 mg of nifedipine surpasses the antihypertensive efficacy of 200 mg of hydralazine. Therefore, I think, in this context, minoxidil might have been a better choice, given that he is taking a β-blocker. In addition, he is taking the diuretic; therefore, some of the expected side effects of minoxidil can be counteracted.
Dr Calhoun: That is the reason for presenting the case at this point. Obviously, we were not controlling his BP, in spite of the 6 medications; so we are looking for feedback in terms of what we might have done differently. Anecdotally, we do see additional benefit adding hydralazine to a dihydropyridine calcium channel blocker, in terms of BP control, so that is routinely done in our clinic.
But before we get to the resolution, I think Professor Sica will advise as to what we should have been doing.
Professor Sica: Echoing the comments, I think one has to be quite careful with filling pressures here. Therefore, comment number 1 would be, “How do you diurese a patient in this current situation, and do you change filling pressures too much with overdiuresis and, therefore, worsen the situation?” I am sure that went through your mind.
Item 2 would have been a trial of isosorbide mononitrate or dinitrate while the patient is in clinic, to see what the hemodynamic changes were with the nitrate therapy. Nitrate therapy may be unusable, it looks like there were fixed coronary lesions here, calcific in nature. Therefore, you may not have had a great response, but nitrate is one of our hidden sources of therapies in resistant hypertension.
Third issue would be whether or not the person had any vestige or hint of sleep apnea. Sleep apnea may have explained some of the right-sided pressures, although this certainly fit with the left-sided phenomenon that is described.
And the fourth thing would be, what would happen if we switched the patient from a dihydropyridine to a nondihydropyridine and tried to use diltiazem to see what the hemodynamic change would be, starting with a low dose and working upward from there? The hemodynamics, I guess the EF was between 50% and 55%; therefore, you have a little margin for EF suppression. However, the dynamics with diltiazem, for example, might be a little bit different than the dynamics with nifedipine. That being said, echoing Dr Phillips’ comments, if in Richmond, the patient would have been in the operating room yesterday.
Dr Calhoun:Would you have considered adding diltiazem to the dihydropyridine instead of substituting?
Professor Sica: Yes, I think the only problem with diltiazem is when we run the medicine list and we look for CYP3A4 (cytochrome P450 3A4)-metabolized drugs. Diltiazem is a potent CYP3A4 inhibitor; so at a dose of 240 mg of sustained release, your area under the plasma drug concentration-time curve for simvastatin, for example, or simvastatin acid will go up 3-fold. Therefore, you almost have to run the list, understanding that you may upset the apple cart, so to speak, by adding a CYP3A4 inhibitor. I guess the patient was on nifedipine, is that correct?
Dr Siddiqui: No, amlodipine.
Professor Sica: Yes, that is CYP3A4 metabolized. You would ramp up the blood levels of amlodipine, concurrent with having a different calcium channel blocker type by using the diltiazem. However, I think these are all just measures where you are trying to get the right amount of drug, but, unfortunately, until there is surgical intervention, you cannot quite figure out what is going on. In addition, the question is, why do you get a derivative product of hypertension with this kind of cardiac pathology? We presume it is either modest cardiac ischemia or changes in contractility. Therefore, you have very hyperdynamic precordium on physical examination and hyperdynamic set of values. Changing from hyperdynamic to more isodynamic in nature can sometimes help the BP, but by no means are you ever going to correct it in this type of patient without surgery.
Dr Goldman: I really appreciate that you are bringing attention to refractory hypertension. I had a poster at the American Society of Hypertension meeting about 3 or 4 years ago, where we had really reached this extreme level of not knowing how to lower the BP. My patient did not have the aortic valvular disease, but it was noted that every time the patient entered the coronary care unit with hypertensive urgency, the BP seemed to be controllable with parenteral nicardipine. Therefore, we created the novel approach of sending the patient home on an intravenous nicardipine infusion just like patients get home milrinone. In addition, it was successful. The patient ended up ultimately going on dialysis and transferring to another facility. But out of desperation, we really did try intravenous nicardipine infusion.
Dr Selvarajah: Thank you very much for sharing this case. Just 2 points: one is pathophysiology. Can I just ask if you think that the aortic regurgitation here is secondary to aortic dilatation in the context of hypertension? This person has a chronic hypertensive resistant disease. In Cambridge, we see a lot of resistant hypertension, and we see a number of patients with aortic regurgitation. We think this is a secondary phenomenon. We also notice this phenomenon is more common in people of black race. They have more cardiac effects of hypertension. That is my first question.
Second is a bit more practical. In terms of expanding therapy, I know the highest licensed dose of amlodipine is 10 mg. What we do, and may be considered, is switching therapy to nifedipine 60 mg, which is the equivalent dose, and uptitrating it in patients of black race. That seems to be quite effective.
Dr Calhoun: In terms of the second comment, I think I would agree. I think nifedipine, probably at the highest dose, is a superior antihypertensive to amlodipine. However, amlodipine is usually preferred by most US insurance companies in terms of the tier system, whereas nifedipine XL is not. Therefore, our choice was limited.
In terms of the first question, we are not going to know for sure, but the aortic regurgitation is probably related to a combination of the high BP and resultant aortic dilation—a structural abnormality—in the aortic valve.
Acute Hospital Admission
The patient was admitted to University of Alabama at Birmingham Hospital on September 6, 2016, for worsening shortness of breath, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, mild productive cough, and abdominal discomfort on distention, urinary frequency, and acute-on-chronic leg edema. The BP on admission was 224/77 mm Hg and heart rate (HR) was 110 bpm. Brain natriuretic peptide (1899 PG/mL) and the troponin were elevated (0.414 NG/mL).
Open-heart surgery for mitral and aortic valve replacement and coronary artery bypass grafting (CABG) was performed on September 12, 2016.
Mitral Valve Replacement
The preprocedure TTE showed moderate-to-severe mitral regurgitation, anterior mitral valve leaflet prolapse with an eccentric, posteriorly directed regurgitant jet. The mitral valve was replaced with a bioprosthetic valve (29 mm mosaic). Postprocedure TTE showed that the valve was well seated and functioning, with no significant perivalvular leak with a mean pressure gradient of 4 mm Hg and no mitral regurgitation.
Aortic Valve Replacement
The preprocedure TTE showed moderate-to-severe aortic insufficiency with an eccentric jet of regurgitation directed toward the anterior mitral valve leaflet. Postprocedure TTE showed replacement of the aortic valve with a bioprosthetic valve (25 mm). The valve was well seated and functioning with no significant perivalvular leak and a mean pressure gradient of 15 mm Hg with no aortic insufficiency.
Coronary Artery Bypass Grafting
The preprocedural heart catheterization showed stenosis in left main artery, left anterior descending artery, left circumflex artery, right coronary artery, and posterior descending artery. The procedure included CABG utilizing a left internal thoracic artery graft to the left anterior descending artery and saphenous vein graft to the posterior descending artery.
Before surgery, the patient had a mean systolic BP of 167.1 mm Hg and a mean diastolic BP of 68.7 mm Hg. After surgery, the patient’s mean systolic BP was 119.5 mm Hg and mean diastolic BP was 68.5 mm Hg. The mean arterial pressure before surgery was 100.6 mm Hg, and after surgery, the mean arterial pressure was 85.5 mm Hg (Figure 1).
As discussed previously, before surgery, the patient was on 6 antihypertensive medications, including an angiotensin receptor blocker, a calcium channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), mineralocorticoid receptor antagonist (spironolactone), vasodilator (hydralazine), and central-acting sympatholytic (clonidine). After surgery, the patient’s BP was controlled (systolic BP, 120 mm Hg) without any antihypertensive medication. Subsequently, amlodipine (5 mg) and then later spironolactone (25 mg) was added (Figure 1).
Mean HR before surgery was 75.3 bpm and regular, but after surgery, the patient had intermittent atrial fibrillation, which resolved spontaneously. The mean HR post-surgery was 73.5 bpm. There was no significant difference in HR before and after surgery (Figure 2).
The SV was evaluated by TTE before and after surgery. Compared with presurgery, there was massive reduction in SV post-surgery (93–53 mL; Figure 3).
Antihypertensive medication adherence was verbally verified by patient interview at every clinic visit. Pill bottles were checked and pharmacy medication refills were verified. In addition, after surgery, the patient’s BP was initially under control without any antihypertensive medications. Therefore, medication adherence did not play a role in BP reduction postoperatively (Figure 1).
There was no significant change in the patient’s weight or body mass index after the surgery, excluding weight loss as a mechanism for the BP reduction observed in this patient (Figure 4).
The patient’s kidney function was stable both before and after surgery, but he did have perioperative acute kidney injury. The mean serum creatinine was 1.35 mg/dL before surgery. After the surgery, the serum creatinine increased to 2.5 mg/dL and returned to 1.5 mg/dL postoperatively (Figure 5). The large decrease in systolic BP postoperatively, ≈53 mm Hg, likely caused a substantial decrease in kidney perfusion after surgery, contributing to the decrease in kidney function.
There can be a short-term BP reduction after anesthesia because of a prolonged anesthetic effect in combination with pain medications, which are given routinely during and after the surgery. Blood loss, dehydration, allergic reactions, and acute infection also may cause BP reduction after surgery. However, none of these factors was known to have occurred in this patient.
Coronary Artery Bypass Grafting
Hypertension commonly occurs after CABG and requires therapy to prevent potentially injurious effects.1 After CABG, there are multiple reasons why BP increases, including pain, stress, and withdrawal of BP medications, which patient was receiving preoperatively. Typically, the BP progressively increases within 24 hours, postoperatively, and daytime systolic and diastolic BP may remain elevated for ≤14 weeks after CABG. In addition, nocturnal BP dipping returns to normal progressively but incompletely 14 weeks after CABG. In parallel, there is a progressive but also incomplete restoration of sympathovagal balance.2 The BP after CABG generally returns to the preoperative levels in 4 to 6 weeks, at which time antihypertensive medications are often reintroduced.3
Aortic Valve Replacement
BP changes are not predicted by the type or size of the valve inserted. Diastolic hypertension is more prevalent after aortic valve replacement for treatment of aortic regurgitation. Hypertension prevalence decreases from 65% to 57% after aortic valve replacement for aortic insufficiency.4
The patient’s left ventricular function was hyperdynamic before surgery as indicated by TTE findings, which showed an elevated SV (93 mL). After surgery, the SV decreased by half (93–53 mL). This decrease in SV is normally compensated for by an increase in HR. As there was no significant difference in HR before and after surgery, HR would not have influenced the cardiac output or the BP.
Since surgery, the patient has been closely followed up at the University of Alabama at Birmingham. His BP has been controlled with only 2 antihypertensive medications, amlodipine and spironolactone.
Discussion: Case Resolution
Dr Phillips: I know you have great surgery in Alabama, but it is not impossible that he could have a late perivalvular leak, which could explain the decreased BP.
Dr Siddiqui: He did not.
Professor Bursztyn: I would say that the reduction in SV is not all that relevant because before surgery, much of the SV was wasted, so it cannot fully explain the decreased BP. Although it is reminiscent of what in the old days was called decapitation of BP after myocardial infarction and subsequent reduction of SV.
Professor Sica: Not uncommon clinical circumstances. The poorly treated, difficult-to-manage hypertensive on 5-drug therapy who gradually develops systolic heart failure and the BPs normalize. That is what you saw here.
In addition, the prediction would be, as the EF goes up gradually over time, you are going to need amlodipine and 2 or 3 other drugs to come on board, so it is just the hyperdynamic nature of it. However, you have a clinical corollary that no doubt you see in Alabama in the same way. Therefore, when someone comes in all of a sudden well controlled, you get asked the question of, “What happened to their EF?”
This is a case of a patient with refractory hypertension, uncontrolled BP on 6 antihypertensive medications with mitral regurgitation, aortic insufficiency, and coronary artery disease. The patient underwent mitral valve and aortic valve replacement and CABG. After surgery, the patient required no BP medications initially and more recently has required only 2 antihypertensive medications for good BP control. Mechanisms like alteration in medication adherence, weight reduction, change in kidney function, prolonged effects of cardiac anesthesia, and CABG, which are known to decrease BP, after surgery were excluded. Most probably, the underlying mechanism likely contributing to the BP reduction was the reversal of the cardiac hyperdynamic state with reduction in SV after aortic and mitral valve replacement without change in HR, resulting in a favorable reduction in cardiac output and the consequential reduction in BP.
We are grateful to the following session audience members for contributing to the discussion: Robert M. Carey, Jesse Goldman, and Viknesh Selvarajah.
Sources of Funding
The National Institutes of Health (NIH R01 HL113004 and 2T32HL007457-36A1) and the American Heart Association Strategically Focused Research Network (AHA 5SFRN2390002) supported this research.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- © 2018 American Heart Association, Inc.
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